Lifespan Journal Issue 1 by Thierry Hertoghe

LIFESPAN M E D I C I N E

J O U R N A L

The journal for health professionals interested in pro-aging

IGF-1 therapy for adults also in this issue:

by Dr. Thierry Hertoghe

Prof. Aubrey de Grey discusses rejuvenation Dr. Abraham Morgentaler & Prof. Claude Schulman describe testosterone and the prostate Prof. Constantine Dimitrakakis debates Testosterone therapy in women Dr. Walter Pierpaoli talks about TRH and aging plus many more cutting-edge articles from world renowned doctors

2014 Issue

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Preface to the Lifespan Medicine Journal Lifespan medicine is a new, more positive and more scientific name for anti-aging medicine. Lifespan medicine’s aim is to improve the quality of life, health and life expectancy of people. It concerns everyone from babies to centenarians. Medical progress in lifespan medicine constantly accelerates. Every physician working in the field is aware of it. The medical therapies that I now prescribe seem to have far more advanced efficacy, not only compared to what I did twenty years ago, but also compared to the medical therapies I prescribed only three years ago! Even more surprising is that all of this recent progress seems to further improve the already important safety of the therapies used in the past. New treatments or rediscovered old treatments with IGF-1 and vasopressin therapies, capillary-opening molecules, telomerase activators, life-extending peptides from research labs in Russia, stem cell therapies, and nanotechnologies are gliding into our daily lifespan medicine practice, and this progress will not stop. How I practiced twenty years ago looks to me as ancient lifespan therapies far from what is possible today! And the progress keeps accelerating. What will we say ten years from now? Or twenty years? This progress opens up new prospects not only in disease reduction, but also in lifespan extension. It could now be possible for a greater number of people to reach the age of Jeanne Calment, the Guiness Book of Record’s human lifespan world record holder of 122 years, and babies born today may have even a greater life expectancy and experience later on at ages above the 100 years much better health and physical appearance than people now at age 70.

To capture more than a glimpse of some of these advances and of other older but important and not well-known therapies, I am happy to present you with the Journal of Lifespan Medicine, a peer-reviewed journal for health professionals, in particular for physicians and researchers working in the field of lifespan medicine. The Journal is the new name of the previous non peer-reviewed Lifespan Magazine. We have a panel of excellent writers who are authorities in the field of lifespan medicine such as professor Aubrey De Grey (editor of Rejuvenation Magazine), professor Abraham Morgenthaler (Harvard University), professor Schulman (Brussels University), Dr. Ward Dean (pioneer in biological age measurement), Dr Rebecca Gassner and professor Constantine Dimitrakis (research in testosterone treatment in women), Walter Pierpaoli (breakthrough studies on melatonin, now on TRH), professor G.E. Seralini (fundamental studies on the dangers GMO’s), and so many more. Please do not hesitate to provide us with your feedback. Thierry Hertoghe, MD, Chief Editor of the Journal of Lifespan Medicine

The Lifespan Medicine Magazine Editor in Chief: Thierry Hertoghe, M.D. Assistant Editor: Phil Micans, MS, PharmB To join our mailing list, or to send us comments about the magazine and features you would like to see in it, please email us at: info@lifespan-journal.com (please note we will not answer or give medical advice). Disclaimer: All information contained within is educational and is not intended to replace the advice of a physician. Any claims, opinions, statements or references contained within are not necessarily the same as those of the LSMJ and cannot be guaranteed as accurate. All copyrights are acknowledged and whist every effort has been made to ensure accuracy, no responsibility can be accepted for illustrations, photographs, artwork or advertising materials while in transmission or with the publisher or their agents.

Lifespan Medicine Journal 2014 - Page 3

Index: Title:

Author:

IGF-1 therapy in adults

Thierry Hertoghe, M.D., et al

Rejuvenation inside as well as outside

Aubrey D.N.J. de Grey, Ph.D.

Antiaging medicine: Testosterone under attack

Edward M. Lichten, M.D.

New randomized study comparing desiccated thyroid extract with levothyroxine

Henri Knafo, M.D., M.Sc, B.Sc

HDL-C: the good cholesterol: bad for the nervous system?

Sus Herbosch, M.D.

Nitric Oxide and its significance to cardiovascular disease

Jorge D. Flechas M.D., MPH

François-André Allaert, Ph.D.

Dihydroquercetine: What do you do for the health of your capillary vessels?

Vladimir Kozlov, M.D, Ph.D. et al

Kisel-10 study shows 3x stronger hearts and less risk of dying with new treatment

Bjorn Falk Madsen, M.D.

Safe and effective weight loss with the protein diet

Ignacio Sajoux, M.D., Ph.D.

Testosterone therapy in women: Myths and misconceptions

Rebecca Glaser, M.D. and Constantine Dimitrakakis, M.D., Ph.D.

A synthesis on the toxicities of GMO’s and Roundup – Studies from Prof Séralini’s group

Joël Spiroux de Vendômois, M.D. and Gilles-Eric Séralini, Ph.D.

Testosterone and prostate safety

Claude Schulman, M.D., Ph.D. and Abraham Morgentaler, M.D., FACS

Vasopressin: The antiaging, cognitive enhancing neuropeptide

Ward Dean, M.D.

The TRH miracle; an interview with Dr. Walter Pierpaoli

Walter Pierpaoli, M.D.

Lifespan Medicine Journal 2014 - Page 4

Page:

IGF-1 therapy in adults: More potent than growth-hormone treatment to reverse aging? by Thierry Hertoghe, Marie-Christine Lhermitte, Benoît Poutet. Guy Gérin, Charlotte Godefroit, Lucie Wetchoko IGF-1 terminology and structure IGF-1 is the abbreviation for insulin-like growth factor I, a term that refers to the hormone’s similarity in structure and activity to insulin. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges, and it has a molecular weight of 7,649 daltons.1 Insulin too forms a single chain with three intramolecular disulfide bridges, but with a lower number of amino acids, namely 51, making the insulin molecule have a molecular weight of 5808 daltons, 24% lighter.2 IGF-1 exerts a weaker insulin-like activity. On a molar basis, it is only 6% as potent as insulin in producing hypoglycemia3, but because of its considerably higher concentration in blood, IGF-1 remains important for glucose control as we will see later. IGF-1 is also called somatomedin C in reference to its major function in executing a great part of somatotropin’s (growth hormone) action. The human-gene that encodes insulin-like growth factor I is located on chromosome 12.4 Both IGF-1 and insulin are part of a family of hormones and growth factors with 10 members in humans: insulin, IGF-I, IGF-II, and seven peptides related to relaxin.5 IGF-1 production and serum levels The liver is the predominant producer of circulating IGF-1.1 When liver production of IGF-1 is blocked, serum IGF-1 levels drop by 75 to 80%.6-7 IGF-1 is also produced in a paracrine/autocrine fashion for local use by target tissues1 such as the brain (astroglial cells, oligodendrocytes, cerebellar Purkinje cells)8-11, anterior pituitary gland (mainly ACTH-producing cells)12-13, eyes (orbital fibroblasts and all types of retina cells: epithelial cells, pericytes, pigment cells and fibroblasts)14-15, heart tissue (fibroblasts)16, skeletal muscle17-19, breast tissue (alveolar cells, fibroblasts)20-21, ovaries (theca cells, granulosa cells)22-24, uterus (endometrial stromal cells)25, uterine tubes26, testicles (Leydig and Sertoli cells)27-28, lungs (bronchial epithelial cells, fibroblasts)29-30,skin (fibroblasts)31, joints (chondrocytes)32-34, bones (osteoblasts)35, fat tissue (preadipocytes)36, stomach (fibroblasts)37, kidneys (both glomerular and aortic endothelial cells)38, thy-

roid (follicular cells)39, fibrous tissue40, etc. With age, the serum level of IGF-I steadily declines and drops down in older adults to one third or less of the levels of young adults.41-43 IGF-1 levels are highest at the end of puberty then decline during adulthood, reaching about one third of their peak adolescent levels at age 70. Average IGF-I levels in a study of a representative Japanese population reached 310 µg/L in males at the age of 14 years and 349 ng/mL in females at the age of 13 years, falling to 124 ng/mL and 103 ng/mL, respectively, by the age of 70 years.42 This age-related IGF-1 deficiency is even more important for two reasons: First, with age, progressively less IGF-1 penetrates from the blood into target cells. This gradual reduction in bioavailable IGF-1 shows up in laboratory tests as a decline in the ratio of IGF-1 to IGF-BP-3 (see later for more explanation). 43 Second, the target cells themselves become with age less responsive to the IGF-1 that reaches them because of a loss in cellular IGF-1 receptors, a phenomenon that reduces IGF-1 efficacy.44-46 Stimulators of IGF-1 production Hormone supplements: The production of IGF-1 is substantially stimulated by growth hormone (GH). Without growth hormone stimulation the IGF-1 level drops to approximately one third of its initial level in healthy adults, as demonstrated after use of a GH-receptor antagonist that blocks growth hormone activity.41-42,47 On the other hand, when in adults with overt growth-hormone deficiency receive growth-hormone therapy the IGF-1 level increases almost threefold: from a very low level situated at a mean of two standard deviations below the mean to one standard deviation above the mean.48 Insulin too can considerably elevate the production of IGF-1.49-52 In prepubertal and pubertal children with type-1 diabetes for example, insulin therapy increases the low serum level of free IGF-1 by approximately two-and-a-half to three times.53 Injections with long-acting insulin work better: A 20 percent higher IGF-1 level is obtained with

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the long-acting insulin analogue glargine administered to adult men with type-1 diabetes than with similarly dosed intermediate-acting insulin.52 An essential condition for insulin to increase the IGF-1 level is a good control of the blood-glucose level. When the glucose levels is poorly controlled, insulin therapy has no beneficial influence on the serum total IGF-1 in patients with type 2 diabetes. On the contrary, in these patients insulin therapy reduces the bioavailable fraction of IGF-1, worsening their condition.53 Thyroid therapy too usually increases the serum IGF-1 level and the efficacy of IGF-1.54 In a study, thyroxine therapy increased the serum IGF-1 level in patients with primary hypothyroidism approximately threefold (3.1 times more with thyroxine, 2.7 times with triiodothyronine), while it had no effects in cretins! The absence of a serum IGF-1 response in endemic cretins despite an effective thyroid therapy could explain their growth failure.54-55 Moreover, thyroid hormones boost not only the production of IGF-1, but also its anabolic effects: protein synthesis with IGF-1 treatment (associated to IGF-BP-3) is 54% higher in rats with normal thyroid function compared to rats with hypothyroidism. 56

ly stimulates IGF-1 production. Injections of 50 mg testosterone every five days, for example, increased by 33% the serum IGF-1 levels in growth hormone-deficient boys.61 Higher, nearly threefold (+2.76 times more) increases of the IGF-1 level were obtained with testosterone injections in adolescent boys with constitutional delay in growth, while dihydrotestosterone injections decreased the serum IGF-1 level by 16% and the (integrated) growth-hormone concentration by 45%.62 Testosterone stimulates the IGF-1 production by converting into estradiol, a mechanism that is impossible with dihydrotestosterone, as it cannot revert back to testosterone and then to estradiol. Another beneficial effect of testosterone therapy is that it potentiates the effects of growth-hormone therapy on IGF-1 production in testosterone-deficient men. A tripling of IGF-1 levels under combined testosterone/ growth-hormone treatment compared to only a doubling with growth-hormone treatment alone has been reported.63

Another activator of IGF-1 production is DHEA supplementation, which increases the IGF-1 level by 15 to 30% in people with initially low DHEA sulfate and IGF-1 levels.64-65 Glucocorticoids such as prednisoTransdermal, but not oral, estrogen supplementa- lone increase the IGF-1 level in rheumatoid patients tion may dose-dependently increase serum the IGF-1 as well.66 level with 25% (50 Âľg 17-beta-estradiol transdermal Nutritional supplements may also help to increase patch)57 to 85% (17-beta-estradiol gel)58 higher lev- IGF-1 levels. Vitamin A showed increases, for exel than oral estradiol in postmenopausal women.57-60 ample, in vitamin A-deficient rats67 and in premenIn fact, oral estrogens such as the synthetic estrogen opausal women where higher vitamin-A levels are ethinylestradiol in oral birth-control pills reduce associated to higher serum IGF-1, but the differences the serum IGF-1 level by an average 30%, which is in IGF-1 levels between the bottom and top quartiles not without adverse consequences on health (read of vitamin A were reported to be less than 10%.68 Vifurther) and physical appearance (less firm body, tamin D supplementation can also increase serum increased fat mass). The reduction in IGF-1 level is IGF-1 levels, mainly in osteoporotic women: two much less, a mean 12% decline, with pills that contain micrograms per day of calcitriol or 1,25-dihydroxthe more androgenic progestogen levonorgestrel, the yvitamine D, the hormonally active form of vitamin same as in the intrauterine device with progestogen.60 D, increases by 26% the level of IGF-1.69 Vitamin D The decline in serum IGF-1 with oral estrogen is due levels are also significantly and positively associated to estrogen accumulation in the liver after intestinal with IGF-1.70 34 Iron may contribute to an increase in absorption. The resulting estrogen overload of the the IGF-1 level, as increasingly higher serum iron levliver makes the liver produce an excessive amount of els are significantly and positively associated with inhormone-transporting proteins, such as growth-hor- creasingly higher serum IGF-1 in adolescent girls71 35 mone binding protein (GHBP), the protein that trans- and increasingly higher IGF-1/IGFBP-3 ratios in preports growth hormone in the blood. The subsequent menopausal women.68 Zinc is another IGF-1 booster. overabundance of GHBP excessively binds growth Zinc deficiency dramatically reduces the level of IGFhormone in blood and, consequently, withholds many 1, by 83%, in young rats.72 By contrast, higher intakes growth hormone molecules from penetrating into liv- of zinc in the diet, situated in the highest quintile of er cells, which should produce IGF-1. Without suffi- intake (more than 11.6 mg/day intake) have been cient growth hormone, liver cells fail then to produce shown to increase the serum IGF-1 level by a mean adequate amounts of IGF-1. 16% in middle-aged and elderly men in comparison

Testosterone too, but not dihydrotestosterone, strong- to men whose zinc intake is in the lowest quintile Lifespan Medicine Journal 2014 - Page 6

(less than 9.3 mg/day intake).73 Even without overt deficiency, zinc supplementation may help to elevate IGF-1 levels. In children with idiopathic short stature and without zinc deficiency, for example, zinc supplements increase after six weeks the serum IGF-1 level by 50 % approximately (46%: from a mean 67.4 to 98.2 ng/ml), while increasing at the same time the IGF-1/ IGFBP-3 ratio by almost 25% (23% to be precise), reflecting greater amounts of IGF-1 becoming bioavailable for the target cells. Zinc directly stimulates IGF-1 production, without increasing growth hormone, as there seems to be no difference in growth-hormone response to clonidine after zinc supplementation.74 Manganese is another trace element that has been reported to restore IGF-1 levels in manganese-deficient rats.75 Among minerals, potassium may be the most important one for IGF-1 production, as potassium repletion completely normalizes the 46%-lower IGF-1 level in potassium-depleted rats76, as does biotin in biotin-deficient mice.77 A high consumption of fish oil, such as 7.5% of total calorie intake per day in heavily burned patients produces a much quicker recovery of the serum IGF-1 level, which markedly decreases after heavy burns.78 Amino-acid supplementation is less likely to increase IGF-1 levels than the growth-hormone secretion. Arginine, lysine, glycine, glutamine, and niacin, which can all increase growth-hormone secretion, do not seem to be able to increase the serum IGF-1 levels, whatever the dose.79-82 Arginine-aspartate, for example, administered at very high doses of 30 grams a day, which can considerably increases growth hormone secretioneven significantly reduced the IGF-1 level in healthy sedentary men.81 Two amino acids however do appear to help. L-carnitine under its activated form acetyl-L-carnitine at 3 grams per day has been shown to significantly increase the plasma IGF-1 in HIV-infected patients.83 This has been confirmed in animal studies with L-carnitine treatment.84-86 Creatine supplementation at doses between 4 and 17 grams a day raises the intramuscular IGF-I content by 24% more than placebo (17.5 grams per day for seven days and then 4.2 grams for 49 days for a 70 kg individual).87 Diet: Improving the diet may increase the IGF-1 level. Ingesting greater amounts of food and thus calories, increases the IGF-1 level by a meager, but significant, 7% to 8%88, while a drastic reduction of the calorie intake in the presence of intense exercise, which consumes a lot of calories, may sharply reduce IGF1 levels by 50 to 64%, an effect that is attenuated by eating protein-rich food73,89 such as meat, poultry, and milk products. Eating more protein-rich foods results

in approximately 12 % to 25 % higher serum IGF-1 levels when the highest quintile of protein intake is compared with the lowest quintile.73,88-95 Increases are better (around 25%) when higher amounts of minerals are also ingested91 Consumption of milk, poultry, and fish is slightly more efficient than whey protein powder: 9 to 10% increases in IGF-192 compared to a 7 % higher IGF-1 level after one year and 8% after two years of consuming 30â&#x20AC;&#x2030;grams a day of whey protein by elderly women compared to placebo.93 Taking soy protein powder is more efficient than milk protein: a 25% increase in IGF-1 level is observed in postmenopausal women after seven weeks of soy powder containing two milligrams of isoflavones per kilogram body weight per day.94-95 When during three months men over age 65 take 40 grams of soy protein powder daily, the increase in IGF-1 is approximately three times greater than when they take the same number of grams of milk protein. In younger men, under age 65, the difference in IGF-1 rise is even greater: fivefold more with soy protein than with whey protein.96 In postmenopausal women, soy protein intake has a greater impact in increasing the IGF-1 level when no female hormones are taken (an increase of 97% versus 35% for women on hormone replacement therapy or HRT).95 The adverse effect of HRT is possibly not due to the female hormones per se, but to the wrong route of administration. Most women take oral estrogens, which reduce the IGF-1 level, and not transdermal estrogen, which increases IGF-1. Carbohydrate intake shows no association with IGF-1 levels, but higher fat intake, in particular saturated fat, is associated with lower levels of IGFBP-3, which increases the IGF-1â&#x20AC;&#x2122;s bioavailable fraction and thus activity for target cells.88 Interestingly, sprouted grains may also increase IGF-1 levels. A lipid called acylated steryl Î˛-glucoside found in pregerminated brown rice substantially increases the very low IGF-1 levels of diabetic rats: IGF-1 levels were initially 17% of levels of control rats. A diet rich in this lipid from germinated rice increased fourfold the IGF-1 levels of diabetic rats, up to 70% of that of control rats. Similar, but smaller twofold increases occurred in the liver and pancreas of the diabetic rats. In healthy control rats, the same substance only increased the normal IGF-1 levels 2 to 5% higher.97 Inhibitors of IGF-1 production Diet: IGF-1 production and levels can substantially be reduced by malnutrition.98-99 Complete fasting for seven days, for example, reduces serum IGF-1 levels by 65% in young healthy men and women.99 What about eating less or calorie restriction? Unlike in rodents, long-term severe calorie restriction does not appear

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to reduce serum IGF-1 concentration and IGF-1/IGFBP-3 ratio in humans following a study by Fontana and colleagues of Washington University. Their data provide evidence that protein intake, not energy intake, is the key determinant of blood IGF-1 levels in humans. Reducing protein intake by 22% for three weeks in six volunteers practicing calorie restriction resulted in a 22% decrease in serum IGF-1 from 194 to 152 µg/L.100 High alcohol intake, daily or occasionally, may substantially reduce the IGF-1. In one study a mean 64% lower serum IGF-1 level was found in high consumers of alcohol compared to people who do not drink alcohol.101 Alcohol abuse lowers the liver production of IGF-I and increases its production of IGFBP-1.102 This relationship with alcohol was not found in more moderate drinking.103

of in the marker of inflammation C-reactive protein (CRP) had a mean 21% lower IGF-1 level, , highest versus lowest, 9% lower in white men with highest CRP (highest CRP quartile compared to lowest), suggesting that inflammation reduces IGF-1 production or breakdown. 111 Why the effect of inflammation is worse in men with black skin than men with white skin is not explained. IGF-1 transport in serum

Approximately 98% of IGF-1 is transported in human blood bound to one of six insulin-like growth factor binding proteins (IGF-BP). Each one of these IGF-1– transporting proteins is named by a number from 1 to 6: IGF-BP-1 to IGF-BP-6. IGFBP-3, the most abundant protein, accounts for 80% of all IGF-1 binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio, meaning Hormone and hormone receptors: Abnormally low one molecule of IGF-1 binds to one molecule of IGFIGF-1 levels can be due to deficiency or malfunction BP-3.112 of growth-hormone receptors as in patients with growth-hormone insensitivity syndrome due to a lack IGF-1 receptors or malfunction of growth-hormone receptors.104 IGF-1 receptors are found on the surface of target oral estrogens: women taking oral estrogens, in particular birth control pills that contain the non– bio-identical estrogen ethinylestradiol60,105-106, encounter important drops in IGF-1 such as -60% delta IGF-1 in girls106, as mentioned before, but even women taking oral bio-identical estrogens (which have the same structure as the human hormones)57-58,60,105-108 aromatase inhibitors: young men {aged 15–22 years}) taking aromatase inhibitors have been reported to have an 18% decrease in plasma IGF-1 concentrations109, but not women who take the same (IGF-1 significantly increased during anastrozole treatment in postmenopausal patients with advanced breast-cancer).110 inflammation: black men with high serum levels Lifespan Medicine Journal 2014 - Page 8

cells. The IGF’s are known to bind with a higher affinity to the IGF-1 receptor, the “physiological” receptor, and in a weaker way to other receptors such as the insulin receptor, the IGF-2 receptor, the insulin-related receptor, and possibly more receptors. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase. This type of receptor, receptor signals by adding a phosphate molecule on tyrosine molecules.113 IGF-1 actions IGF-1 performs an important part of the actions of growth hormone, and more precisely those involved in growth and tissue and organ development. In children, for example, IGF-1 stimulates cell, organ, and skeletal growth. During pregnancy (prenatally), the level of IGF-1 partially determines the height of the fetus and the newborn baby, while growth hormone doesn’t.114-115 Refer to table 1 below for a comparison of their respective actions. In adults, IGF-1 is important to maintain size, volume, and firmness of the skin, hair, muscles, and skeleton (bones). It stimulates carbohydrate metabolism in both adults and children. IGF-1 to prevent or treat age-related diseases IGF-1 therapy could be used as an adjuvant treatment to traditional therapy in preventing and treating several major age-related diseases. What follows represents some of the evidence.

to prevent or reduce hypertension. Cardiovascular disease: Several observational studies have suggested that IGF-1 may protect against the development of heart disease. The likelihood of finding signs of angina pectoris or previous myocardial infarction on electrocardiogram (ECG), for example, becomes increasingly greater at gradually lower serum IGF-1 levels within the reference range.149 Similarly, the lower the serum IGF-1 levels within the reference range are, the greater the likelihood of ischemic heart disease. In fact, the risk of getting ischemic heart disease doubles in people with a serum IGF-1 level situated in the lower 25% (quartile) of levels of the population in comparison with people who have a higher IGF-1 situated in the upper quartile. Most of these lower levels are still situated within the reference range.191 The risk of dying from ischemic heart disease is 38% higher for every 40 µg/L lower level of IGF-1. 40 µg/L or 5.24 nmol/L of IGF-1 corresponds to one standard deviation from the mean. As in the reference interval of IGF-1 there are four standard deviations (two standard deviations above and two below the mean), a person who has an IGF-1 level situated at the lower limit of the reference range has a 4 x 38% = 152% higher risk of dying from ischemic heart disease than an individual situated at the upper limit, both individuals being within the reference range.192 Furthermore, cardiac patients with low serum levels also are at higher risk of developing heart failure.193 The risk is particularly high when the serum IGF-1 level falls below the 140 µg/L (18.3 nmol/l).194

Overall health: The average serum-free IGF-1 level has been found to a significantly 26 % lower in subjects who find their health to be worse than that of their peers.185 This suggests that increasing the free Stroke: Patients with ischemic stroke and a low level IGF-1 level in the serum might improve health. of IGF-1 and/or of IGF-1 to IGFBP-3 ratio within the Atherosclerosis: Lower serum IGF-1 levels within the reference range may die earlier195 and have other poor (laboratory) reference range are associated with raised outcomes. In contrast, for each 20 µg/L increase in seserum levels of triglycerides186, higher risks of atherrum IGF-1 the risk of poor outcome (mainly death) osclerotic plaques in the carotid arteries186, increased decreases by 30%. IGF-1 treatment may also help thickness of the intima media of the common carotid stroke patients, as suggested by the effect of IGF-1 artery187-189, a sign of premature atherosclerosis, hightherapy on rats with experimental stroke, where IGFer CRP levels, and other disturbed cardiovascular pa1 both reduced the damage from stroke, while accelrameters.186 This indicates that IGF-1 levels towards erating the recovery.196-198 the lower reference limits may be harmful for the blood vessels and to avoid vascular degeneration or Sarcopenia: IGF-1 helps to preserve muscle mass, injury, IGF-1 levels might have to be increased to a a dominant feature of aging. In humans with severe burns or sex-hormone deficiencies, IGF-1 supplelevel above the average level of young adults.186-189 mentation preserves lean mass, thereby maintaining Arterial hypertension: Lower IGF-1 levels within the muscle volume63,142,144,199-202 and this, to our experience, reference range have been reported to be significantly to a greater degree in aging adults than growth horassociated with both higher systolic and higher diasmone or testosterone treatment. However, in muscle tolic blood pressures.190 This suggest that hypertension dystrophy its beneficial effects may be limited as IGFmight be caused by IGF-1 deficiency and that for peo1 therapy improves only the milder forms of dystrople with hypertension or predisposition to hypertenphy.200-201 sion it might be indicated to increase the IGF-1 levels Lifespan Medicine Journal 2014 - Page 9

Obesity: People with serum IGF-1 levels within the of hyperglycemia215-216, insulin resistance and type 2 lower half, third, or quarter of levels of the laboratory diabetes217, pregnancy-induced type-2 diabetes218, and reference range have more risk to be overweight with: raise the risk of higher serum hemoglobulin A1C in 219 a higher body mass and obesity index as reported in type-1 diabetes. By contrast, IGF-1 levels above 152 normal boys at various ages of puberty and young µg/L (19.9 nmol/L), the average level at age 60–65, are adulthood aged 7 to 27 years203, and in adolescent significantly associated with a fifty percent lower risk of hyperglycemia, impaired glucose tolerance or typeboys and girls aged 13 to 18 years204 2 diabetes in normal men and women aged 45–65 a higher visceral fat mass as shown in normal men205 years.217 All these data explain why recombinant IGF-1 a higher number of metabolic-syndrome features treatment reduces glucose and glycosylated hemoglosuch as dyslipidemia, hypertension, and higher body bin in all types of diabetes, as well as it reduces insu122-123 mass index206-207, and increased obesity incidence (in lin levels in insulin resistance and type 2 diabetes and in patients with Laron syndrome122-124, and it deadults);208-209 creases the insulin requirement in type 1 diabetes.220 In rodents, the vascular tissue of obese mice and IGF-1 therapy was shown to prevent the appearance rats has a lower number of IGF-1 receptor levels, of type 1 diabetes.221 suggesting that obesity itself produces an IGF-1 resistance210-211 similar to the obesity-induced insulin Osteoporosis: Lower serum IGF-1 levels are associresistance. The inadequate response to IGF-1 at the ated with lower bone-mineral density in postmenoreceptor level further aggravates the existing IGF-1 pausal women with endogenous subclinical hyperthyroidism222 and with osteoporotic bone fractures in deficiency in overweight subjects. elderly persons.223 IGF-1 therapy itself increases bone However, IGF-1 treatment alone does not reduce fat density as compared to placebo, as shown in osteomass or increase lean mass more than placebo, unporotic patients with proximal femoral fracture and in less growth hormone treatment is added to IGF-1. anorexia nervosa patients.224-225 This is illustrated in a study in obese postmenopausal women who consumed a 500 kcal diet. Women tak- Immune dysfunction: Lower IGF-1 levels are assoing growth-hormone therapy alone lost 3 kg fat more ciated with lower number of the protective natural 226 than the placebo group, while those who took IGF- killer cells in young adults and a lower number of 1 alone as a treatment had no significantly greater immune-stimulating CD4 helper lymphocytes in 227-228 Other weight loss than placebo, and those women who took children and adults affected with HIV. a combination of growth hormone and IGF-1 lost 5.5 immune parameters may be disturbed at low IGF-1 kg fat more than placebo takers. Lean mass increased levels. IGF-1 may modestly reverse these changes as 229 by 3.6 and 2.7 kg in the growth hormone and in the shown in patients with severe burns , head injury 230 231 growth-hormone-plus IGF-I-treated women, respec- (with increases in the CD4/CD8 ratio) and AIDS. tively, whereas IGF-1 and placebo groups showed vir- One study showed no improvement in immunologic tually no change.152 In children with Laron syndrome, response with IGF-1 therapy in AIDS patients but a 145 IGF-1 treatment has been shown to reduce subcuta- positive effect on body composition was seen. Stud232 233 ies in aged monkeys , and in stressed or malnourneous fat.212 ished rats234 confirmed these findings, showing that Diabetes: IGF-1, as its name ‘insulin-like’ growth facIGF-1 restores many immunological parameters, intor I suggests, reduces the blood sugar level in a simcluding a recovery of T-lymphocyte function. ilar fashion as insulin does. At equivalent molar doses, IGF-1’s hypoglycemic effect is approximately 6% Cancer: Several studies have shown that lower serum as potent as insulin3, but as IGF-1’s concentration in IGF-1 levels within the normal reference ranges are the blood is approximately 500 times greater than that associated with a higher risk of cancer, namely of en235 of insulin (fasting serum reference ranges of IGF-1: dometrial cancer in postmenopausal women , cervi236-237 238-239 , prostate cancer , glioma in normal 18 000 to 60 000 pmol/L or 130-450 µg/L compared cal cancer 240 to those of insulin (14-140 pmol/L or 2.0-20.0 µIU/ men aged 50 to 69 years , pancreatic cancer in male 241 242 ml)213-214, but in similar amounts administrated (26 to smokers , and rectal cancer. Nine months before 260 nmol or 0.2 to 2 mg per day of IGF-1 compared diagnosis of liver cancer, IGF-1 levels have been reto the 35 to 350 nmol or 0.19 to 1.90 or 5 to 50 IU per ported to reduce, suggesting that here too lower IGF-1 243 day of insulin), the presence of IGF-1 in the serum levels may facilitate the development of liver cancer. makes a difference in the blood-sugar level. Therefore, These studies imply that raising the IGF-1 levels with not surprisingly, lower IGF-1 levels enhance the risk supplementation could reduce the risk of developing Lifespan Medicine Journal 2014 - Page 10

these cancers.

What is the effect of IGF-1 therapy in subjects with In contrast to these reassuring studies, research in cancer? In mice with cancer, IGF-1 therapy did not and substantially women has shown that women with higher IGF-1 stimulate tumor growth, but quickly 258 reduced the cancer progression. levels seem to be at greater risk of developing breast cancer244-246, and some reports, a minority, have shown Memory impairment and dementia: Lower serum that higher IGF-1 levels may be associated with a high- IGF-1 levels within the reference range are associater risk of colon cancer242, 247 and even prostate cancer248 ed with a higher risk of cognitive decline259, demenin contradiction with most other reports that suggest tia260, and episodes of delirium in elderly men. 261 The that IGF-1 is neutral or—more rarely—protective threshold for mental deterioration appears to be situagainst prostate cancer.249-251 In fact, the high IGF-1 ated at a serum IGF-1 level of 140 µg/L. At or below levels that are found with prospective or retrospective this threshold, which corresponds to the median levstudies in women who develop breast cancer appear el found in Japanese elderly subjects - meaning that to be the expression of an IGF-1 resistance similar half of them are below the mean IGF-1 threshold, to insulin resistance in obese people. Lower levels of scores deteriorate in the basic test to detect cognitive IGF-1 and IGF-1–receptor messenger RNA have been decline, the mini-mental state examination.262 In rats found in malignant breast tissue compared to normal with experimental brain injury, treatment with IGF-1 tissue. The number of IGF-1 receptors is reported to improved cognition, improving neuromotor function be 61% decreased in breast cancer tissue from all ori- and learning ability compared with those receiving gins. In particular, a 72% decrease in messenger RNA vehicle.263 These studies suggest that optimizing the for IGF-1 receptors has been found in sporadic breast level of IGF-1 in humans may help optimize memory cancer, while in familial breast cancer the mean IGF-1 retention and thinking. receptor level was found to be 28% lower. More strik- Hearing loss: Patients with congenital deficiency in ing is the fact that messenger RNA expression of IGF- IGF-1, called Laron syndrome, have impaired hear1 itself (and not of IGF-1 receptors) is even 18 times ing.147 Mice with IGF-1 deficiency264 or IGF-1 receplower in breast-cancer tissue than in normal breast tor deficiency265 also show hearing loss. On the other tissue.252 However, this is not all. Researchers have un- hand, local administration of IGF-1 to the inner ear covered that lower serum IGF-1 levels in breast can- through injection266 or locally applying a gelatin hycer patients are associated with more aggressive breast drogel148,267-270 has shown to reverse hearing loss incancer: the TNM (tumour-node-metastasis) stage, duced by the antibiotic gentamycin in guinea pigs266, indicating the severity of the malignancy, is worse at hearing loss caused by ischemic injury in mice270 224, lower IGF-1 levels within the reference range despite and sudden hearing loss (a condition in which pahigher serum IGF-1 levels in breast cancer patients tients lose the hearing in one ear within three days) compared to controls. So, breast cancer was found that resists to glucocorticoids in humans148 111. What to be less aggressive at higher IGF-1 levels.253 IGF-1 is the mechanism behind the hearing improvement by might thus be protective. Moreover, serum IGF-1 IGF-1? IGF-1 rescues cochlear cells270 224 and makes levels may be a tumor marker for breast and prostate them proliferate.271 cancer, a consequence of cancer and not an etiological factor. Studies have shown that prostate-cancer tis- Mortality: Several studies have shown that high IGFsue as well as breast-cancer tissue can locally produce 1 levels within the reference range may significantly IGF-1.254-256 Higher levels of serum IGF-1 levels may reduce the risk of dying. Each 100 µg/L increase in in fact constitute a marker that something is wrong in serum IGF-1 levels has been reported to decrease 272 a patient, that he or she is developing or may develop mortality by 30% in very old men and women. This cancer. Moreover, in cancer patients who are on pal- is particularly true for patients with diseases such as liative care, higher serum IGF-1 levels provide higher ischemic heart disease (each 40 µg/L increase in IGF1, which corresponds to one standard deviation from survival chances.257 the mean, reduces ischemic heart disease mortality In colon cancer, IGF-1 levels seem not to be associ- by 38%!)192, heart failure193, ischemic stroke195, cirrhoated, except in patients whose IGF-1 levels are in the sis273, renal failure necessitating hemodialysis274, and highest tertile (33.3%) and whose IGFBP-3 (IGF-1’s kidney cancer.275 Thus, having higher IGF-1 levels major plasma-transporting binding globulin) levels might help in living longer and better surviving disare at the same time in the lowest tertile of the normal ease. levels in a population, otherwise there should be no Diagnosis of IGF-1 deficiency in the adult higher colon cancer risk.247 Lifespan Medicine Journal 2014 - Page 11

As for other hormone deficiencies, the diagnosis should be based on medical history, psychic and somatic complaints, signs at physical examination, laboratory tests, and a therapeutic trial.

alone can be at percentile three or slightly below, i.e., at two to three standard deviations of the mean, while children with growth hormone receptor insensitivity and, consequently, severe IGF-1 deficiency, are at 4 to 5 standard deviations below the Medical history: Being older than 30â&#x20AC;&#x201C;35 years, brain an exceptional 116-117 Additionally, the face is smaller and flatter and liver trauma, pituitary gland and liver disease (the mean. in children with Laron syndrome compared to chilpituitary gland produces growth hormone secretion, 119-121 which is the dominant hormone to stimulate the pro- dren with growth-hormone deficiency. duction of IGF-1 by the liver, while the liver produces Similarly to the severe tissue hypotrophy occurring in most of the IGF-1 in the blood) are conditions that children suffering from IGF-1 deficiency, aging adults cause IGF-1 deficiency and should alert the physician. undergo important tissue atrophy when IGF-1 proPsychic and somatic complaints: The psychological duction substantially drops with age due to reduced and physical complaints due to IGF-1 deficiency alone growth-hormone secretion and reduced liver responhave been far less studied in adults than those due to siveness to growth hormone with aging. This may exgrowth hormone deficiency. Some symptoms of IGF- plain part of their physical aging with skin and muscle 1 deficiency in adults can be deduced from the clinical loss. symptoms of Laron syndrome in children, others from The table below contains an overview of the possible symptoms found in adult growth hormone deficiency. physical characteristics of adults with IGF-1 deficienThe following have been reported: cy acquired in adulthood. The signs of IGF-1 deficien-

cy in aging adults seem similar to the physical signs of adult-onset growth-hormone deficiency, but may be During pregnancy, the absence of IGF-1 markedly remore severe: greater tissue atrophy, including greater duces the growth of the embryo and the fetus, while hair and skin thinning, and additional muscle loss. the absence of growth hormone has no influence. The final size and height of a baby at birth is mainly determined by the IGF-1 levels that were present during Laboratory tests for diagnosis of adult IGF-1 defithe pregnancy.114-115 When IGF-1 levels during child- ciency hood are very low, such as in Laron syndrome (named for professor Laron, who first discovered and studied Next to the clinical assessment, which consists of it), the growth and height of the child are far more im- searching for complaints and physical signs suggespaired than in growth-hormone deficiency alone. In tive of IGF-1 deficiency, two tests confirm the diagnochildren with Laron syndrome, the growth-hormone sis: the serum levels of IGF-1 and those of its major receptor does not respond to growth hormone. These plasma-binding and transporting protein, IGF-BP-3 220,294-304 patients are virtually insensitive to growth hormone. (IGF-binding protein 3). Thus, growth hormone cannot in these patients stim- Based on our personal experience we recommend ulate IGF-1 production by the liver. Without treat- that the measurement of IGF-1 is done by radio-imment, the height of a child with growth deficiency munoassay. Measuring IGF-1 by the too frequently Physical signs of IGF-1 deficiency

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used chemiluminescence test, which avoids the use of radioactive material and thus the need for a specialized laboratory with high security guarantees, offers, in our experience, often insufficiently reliable IGF-1â&#x20AC;&#x201C; test results.

glycaemia215-216 and diabetes217-219, osteoporosis222, immune dysfunction225, several types of cancer235-242, cognitive decline259-262, and earlier death192-193, 195, 272275 (read the above paragraph on IGF-1 to prevent or treat age-related diseases). In fact, reference ranges are statistical ranges comprehending 95% of people of the same age in a population, where only 2.5% of the population has an IGF-1 level below the lower reference limit and 2.5% above the upper reference limit. As mentioned before, many researchers have shown that people with higher IGF-1 levels in the upper half or third or fourth of levels within the reference range of younger adults are less likely to develop disease and die an earlier death (see further). This suggests that healthy IGF-1 concentrations for many patients are probably in the upper half, upper third (tertile), or upper fourth (quartile) of the levels of young adults, and not just within reference ranges. If not, they might be deficient and Interpretation of IGF-1 tests need supplementation. The situation is such that even Once physicians receive the results of the serum IGF- slight decreases of IGF-1 levels in the order of 10% 1 and IGF-BP-3 tests of a patient, they should inter- may alter the risk. pret them. It is suggested to do the following294: Thus, not all levels of IGF-1 within the reference range Compare the IGF-1 level to the levels appearing in the are good for health. Table 1 below shows an overview healthier reference range of young 20- to 30-year- of some thresholds, IGF-1 levels within the reference old adults, because most serum IGF-1 levels situ- range where below there is an increased risk of physated within the youthful ranges are associated with ical or mental deterioration and above the threshold health for people of all ages. Avoid comparing them level no increased risk. Table 2 shows studies where to the lower levels of the older age reference catego- the progressive risk reduction with increasingly highry to which the patient generally belongs (older than er levels of IGF-1 have been calculated by the research age 30) as many if not most levels situated within the team. (much) lower IGF-1 ranges of older (above age 40) to Personalize the interpretation. Adults have developed very old (above age 80) people are associated with disand adapted their body and tissues in size and volume ease and earlier death.294, 296, 298 to the level of IGF-1 they had during early adulthood Try to bring the serum IGF-1 levels to a level associat- (age 20 to 25). The body of older adults is most of ed with optimal health. Such optimal level for the pa- the time still as tall and voluminous as it was in early tient is likely to be found at levels situated in the higher adulthood, which means that they still have the same 50%, 33%, 25%, or higher 20% of levels of the IGF-1 amount of tissues that need the same level of IGF-1 as reference range of young 20- to 30-year-old adults, was initially necessary to keep or restore their health. as a great number of scientific epidemiologic studies IGF-1 is possibly the main hormone to develop and show these levels to be associated with the lowest risk enlarge tissues and organs, and thus reverse the of poor reported health185 and of developing diseases age-related tissue atrophy. Whenever people acquire such as atherosclerosis186-189, arterial hypertension190, a low IGF-1 level that is below the average level they cardiovascular disease191-194, stroke195, sarcopenia142, had in their twenties, they may feel complaints and metabolic X syndrome206-207 and obesity203-209, hyper- physical signs typical of an IGF-1 deficiency and sufLifespan Medicine Journal 2014 - Page 13

fer from loss of lean mass (tissue and organ), at least in volume. Therefore, patients need to get back to their personal youthful levels. Tall and thickly muscled persons usually need to get back to the above-average IGF-1 level they had in their twenties, which permitted them to develop a bigger and more muscled body, while smaller and thinner persons may be satisfied by a moderately below-the-average level similar to the one they had as young adults. Interpret the IGF-1 level in function of the level of IGFBP-3. IGFBP-3 is the main protein that binds IGF-1, transports it in the blood and delivers it to peripheral tissues.195,220,294-306 Non-complexed IGF-1 and IGFBP-3 have short half-lives (t1/2) of 10 minutes and 30 to 90 minutes, respectively. Their short half-lives make them less reliable to measure, because frequent fluctuations of their levels may occur, while the IGFBP-3/ IGF-1 complex is cleared with a much slower t1/2 of 12 hours, thus more trustable.295 Excessive amounts of IGFBP-3 in the serum keeps IGF-1 strongly attached and withholds it from penetrating sufficiently into target cells, thus creating an IGF-1 deficiency. This results in a low IGF-1 to IGF-BP-3 ratio, a marker of

low IGF-1 bioavailability. In contrast, a high IGF-1 to IGF-BP-3 ratio suggests the opposite—a high IGF-1 bioavailability and bioactivity, with higher amounts of IGF-1 penetrating into the target cells, as there is little IGF-BP-3 to fix IGF-1 inside the blood vessels and retain it from penetrating target cells. What is the ‘ideal’ IGF-1 /IGFBP-3 ratio in blood? Our experience teaches us that the ‘ideal’ IGF-1 /IGFBP-3 ratio, when both tests are expressed in micrograms per liter, might be approximately 1 to 10, and up to 1 to 14, based on the average serum levels of IGF-1 and IGFBP-3 found in young 20- to 30-year-old adults294,296, i.e. 300 µg/L IGF-1 to 3000 to 4200 µg/L or in moles of IGF-BP-3 for example, a little higher IGF-1 in men, a little lower IGF-1 in women (as men, thanks to their higher levels of testosterone, which stimulates growth hormone and IGF-1 secretion, usually have a 20% higher IGF-1 level than women). In moles, the ‘ideal’ IGF-1 /IGFBP-3 ratio is 1 to 3 up to 1 to 4 (conversion factors: 1 μg/L = 0. 131 nmol/L; 1 μg/L IGFBP-3 = 0.036 nmol/L IGFBP-3). The IGF-1 /IGF-BP-3 ratio declines with age, increasing the risk of disease and mortality as we have see above.195,303-304 Below is a table that represents

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IGF-1, IGFBP-3, and their ratio with age following Kucera and colleagues.296

of half-life of IGF-1 or 12 hours of the complex IGF-1 bound to IGF-BP-3.295,317-318 This leads to an increased concentration of free IGF-1 LR3 in plasma, which has been reported to result in greater insulin-like growth factor I effects on the IGF type 1 receptors in than the endogenous IGF-1.

Producers claim that it is three times more potent on a milligram basis than IGF-1.315-316 Anecdotally, personal use of this product and reports of volunteers taking it provide the impression of a 10 times greater potency: 1 mg of R3 being equivalent to 10 mg of IGF-1. FDA approval is pending for it to officially beIGF-1 therapy in adults come recommendable as a treatment. Only animal IGF-1 must be subcutaneously injected. Efficient dos- studies on LR3’s action are found in a pubmed search: es for aging adults are between the 0.1 and 1 mg per cell cultures319-320, mice321, rats322-325, calves317,326-327, and day (0.01 to 0.1 ml of the 40 ml solution actually on pigs318, 328-329. the market called mecasermin, which has exactly the same structure as the human IGF-1).307-311 This dose is Side effects of IGF-1 therapy about 5 to 20 times lower than the doses administered The most frequent, side effect of IGF-1 treatment is to children and adults with Laron syndrome.310-311 hypoglycemia330-335, but in adults it is rare with the use IGF-1 therapy and combined IGF-1 with IGFBP-3 of small physiological doses. Hypoglycemia is easily avoided by injecting the IGF-1 before meals or in comtherapy bination with growth hormone, as growth hormone A solution is on the market that combines both IGF-1 with its hyperglycemic effect counters the hypoglycewith IGF-BP-3 in the same preparation and may pro- mic effect of IGF-1. Patients with a tendency toward vide greater and longer-acting effects with fewer side hypoglycemia, such as cortisol-deficient patients, effects. It is designed for people with disease whose should start the IGF-1 injection on the lower doses IGF-BP-3 level is too low.312-314 The binding of IGF-1 such as 0.1 mg/day and inject it before meals. Othto IGFBP-3 is then weaker, permitting IGF-1 to too er possible side effects with IGF-1 therapy are similar quickly penetrate the first target cells of an organ, to those for growth hormone treatment, and usually which then get most of the IGF-1, leaving much less consist of overdose effects. Among the most imporIGF-1 for the remaining target cells that are further tant is fluid retention with feet edema, carpal tunnel away in the bloodstream. When blood levels of IGF- syndrome, and swelling of nose and eyelids. Stiffness BP-3 are low, only nearby tissues and parts of organs caused by the excessive swelling of tissues, especially get most of the IGF-1 and not tissues or organ parts in the spine and limb muscles, is a phenomenon that further down in the bloodstream. In practice, this occurs more often with IGF-1 treatment than with association did not prove to be clearly more efficient growth-hormone therapy and requires to reduce the than IGF-1 alone. Thus, Low serum levels of IGFBP-3 dose of IGF-1 by at least 30 to 50%.336-337 do not permit adequate transportation of IGF-1 in the Risks of IGF-1 therapy blood to all the target cells. As mentioned before, there is no real evidence indiLong-acting IGF-1 cating that IGF-1 therapy at low physiological doses R3 or LR3 or Long-acting IGF-1 is an 83 amino acid would promote the risk of cancer. A not negligible analog of IGF-1 comprising the complete human IGF- number of studies have shown a positive association 1 sequence with the substitution of the amino acid between higher serum IGF-1 levels and increased arginine (R) for the glutamine (E) at position three, risk of breast cancer, but the evidence is inconsisthence the name R3, and a 13-amino-acid extension ent.244-246,338 In a survey of 17 prospective studies peptide at the N terminus.315-316 LR3 has an enhanced (14218 participants) the increase in risk was a modest potency compared to IGF-1 due to the decreased 28%. A higher risk was found especially for the more binding of Long R3 IGF1 to all known IGF-1–bind- differentiated and less aggressive estrogen-receping proteins. These binding proteins normally inhibit tor-positive breast cancer.339 Compare these figures the biological actions of IGF’s. The half-life of R3 is to the + 362% higher risk found in women who eat around 20–30 hours, much longer than the 10 minutes very well-done (cooked) meat three or more times per Lifespan Medicine Journal 2014 - Page 15

week in comparison with women who eat rare or me- may help cancer patients, especially with cancer-indium-done meat.340 duced cachexia, to slow down the progression of can258 other lean tissues, A Japanese cohort study did not find any relation- cer and build up muscle, skin and344-345 and thereby prolonging survival. More studies ship.341 As the Japanese are low consumers of meat and meat intake increases IGF-1 levels, it might be are necessary before editing guidelines for cancer pathat the higher risk in Europeans and Americans, tients. In the meantime, each patient should be exwho are high meat consumers, is not due to the IGF-1 amined separately to see if he or she is a candidate levels per se, but to the larger consumption of meat for IGF-1 therapy and, once on treatment, thorough cooked at high temperatures where carcinogens such follow-up with tests and a physical examination. Furthermore, as IGF-1 therapy increases cortisol producas polycyclic aromatic hydrocarbons are produced. tion, it is not contraindicated and can be safely used Some evidence points to the possibility that colon for patients with borderline low cortisol levels.346-347 cancer might be favored by increased IGF-1 levels, such as in acromegaly or, as mentioned before, in in- Treatments associating IGF-1 to growth hormone dividuals without acromegaly but with IGF-1 levels in may work better the upper tertile (33%) of levels, and with a concentra- In most people, IGF-1 levels start to decline at age 30, tion of IGF-BP-3, its transporting binding protein, in requiring small doses of growth hormone to stimuthe lowest tertile of values.247 However, IGF-1 therapy late the IGF-1 production and correct the deficiency. itself does not reduce, but increases the serum IGF- However, sooner or later, between ages 30 and 55, BP-3 level, which should be considered as reassur- growth-hormone supplementation does not suffice ing. Jacobs and colleagues showed that higher plasma in our experience, and additional IGF-1 supplemenIGF-1 levels were significantly positively associated tation may be necessary to maintain optimal IGF-1 in the colon with the presence of adenomas, while levels. Several human145,152,348-349 and rat350-352 studies in contrast, lower IGF-1 levels were associated with have shown that associating IGF-1 to a growth-hora higher risk of colorectal adenoma recurrence, -45% mone treatment provided better results than either and -51% for the second and third tertiles of IGF-1, treatment alone. To improve patient compliance, both respectively, compared with the first tertile. The in- growth hormone and IGf-1 can be put in the same inverse association was stronger for advanced adeno- jection vial or cartridge, carefully adjusting the right ma recurrence than for non-advanced recurrence (P proportions of both. (trend) = 0.10)342, meaning that patients who have had Conclusion colon cancer (but had it removed) may need higher IGF-1 levels to avoid recurrence, and thus possibly Many studies have shown that having a serum total and bioavailable (calculated on the ratio of IGF-1 on IGF-1 supplementation. IGF-BP-3) IGF-1 level in the lower half, third, or fourth It is noteworthy to mention that patients with overt of the reference range is unhealthy, as it is linked to a growth-hormone deficiency and thus IGF-1 deficien- higher risk of disease and of dying. These investigacy have been reported to have a four- to fivefold high- tions suggest that middle-aged and elderly individuals er risk of colon and rectum cancer341, implying that and sick people, whose IGF-1 levels decline, may need for cancer an IGF-1 deficiency might be more danger- IGF-1 therapy to correct their progressively declining ous than IGF-1 excess. Moreover, patients with overt IGF-1 level and preserve or restore health and delay or growth-hormone deficiency and thus low IGF-1 levels reduce a variety of age-related diseases, just as it may have, following the study of Bengtsson and colleagues, be necessary to correct sex-hormone deficiencies in approximately two times more risk of developing can- (pre)menopause or (pre)andropause individuals. Excer and four times a higher risk of dying from cancer. perience with IGF-1 therapy demonstrates that IGF-1 This risk decreases by about 50% when these patients also improves physical appearance: thickening of hair, take growth-hormone treatment, which increases the skin, and muscles; firming of the body; and partial reIGF-1 levels.343 versing of physical aging. IGF-1 appears to be a potent Contraindications for IGF-1 therapy hormone to reduce and possibly reverse internal as 353-354 Caution should be applied with cancer patients, al- well as external senescence. though there is no solid evidence to prove that IGF-1 may be detrimental to these patients. On the contrary, animal experiences have shown that the potent anabolic and lifespan-extending effects of IGF-1 therapy

In adults, IGF-1 therapy exerts beneficial effects that seem to be equally or more potent than those of growth-hormone therapy. In particular, after age 50 growth-hormone treatment alone does not seem to

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be sufficient to keep the IGF-1 levels high enough in laboratory tests, indicating a need for IGF-1 supplementation coupled with growth-hormone therapy after the age of 50. In order to ensure safety, the use of low doses of 0.1–0.3 mg to a maximum of 1 mg per day should be recommended. These doses appear safe while still offering positive efficacy. IGF-1 therapy in adults: References: IGF-1 terminology and structure http://en.wikipedia.org/wiki/Insulin-like_growth_factor_1 https://en.wikipedia.org/wiki/Insulin Guler HP, Zapf J, Froesch ER. Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med. 1987 Jul 16;317(3):137-40. Lips CJ, Sussenbach JS (1985). Höppener JW, de Pagter-Holthuizen P, Geurts van Kessel AH, Jansen M, Kittur SD, Antonarakis SE, Lips CJ, Sussenbach JS.human gene encoding insulin-like growth factor I is located on chromosome 12”. Hum. Genet. 69 (2): 157–60 Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Bathgate RA, Sherwood OD, Hsueh AJ. Relaxin signaling in reproductive tissues. Mol Cell Endocrinol. 2003 Apr 28;202(1-2):165-70. IGF-1 production and serum levels Ohlsson C, Jansson JO, Isaksson O. Effects of growth hormone and insulin-like growth factor-I on body growth and adult bone metabolism. Curr Opin Rheumatol. 2000 Jul;12(4):346-8. Ohlsson C, Sjögren K, Jansson JO, Isaksson OG. The relative importance of endocrine versus autocrine/paracrine insulin-like growth factor-I in the regulation of body growth. Pediatr Nephrol. 2000 Jul;14(7):541-3. Kitiyanant N, Kitiyanant Y, Svendsen CN, Thangnipon W. BDNF-, IGF-1- and GDNF-secreting human neural progenitor cells rescue amyloid β-induced toxicity in cultured rat septal neurons. Neurochem Res. 2012 Jan;37(1):143-52 Ebert AD, Beres AJ, Barber AE, Svendsen CN. Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson’s disease. Exp Neurol. 2008 Jan;209(1):213-23. Wilkins A, Chandran S, Compston A. A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons. Glia. 2001 Oct;36(1):48-57. Croci L, Barili V, Chia D, Massimino L, van Vugt R, Masserdotti G, Longhi R, Rotwein P, Consalez GG. Local insulin-like growth factor I expression is essential for Purkinje neuron survival at birth. Cell Death Differ. 2011 Jan;18(1):48-59. Jevdjovic T, Bernays RL, Eppler E. Insulin-like growth factor-I mRNA and peptide in the human anterior pituitary. J Neuroendocrinol. 2007 May;19(5):335-41.

tients with thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol. 2012 Mar;250(3):433-40. Moriarty P, Boulton M, Dickson A, McLeod D. Production of IGF-I and IGF binding proteins by retinal cells in vitro. Br J Ophthalmol. 1994 Aug;78(8):638-42. Horio T, Maki T, Kishimoto I, Tokudome T, Okumura H, Yoshihara F, Suga S, Takeo S, Kawano Y, Kangawa K. Production and autocrine/paracrine effects of endogenous insulin-like growth factor-1 in rat cardiac fibroblasts. Regul Pept. 2005 Jan 15;124(1-3):65-72. Adams GR. Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal muscle. Clin Orthop Relat Res. 2002 Oct;(403 Suppl):S188-96. Adams GR. Role of insulin-like growth factor-I in the regulation of skeletal muscle adaptation to increased loading. Exerc Sport Sci Rev. 1998;26:31-60. McKoy G, Ashley W, Mander J, Yang SY, Williams N, Russell B, Goldspink G. Expression of insulin growth factor-1 splice variants and structural genes in rabbit skeletal muscle induced by stretch and stimulation. J Physiol. 1999 Apr 15;516 ( Pt 2):583-92. Paye JM, Akers RM, Huckle WR, Forsten-Williams K. Autocrine production of insulin-like growth factor-I (IGF-I) affects paracellular transport across epithelial cells in vitro. Cell Commun Adhes. 2007 Mar-Jun;14(2-3):85-98. Yee D, Rosen N, Favoni RE, Cullen KJ. The insulin-like growth factors, their receptors, and their binding proteins in human breast cancer. Cancer Treat Res.1991;53:93-106. Vasiljević M, Prorocić M, Dragojević S, Tasić L, Ganović R, Stanimirović B. [The role of insulin-like growth-factor binding proteins in normal and polycystic ovaries]. Srp Arh Celok Lek. 1998 Nov-Dec;126(11-12):488-94. Sirotkin AV, Schaeffer HJ, Mlyncek M, Missik J, Bulla J. Oxytocin affects the release of steroids, insulin-like growth factor-I, prostaglandin F2alpha and cyclic nucleotides by human granulosa cells in vitro. Hum Reprod. 1996 Jan;11(1):152-5. Davoren JB, Hsueh AJ. Growth hormone increases ovarian levels of immunoreactive somatomedin C/insulin-like growth factor I in vivo. Endocrinology. 1986 Feb;118(2):888-90. Kuşcu NK, Koyuncu FM, Inan S, Tuglu I, Uyar Y, Ozbilgin K. The effect of tibolone on endometrial IGF-1 and IGFBP-1 levels in ovariectomized rats. Maturitas. 2002 Jul 25;42(3):247-52. Carlsson B, Hillensjö T, Nilsson A, Törnell J, Billig H. Expression of insulin-like growth factor-I (IGF-I) in the rat fallopian tube: possible autocrine and paracrine action of fallopian tube-derived IGF-I on the fallopian tube and on the preimplantation embryo. Endocrinology. 1993 Nov;133(5):2031-9. 27. Le Roy C, Lejeune H, Chuzel F, Saez JM, Langlois D. Autocrine regulation of Leydig cell differentiated functions by insulin-like growth factor I and transforming growth factor beta. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):379-84.

Eppler E, Jevdjovic T, Maake C, Reinecke M. Insulin-like growth factor I (IGF-I) and its receptor (IGF-1R) in the rat anterior pituitary. Eur J Neurosci. 2007 Jan;25(1):191-200.

28. Naville D, Chatelain PG, Avallet O, Saez JM. Control of production of insulin-like growth factor I by pig Leydig and Sertoli cells cultured alone or together. Cell-cell interactions. Mol Cell Endocrinol. 1990 May 7;70(3):217-24.

Song D, Wang R, Zhong Y, Li W, Li H, Dong F. Locally produced insulin-like growth factor-1 by orbital fibroblasts as implicative pathogenic factor rather than systemically circulated IGF-1 for pa-

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sulin-like growth factor (IGF)-system mRNA quantities in normal and tumor breast tissue of women with sporadic and familial breast cancer risk. Breast Cancer Res Treat. 2004 Apr;84(3):225-33. Agurs-Collins T, Adams-Campbell LL, Kim KS, Cullen KJ.Ins ulinlike growth factor-1 and breast cancer risk in postmenopausal African-American women. Cancer Detect Prev. 2000;24(3):199-206. Cohen P, Clemmons DR, Rosenfeld RG. Does the GH-IGF axis play a role in cancer pathogenesis? GH & IGF Research 2000; 10: 297-305 DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltrán L, Moats S, Ramirez A, Jorcano J, Conti C. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3455-60. Kaplan PJ, Mohan S, Cohen P, Foster BA, Greenberg NM. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res. 1999 May 1;59(9):2203-9. Fouladiun M, Korner U, Bosaeus I, Daneryd P, Hyltander A, Lundholm KG. Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care--correlations with food intake, metabolism, exercise capacity, and hormones. Cancer. 2005 May 15;103(10):2189-98. Dong YL, Fleming RY, Huang KF, Herndon DN, Yan TZ, Waymack JP. Effect of insulin-like growth factor 1 on host response to tumor. J Surg Oncol. 1993 Jun;53(2):121-7 Memory impairment and dementia Kalmijn S, Janssen JA, Pols HA, Lamberts SW, Breteler MM. A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab. 2000 Dec;85(12):4551-5. AA, Drinka PJ, Mattson DE, Rudman D. Low circulating levels of insulin-like growth factors and testosterone in chronically institutionalized elderly men. J Am Geriatr Soc. 1993 Sep;41(9):975-82 Wilson K, Broadhurst C, Diver M, Jackson M, Mottram P. Plasma insulin growth factor-1 and incident delirium in older people. Int J Geriatr Psychiatry. 2005 Feb;20(2):154-9. Higher risk of cognitive decline Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, Idei T, Iguchi T. Relationship between serum insulin-like growth factor-1 levels and Alzheimer’s disease and vascular dementia. J Am Geriatr Soc. 2005 Oct;53(10):1748-53. Saatman KE, Contreras PC, Smith DH, Raghupathi R, McDermott KL, Fernandez SC, Sanderson KL, Voddi M, McIntosh TK. Insulin-like growth factor-1 (IGF-1) improves both neurological motor and cognitive outcome following experimental brain injury. Exp Neurol. 1997 Oct;147(2):418-27. – Hearing loss Camarero G, Avendano C, Fernandez-Moreno C, Villar A, Contreras J, de Pablo F, Pichel JG, Varela-Nieto I. Delayed inner ear maturation and neuronal loss in postnatal Igf-1-deficient mice. J Neurosci. 2001 Oct 1;21(19):7630-41. Murillo-Cuesta S, Camarero G, González-Rodríguez A, De La Rosa LR, Burks DJ, Avendaño C, Valverde AM, Varela-Nieto I. Insulin receptor substrate 2 (IRS2)-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function. Mol Med. 2012 Mar

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30;18:260-9. Li YH, Chen H, Guo MH. Therapeutic effect of insulin-like growth factor-1 injection into the inner ears through scala tympani fenestration on gentamicin-induced hearing loss in guinea pigs. Nan Fang Yi Ke Da Xue Xue Bao. Young S, Wong M, Tabata Y, Mikos AG: Gelatin as a delivery vehicle for the controlled release of bioactive molecules. J Control Release 2005, 109:256-274. Iwai K, Nakagawa T, Endo T, Matsuoka Y, Kita T, Kim TS, Tabata Y, Ito J. Cochlear protection by local insulin-like growth factor-1 application using biodegradable hydrogel. Laryngoscope. 2006 Apr;116(4):529-33. Lee KY, Nakagawa T, Okano T, Hori R, Ono K, Tabata Y, Lee SH, Ito J. Novel therapy for hearing loss: delivery of insulin-like growth factor 1 to the cochlea using gelatin hydrogel. Otol Neurotol. 2007 Oct;28(7):976-81. 270 224. 317. Fujiwara T, Hato N, Nakagawa T, Tabata Y, Yoshida T, Komobuchi H, Takeda S, Hyodo J, Hakuba N, Gyo K. Insulin-like growth factor 1 treatment via hydrogels rescues cochlear hair cells from ischemic injury. Neuroreport. 2008 Oct 29;19(16):1585-8. Oesterle EC, Tsue TT, Rubel EW. Induction of cell proliferation in avian inner ear sensory epithelia by insulin-like growth factor-I and insulin. J Comp Neurol. 1997 Apr 7;380(2):262-74. Mortality Roubenoff R, Parise H, Payette HA, Abad LW, D’Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. Am J Med. 2003 Oct 15;115(6):429-35. Caregaro L, Alberino F, Amodio P, Merkel C, Angeli P, Plebani M, Bolognesi M, Gatta A. Nutritional and prognostic significance of insulin-like growth factor 1 in patients with liver cirrhosis. Nutrition. 1997 Mar;13(3):185-90. Fernández-Reyes MJ, Alvarez-Ude F, Sánchez R, Mon C, Iglesias P, Díez JJ, Vázquez A. Inflammation and malnutrition as predictors of mortality in patients on hemodialysis. J Nephrol. 2002 Mar-Apr;15(2):136-43. Rasmuson T, Grankvist K, Jacobsen J, Olsson T, Ljungberg B. Serum insulin-like growth factor-1 is an independent predictor of prognosis in patients with renal cell carcinoma. Acta Oncol. 2004;43(8):744-8.

Aleman A, de Vries WR, Koppeschaar HP, Osman-Dualeh M, Verhaar HJ, Samson MM, Bol E, de Haan EH. Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res. 2001 Jul-Sep;27(3):283-91 Toledo-Corral CM, Roberts CK, Shaibi GQ, Lane CJ, Higgins PB, Davis JN, Weigensberg MJ, Goran MI. Insulin-like growth factor-I is inversely related to adiposity in overweight Latino children. J Pediatr Endocrinol Metab. 2008 Sep;21(9):855-64 Henderson KD, Goran MI, Kolonel LN, Henderson BE, Le Marchand L. Ethnic disparity in the relationship between obesity and plasma insulin-like growth factors: the multiethnic cohort. Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2298-302 Mårin P, Kvist H, Lindstedt G, Sjöström L, Björntorp P. Low concentrations of insulin-like growth factor-I in abdominal obesity. Int J Obes Relat Metab Disord. 1993 Feb;17(2):83-9 Gómez JM. Serum leptin, insulin-like growth factor-I components and sex-hormone binding globulin. Relationship with sex, age and body composition in healthy population. Brat O, Ziv I, Klinger B, Avraham M, Laron Z. Muscle force and endurance in untreated and human growth hormone or insulin-like growth factor-I-treated patients with growth hormone deficiency or Laron syndrome. Horm Res. 1997;47(2):45-8. Hayes VY, Urban RJ, Jiang J, Marcell TJ, Helgeson K, Mauras N. Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects. J Clin Endocrinol Metab. 2001 May;86(5):2211-9 Physical signs of IGF-1 deficiency 148. Burren CP, Woods KA, Rose SJ, Tauber M, Price DA, Heinrich U, Gilli G, Razzaghy-Azar M, Al-Ashwal A, Crock PA, Rochiccioli P, Yordam N, Ranke MB, Chatelain PG, Preece MA, Rosenfeld RG, Savage MO. Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome Horm Res. 2001;55(3):125-30. Puche JE, Castilla-Cortázar I. Human conditions of insulin-like growth factor-I (IGF-I) deficiency. J Transl Med. 2012 Nov 14;10:224. Hertoghe T. Atlas of endocrinology for hormone therapy, Ed Int Med Books; ed. 2011, p. 13-42, ISBN 978-2-9599713-6-5

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Diagnosis of IGF-1 deficiency in the adult

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Shechter M, Ginsberg S, Scheinowitz M, Feinberg MS, Laron Z. Obese adults with primary growth hormone resistance (Laron Syndrome) have normal endothelial function. Growth Horm IGF Res. 2007 Apr;17(2):165-70.

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Laboratory tests for diagnosis of adult IGF-1 deficiency

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Hertoghe T, Hormone Handbook, 2nd ed., ed Int Med Books; p.:17”, ISBN 978-2-9599713-5-8 Mayo Cilinic. Interpretive Handbook http://www.mayomedicallaboratories.com/interpretive-guide/?alpha=I&unit_code=83300 Kučera R., Vrzalová J., Fuchsová R., Topolčan O., Tichopád A. Normal values of IGF1 and IGFBP3 at http://www.imunokurzy. cz/prilohy/iad12/PO/O%20V/Kucera_Normal%20values%20 of%20IGF1%20and%20IGFBP3%20final.pdf Elmlinger MW, Kühnel W, Weber MM, Ranke MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med. 2004;42(6):654-64. Clark RG. Recombinant human insulin-like growth factor I (IGF-I): risks and benefits of normalizing blood IGF-I concentrations. Horm Res. 2004;62 Suppl 1:93-100. Shinobe M, Sanaka T, Nihei H, Sugino N. IGF-I/IGFBP-1 as an index for discrimination between responder and nonresponder to recombinant human growth hormone in malnourished uremic patients on hemodialysis. Nephron. 1997;77(1):29-36. Sierra-Johnson J, Romero-Corral A, Somers VK, Lopez-Jimenez F, Mälarstig A, Brismar K, Hamsten A, Fisher RM, Hellénius ML. IGF-I/IGFBP-3 ratio: a mechanistic insight into the metabolic syndrome. Clin Sci (Lond). 2009 Mar;116(6):507-12. Alberti C, Chevenne D, Mercat I, Josserand E, Armoogum-Boizeau P, Sıklar Z, Öcal G, Berberoğlu M, Bilir P. Combined evaluation of IGF-1 and IGFBP-3 as an index of efficacy and safety in growth hormone treated patients. J Clin Res Pediatr Endocrinol. 2009;1(5):240-3 Tichet J, Léger J. Serum concentrations of insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio, and markers of bone turnover: reference values for French children and adolescents and z-score comparability with other references. Clin Chem. 2011 Oct;57(10):1424-35. Smyczynska J, Hilczer M, Stawerska R, Lewinski A. Significant increase of IGF-I concentration and of IGF-I/IGFBP-3 molar ratio in generation test predicts the good response to growth hormone (GH) therapy in children with short stature and normal results of GH stimulating tests. Neuro Endocrinol Lett. 2013;34(3):222-8 Granada ML, Murillo J, Lucas A, et al: Diagnostic efficiency of serum IGF-1, IGF-binding protein-3 (IGFBP-3), IGF/IGFBP-3 molar ratio and urinary GH measurements in the diagnosis of adult GH deficiency: importance of an appropriate reference population. Eur J Endocrinol 2000;142:243-253 Lam CS, Chen MH, Lacey SM, Yang Q, Sullivan LM, Xanthakis V, Safa R, Smith HM, Peng X, Sawyer DB, Vasan RS. Circulating insulin-like growth factor-1 and its binding protein-3: metabolic and genetic correlates in the community. Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1479-84. Maggio M, Cattabiani C, Lauretani F, Bandinelli S, De Vita F, Dall’aglio E, Corsonello A, Lattanzio F, Paolisso G, Ferrucci L, Ceda GP. Insulin-Like Growth Factor-1 Bioactivity Plays a Prosurvival Role in Older Participants. J Gerontol A Biol Sci Med Sci.

IGF-I therapy in adults IGF-1 medications: mecasermin

Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rh IGF-I/ rhIGFBP-3. Drugs R D. 2005;6(2):120-7 Fintini D, Brufani C, Cappa M. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag. 2009 Jun;5(3):553-9 Laron Z, Klinger B, Silbergeld A. Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome). J Pediatr Endocrinol Metab. 1999 Mar-Apr;12(2):145-52. Fintini D, Brufani C, Cappa M. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag. 2009 Jun;5(3):553-9 IGF-1 therapy and combined IGF-1 with IGFBP-3 therapy Kemp SF, Fowlkes JL, Thrailkill KM. Efficacy and safety of mecasermin rinfabate. Expert Opin Biol Ther. 2006 May;6(5):533-8 Kemp SF. Mecasermin rinfabate. Drugs Today (Barc). 2007 Mar;43(3):149-55. Williams RM, McDonald A, O’Savage M, Dunger DB. Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX. Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):311-24 Long-acting IGF-1 http://www.revitropin.com/resources.htm http://www.abcam.com/R3-IGF1-protein-ab58738.html Hammon H, Blum JW. Endocrine and metabolic changes in neonatal calves in response to growth hormone and long-R3-insulin-like growth factor-I administration. Biol Neonate. 1998;73(2):121-8 Walton PE, Dunshea FR, Ballard FJ. In vivo actions of IGF analogues with poor affinities for IGFBPs: metabolic and growth effects in pigs of different ages and GH responsiveness. Prog Growth Factor Res. 1995;6(2-4):385-95. Pampusch MS, Xi G, Kamanga-Sollo E, Loseth KJ, Hathaway MR, Dayton WR, White ME. Production of recombinant porcine IGF-binding protein-5 and its effect on proliferation of porcine embryonic myoblast cultures in the presence and absence of IGF-I and Long-R3-IGF-I. J Endocrinol. 2005 Apr;185(1):197-206 Xi G, Kamanga-Sollo E, Pampusch MS, White ME, Hathaway MR, Dayton WR. Effect of recombinant porcine IGFBP-3 on IGF-I and long-R3-IGF-I-stimulated proliferation and differentiation of L6 myogenic cells. J Cell Physiol. 2004 Sep;200(3):387-94. Hadsell DL, Parlow AF, Torres D, George J, Olea W. Enhancement of maternal lactation performance during prolonged lactation in the mouse by mouse GH and long-R3-IGF-I is linked to changes in mammary signaling and gene expression. J Endocrinol. 2008 Jul;198(1):61-70. Bastian SE, Walton PE, Wallace JC, Ballard FJ. Plasma clearance and tissue distribution of labelled insulin-like growth factor-I

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(IGF-I) and an analogue LR3IGF-I in pregnant rats. IGF-I antibody may be behaving in a similar manner to a high molecular weight IGFBP and is effective in potentiating IGF-I action in vivo. J Endocrinol. 1993 Aug;138(2):327-36. Garnaut SM, Howarth GS, Read LC. Effects of insulin-like growth factor-I and its analogue, long-R3-IGF-I, on intestinal absorption of 3-O-methyl-D-glucose are less pronounced than gut mucosal growth responses. Growth Factors. 2002 Mar;20(1):17-25 Steeb CB, Shoubridge CA, Tivey DR, Read LC. Systemic infusion of IGF-I or LR(3)IGF-I stimulates visceral organ growth and proliferation of gut tissues in suckling rats. Am J Physiol. 1997 Mar;272(3 Pt 1):G522-33. Steeb CB, Trahair JF, Read LC. Administration of insulin-like growth factor-I (IGF-I) peptides for three days stimulates proliferation of the small intestinal epithelium in rats. Gut. 1995 Nov;37(5):630-8. Hammon H, Blum JW. The somatotropic axis in neonatal calves can be modulated by nutrition, growth hormone, and Long-R3IGF-I. Am J Physiol. 1997 Jul;273(1 Pt 1):E130-8 Bühler C, Hammon H, Rossi GL, Blum JW. Small intestinal morphology in eight-day-old calves fed colostrum for different durations or only milk replacer and treated with long-R3-insulin-like growth factor I and growth hormone. J Anim Sci. 1998 Mar;76(3):758-65. Dunshea FR, Chung CS, Owens PC, Ballard JF, Walton PE. Insulin-like growth factor-I and analogues increase growth in artificially-reared neonatal pigs. Br J Nutr. 2002 Jun;87(6):587-93 Dunaiski V, Dunshea FR, Walton PE, Goddard C. Long [R3] insulin-like growth factor-I reduces growth, plasma growth hormone, IGF binding protein-3 and endogenous IGF-I concentrations in pigs. J Endocrinol. 1997 Dec;155(3):559-65. Side effects of IGF-1 therapy Guevara-Aguirre J, Guevara-Aguirre M, Rosenbloom AL. Absence of hypoglycemia in response to varying doses of recombinant human insulin-like growth factor-I (rhIGF-I) in children and adolescents with low serum concentrations of IGF-I. Acta Paediatr. 2006 Feb;95(2):199-202. Kerr D, Tamborlane WV, Rife F, Sherwin RS. Effect of insulin-like growth factor-1 on the responses to and recognition of hypoglycemia in humans. A comparison with insulin. J Clin Invest. 1993 Jan;91(1):141-7.( infusions of rhIGF-1 (0.7 micrograms/kg per min) and insulin (0.8 mU/kg.min) for 120 min in 10 healthy volunteers) Fouque D, Peng SC, Kopple JD. Impaired metabolic response to recombinant insulin-like growth factor-1 in dialysis patients. Kidney Int. 1995 Mar;47(3):876-83.After the rhIGF-1 injection, plasma insulin, C-peptide, cortisol, amino acids and glucose decreased. The magnitude of the decrease was greater with the larger rhIGF-1 dose. Mohamed-Ali V, Pinkney J. Therapeutic potential of insulin-like growth factor-1 in patients with diabetes mellitus. Treat Endocrinol. 2002;1(6):399-410. Guler HP, Zapf J, Froesch ER. Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med. 1987 Jul 16;317(3):137-40. Clemmons DR, Sleevi M, Allan G, Sommer A. Effects of combined recombinant insulin-like growth factor (IGF)-I and IGF binding protein-3 in type 2 diabetic patients on glycemic control and distri-

bution of IGF-I and IGF-II among serum binding protein complexes. J Clin Endocrinol Metab. 2007 Jul;92(7):2652-8. Dahlgren LA, van der Meulen MC, Bertram JE, Starrak GS, Nixon AJ. Insulin-like growth factor-I improves cellular and molecular aspects of healing in a collagenase-induced model of flexor tendinitis. J Orthop Res. 2002 Sep;20(5):910-9.( on tendon healing in an equine model of flexor tendinitis…Local soft tissue swelling was reduced in the IGF-I treated limbs. Similarly, lesion size in IGF-I treated tendons was smaller 3 and 4 weeks after initiation of treatment. Cell proliferation and collagen content of the IGF-I treated tendons were increased compared to controls. Mechanically, IGF-I treated tendons showed a trend toward increased stiffness compared to saline treated controls.) Lyras DN, Kazakos K, Verettas D, Chronopoulos E, Folaranmi S, Agrogiannis G. Effect of combined administration of transforming growth factor-b1 and insulin-like growth factor I on the mechanical properties of a patellar tendon defect model in rabbits. Acta Orthop Belg. 2010 Jun;76(3):380-6.( Application of the growth factors resulted in a significant increase in force at failure, ultimate stress, stiffness, and energy uptake at 2 weeks,) Risks of IGF-1 therapy Schernhammer ES, Holly JM, Pollak MN, Hankinson SE. Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):699-704. Endogenous Hormones and Breast Cancer Collaborative Group, Key TJ, Appleby PN, Reeves GK, Roddam AW. Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol. 2010 Jun;11(6):530-42. Zheng W, Gustafson DR, Sinha R, Cerhan JR, Moore D, Hong CP, Anderson KE, Kushi LH, Sellers TA, Folsom AR. Well-done meat intake and the risk of breast cancer. Natl Cancer Inst. 1998 Nov 18;90(22):1724-9. Sakauchi F, Nojima M, Mori M, Wakai K, Suzuki S, Tamakoshi A, Ito Y, Watanabe Y, Inaba Y, Tajima K, Nakachi K. Serum insulin-like growth factors I and II, insulin-like growth factor binding protein-3 and risk of breast cancer in the Japan Collaborative Cohort study. Asian Pac J Cancer Prev. 2009 Dec;10 Suppl:51-5. (no increased risk in a Japanese chort study). Jacobs ET, Martínez ME, Alberts DS, Ashbeck EL, Gapstur SM, Lance P, Thompson PA. Plasma insulin-like growth factor I is inversely associated with colorectal adenoma recurrence: a novel hypothesis. Cancer Epidemiol Biomarkers Prev. 2008 Feb;17(2):300-5 J. Svensson, B.-Å. Bengtsson, T. Rosén, A. Odén, G. Johannsson. Malignant Disease and Cardiovascular Morbidity in Hypopituitary Adults with or without Growth Hormone Replacement Therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12 Contraindications for IGF-1 therapy Schmidt K, von Haehling S, Doehner W, Palus S, Anker SD, Springer J. IGF-1 treatment reduces weight loss and improves outcome in a rat model of cancer cachexia. J Cachexia Sarcopenia Muscle. 2011 Jun;2(2):105-109. (longer survival at lower doqses IGF-1) Ng EH, Rock CS, Lazarus DD, Stiaino-Coico L, Moldawer LL, Lowry SF. Insulin-like growth factor I preserves host lean tissue mass in cancer cachexia. Am J Physiol. 1992 Mar;262(3 Pt 2):R426-31. Mesiano S, Katz SL, Lee JY, Jaffe RB. Insulin-like growth fac-

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tors augment steroid production and expression of steroidogenic enzymes in human fetal adrenal cortical cells: implications for adrenal androgen regulation. J Clin Endocrinol Metab. 1997 May;82(5):1390-6. Maccagno B, Giordano R, Broglio F, Maccario M, Muller EE, Ghigo E, Arvat E. Recombinant human IGF-I does not modify the ACTH and cortisol responses to hCRH and hexarelin, a peptidyl GH secretagogue, in humans. J Endocrinol Invest. 2001 Feb;24(2):67-71. Treatments associating IGF-1 to growth hormone may work better Thompson JL, Butterfield GE, Marcus R, Hintz RL, Van Loan M, Ghiron L, Hoffman AR. The effects of recombinant human insulin-like growth factor-I and growth hormone on body composition in elderly women. J Clin Endocrinol Metab. 1995 Jun;80(6):184552. Guebre-Egziabher F, Juillard L, Boirie Y, Laville M, Beaufrère B, Fouque D. Short-term administration of a combination of recombinant growth hormone and insulin-like growth factor-I induces anabolism in maintenance hemodialysis. J Clin Endocrinol Metab. 2009 Jul;94(7):2299-305. Dubuis JM, Deal C, Tsagaroulis P, Clark RG, Van Vliet G. Effects of 14-day infusions of growth hormone and/or insulin-like growth factor I on the obesity of growing Zucker rats. Endocrinology. 1996

Jul;137(7):2799-806 (In growing genetically obese rats the combination of IGF-1 and GH reduces inguinal fat better than either alone)) Clark RG, Mortensen DL, Carlsson LM, Carlsson B, Carmignac D, Robinson IC. The obese growth hormone (GH)-deficient dwarf rat: body fat responses to patterned delivery of GH and insulin-like growth factor-I. Endocrinology. 1996 May;137(5):1904-12 (In rats with obesity induced by a high fat diet the combination of IGF-1 and GH reduces weight better than either treatment alone) Mendenhall CL, Roselle GA, Gartside P, Grossman CJ. Effects of recombinant human insulin-like growth factor-1 and recombinant human growth hormone on anabolism and immunity in calorie-restricted alcoholic rats. Alcohol Clin Exp Res. 1997 Feb;21(1):1-10 Conclusion Ugalde AP, Mariño G, López-Otín C. Rejuvenating somatotropic signaling: a therapeutical opportunity for premature aging? Aging (Albany NY). 2010 Dec;2(12):1017-22. Mariño G, Ugalde AP, Fernández AF, Osorio FG, Fueyo A, Freije JM, López-Otín C. Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16268-73.

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Rejuvenation inside as well as outside Aubrey D.N.J. de Grey, Ph.D. Chief Science Officer, SENS Research Foundation 110 Pioneer Way, Suite J, Mountain View, CA 94041, USA Email: aubrey@sens.org Abstract

skin aging and its prevention.

The term “rejuvenation” is often colloquially understood to refer mainly to cosmetic restoration of the appearance of youth. However, a more rigorous definition should encompass overall bodily function, not merely appearance: any intervention, in fact, that restores youthful structure and/or function to a tissue or organ that has accumulated age-related deterioration. Here I outline what rejuvenation means in practice, with emphasis on interventions that are currently in development and will far outperform anything that exists today.

Elasticity of the extracellular matrix Wrinkles and sagging skin are arguably the single most prominent aspect of skin aging. This loss of skin elasticity largely (though not entirely, as will be discussed below) arises from the molecular disorganisation of the extracellular matrix (ECM), the lattice of proteins that holds not only the skin but the whole body together.

The ECM’s principal constituent is collagen. Triplets of collagen chains are arranged in a helix, and these triple helices are themselves linked together by The skin: a conspicuous but subordinate tissue chemical bonds created via the action of certain en“Cosmetic” is a curiously double-edged term. On the zymes, such as lysyl oxidase and transglutaminase.1 one hand it has the positive connotation of improv- The overall structure’s biomechanical properties, and ing one’s looks, but at the same time it refers to inter- in particular its elasticity, arise from the regularity of ventions that do not work, only having the illusion of these links, which are formed only between particular efficacy. Perhaps this is not an accident. The various amino acids. changes that the skin undergoes during aging – loss of However, as a result of the ECM’s very slow turnover, elasticity, loss of moisture, variability of pigmentation its constituent proteins also undergo an accumulation and more – are not solely autonomous, but are driven of non-enzymatic crosslinking, resulting from the by the age-related changes in what lies beneath, nota- reaction of some of its constituent amino acids with bly the circulation. Accordingly, while measures to re- circulating sugar molecules (a process known as glyjuvenate skin structure and function are relatively easy cation).2 These reactions sometimes culminate in the to develop as compared to rejuvenation of internal formation of random chemical bonds between neighorgans (not least because topical delivery is so much bouring collagen chains, progressively stiffening the more straightforward than injection or surgery), they ECM overall. Additionally, though the ECM is slowly ultimately face a losing battle, as the pro-aging influ- recycled over time, this turnover is likely to be retardences bringing about these changes become progres- ed by crosslinking. sively stronger and more difficult to hold back. There has long been an interest in developing drugs that However, this sombre reality can also be viewed in a will selectively cleave these adventitious crosslinks, positive light. Just as the aging of the body dominates but the challenge has proven daunting, leading most the aging of the skin, so, conversely, interventions that researchers to focus on reducing the rate at which they robustly rejuvenate our internal tissues and organs form.3 However, bona fide rejuvenation must consist will potentiate cosmetic interventions, making them of restoring structure, so at SENS Research Foundafar more effective and long-lasting than they are to- tion we are funding a collaboration between groups day. For this reason, those with an eye on the future of at the prestigious universities of Cambridge and Yale skin rejuvenation must pay close attention to rejuve- focused on the identification of compounds that can nation research more generally. cleave the crosslink known to be the most abundant In what follows, I shall highlight a non-exhaustive se- in human ECM, namely glucosepane.4 If such a drug lection of the specific ways in which foreseeable medi- can be developed, skin elasticity will be substantially cal interventions to restore youthful function to inter- restored. However, it must always be borne in mind, nal organs are likely to exert these knock-on effects on as already stressed above, that aging of internal organs Lifespan Medicine Journal 2014 - Page 33

affects this process too. In particular, the rate of formation of glucosepane accelerates with age as a result of progressive loss of glycemic control. Thus, maintenance and restoration of youthful levels of insulin sensitivity must be viewed as a core underpinning of the long-term maintenance of youthful skin elasticity. Factors contributing to the decline of insulin sensitivity, such as the accumulation of fat deposits in skeletal muscle,5 are therefore of necessary interest as aspects of regenerative medicine for the aging skin. Thinning of the dermis Skin elasticity is affected not only by its molecular structure but also by its simple dimensions. As we age, the lower layer of the skin (the dermis), which is where the elastic ECM is located, becomes thinner and thus weaker, with inevitable consequences for elasticity.6 This change is largely driven by the aging of the main resident cells of the dermis, the fibroblasts. Fibroblasts are, as their name suggests, the cells responsible for laying down the collagen fibres that make up the ECM, and during aging they decline in both number and function, leading to impairment not only of wound healing (a process in which the rapid division of fibroblasts, when stimulated by removal of contact inhibition, is fundamental) but also of steadystate skin maintenance. Since fibroblasts are perfectly capable of dividing on demand (and it has been firmly established that this capacity is not intrinsically diminished with age7), it logically follows that this decline is a consequence of changes to those cells’ environment, specifically the composition of the blood stream that provides them with nutrients. It is unclear which factors’ changes to blood concentrations are of greatest significance in promoting fibroblast dysfunction, but we can nonetheless say for sure that these changes are themselves the result of changes in function of internal tissues and organs, whose rejuvenation would thus lead to – or at least facilitate – a revival in fibroblast activity. Age spots and other pigmentation disorders The emergence of discoloration is another major feature of skin aging of great commercial and medical interest. It arises from the focal accumulation of pigmented material, both inside and outside the cell.8 But why should material ever accumulate? The skin is generally thought of as a labile tissue, whose constituent cells and molecules have a half-life that is a small proportion of the human lifespan, so the natural prediction is that detritus, of whatever kind, would be eliminated as rapidly as it is created.

changes during aging are closely linked, in terms of etiology, to other changes, especially to the loss of elasticity reviewed above. Crosslinking driven by glycation renders not only ECM but also isolated macromolecules progressively more resistant to turnover, and it happens that several major products of glycation are pigmented, in some cases autofluorescent.9 The result is that aggregates of proteinaceous, lipid and carbohydrate origin are prone to accumulate as we age; the non-uniform distribution of that material arises from its inherently autocatalytic nature (the longer an aggregate persists, the more crosslinked it becomes, and vice versa). The heartening implication of the above is that interventions which reverse ECM elasticity are very likely also to contribute to disaggregation and clearance of pigmented material, with desirable cosmetic consequences. Conclusion Cosmetic medicine is in its infancy, like the rest of medicine. However, the progress being made in disparate areas of medical research is more interconnected than it may superficially seem. In particular, work mainly aimed at rejuvenation of internal organs is likely to synergise powerfully with skin rejuvenation medicine. References 1. Tabolacci C, Lentini A, Provenzano B, Beninati S. Evidences for a role of protein cross-links in transglutaminase-related disease. Amino Acids 2012;42(2-3):975-986. 2. Verzijl N, DeGroot J, Thorpe SR, Bank RA, Shaw JN, Lyons TJ, Bijlsma JW, Lafeber FP, Baynes JW, TeKoppele JM. Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 2000;275(50):39027-39031. 3. Aldini G, Vistoli G, Stefek M, Chondrogianni N, Grune T, Sereikaite J, Sadowska-Bartosz I, Bartosz G. Molecular strategies to prevent, inhibit and degrade advanced glycoxidation and advanced lipoxidation end products. Free Radic Res. 2013, in press. 4. Sjöberg JS, Bulterijs S. Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link. Rejuvenation Res 2009;12(2):137-148. 5. Muoio DM. Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim Biophys Acta. 2010;1801(3):281-288. 6. Waller JM, Maibach HI. Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. Skin Res Technol 2005;11(4):221-235. 7. Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG, Beck JC. Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc Natl Acad Sci USA 1998;95(18):10614-10619.

The explanation of this paradox is that pigmentation 8. Osborne R, Hakozaki T, Laughlin T, Finlay DR. Application of genomics to breakthroughs in the cosmetic treatment of skin ageing

Lifespan Medicine Journal 2014 - Page 34

and discoloration. Br J Dermatol 2012;166 Suppl 2:16-19. 9. Bos DC, de Ranitz-Greven WL, de Valk HW. Advanced glycation end products, measured as skin autofluorescence and di-

abetes complications: a systematic review. Diabetes Technol Ther 2011;13(7):773-779.

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Anti-Aging Medicine: Testosterone Under Attack By Dr. Edward Lichten Overview: Testosterone is the power that drives man. In history, the bravest, strongest men were the Spartan 300 who withstood the onslaught of upwards of a million Persians for days. It is a fact that testosterone has the ability to generate almost limitless energy. Until recently, the only way of increasing testosterone came from vigorous exercise. Exercise, strength, endurance and mental clarity are clearly the effects of testosterone. However, mankind is under attack. The attack is of our own doing—it is the synthetic estrogens that are classified as pesticides, plastics, fire retardants and many of the more than 80,000 chemicals humans dump into their environment every year. Although epidemiologists such as TEDX founder, Theo Colborn1, Ph.D., has heralded a call for action in her book entitled Our Stolen Future, the key money players have stifled research and scientists and those whom herald the warnings. The facts connect these toxins to not only alligator genital malformations, polar bears killing their cubs, but also to the poisoning of us. These chemicals have a direct effect on the human endocrine system, and, can be shown, to have a direction connection to increases in the early appearance of chronic disease. Mankind is at a crossroads, and if all we have is Theo Colborn’s plea to clean up the environment, then the human race may well become sterile in our children’s lifetime.

Part I: TESTOSTERONE LEVELS ARE FALLING There is a world-wide epidemic of low sperm counts and male infertility. The post- World War II sperm counts was typically 150 million per cubic centimeter. From London, to New York to Singapore, the sperm counts now hovers around 30 million. Twenty million is considered the level of infertility. What has poisoned our men?

In Richard Conniff ’s2 article in Men’s Health he speaks about professional golfer, Shaun Micheel, whose life fell apart at the age of 36. This professional golfer lost his strength, his sex drive, his focus and became depressed. He was fortunate that his doctor checked his testosterone and confirmed that it was half of what it should have been. He like thousands of men started topical testosterone. Unfortunately for him and those who use the topical gels, the initial rebound never brought him back to his old self. “One step in the But, we do have treatments, answers and a methodol- right direction,” the doctor might say. ogy to treat ‘Low-T.’ Travison3 has documented the normal fall of total tesThe articles that follow with focus on six distinct as- tosterone to be about 1.5% per year. But in analysis of pects of testosterone deficiency: men at age 50, comparisons show that levels of testos1. Testosterone and sperm count levels are falling terone at the same age shows that your grandfather’s 2. Endocrine Disrupting Chemicals (EDCs) are testosterone at 50 years of age was, on average, 15% ubiquitous throughout the world, affecting ani- higher than your father’s and your father was 15% higher than yours. Men at the same age now have onemals of all species third less total testosterone than 50 years ago. 3. The incidence of chronic diseases is increasing exBut measurement of total testosterone is a poor test. ponentially from the 1950’s Fully 98% of testosterone is bound to a carrier pro4. There is a direct link between falling testosterone tein called Sex Hormone Binding Globulin (SHBG). levels and Endocrine Disrupting Chemicals—and Normally, SHBG increases by 1.5% per year just as the the problem is worse than anyone can imagine testosterone decreases. 5. There is a treatment that can block the progressive As gynecologist treating couples for infertility I came effect of EDCs on adult men and women to realize that the world was experiencing low sperm 6. There is a treatment that for many, can reverse counts. And as a gynecologist, I did not think about men having low testosterone until I came face-to-face some of these chronic diseases Lifespan Medicine Journal 2014 - Page 36

with the man-change that struck me down at 40 years ing for an alternative source of testosterone, I was inof age. troduced to compounded testosterone pellets. These When I experience exhaustion, night-sweats, inability pellets provided stable testosterone serum levels when to focus and lack of energy to play even 5 minutes of implanted at 8 week intervals. I had that same testostennis, my medical colleagues had no clue. One of terone surge that I had appreciated originally with the my gynecologic patients told me her husband had the testosterone cream. My youth was back. And these same symptoms, but to my chagrin, he was 74 years pellets worked well for 15 years: allowing the 5-minof age. A man’s testosterone and estradiol levels are ute exhausted weekend tennis athlete to win his league dependent on the pituitary’s release of follicle stimu- three years in a row against younger and younger oplating hormone (FSH) and luteinizing hormone (LH), ponents. The SHBG level fell below even my pre-tesjust as occurs in women. I measured my FSH, LH, tosterone gel levels. testosterone, estradiol and that interesting protein called Sex Hormone Binding Globulin. My testosterone was at the lowest limits of normal (250 ng/dl). My research showed that my father’s generation at the same middle-age had a testosterone range of 600 to 1200ng/dl. So I was operating on, figuratively, only 2 of 8 cylinders. But more telling was the fact that my pituitary was crying for more testosterone: normal FSH is less than 3.5mIU/ml and LH, less than 2.5 mIU/ml. Mine were both over 20mIU/ml. Why had I stopped producing adequate testosterone? Was it due in part to the vasectomy I had 9 years early? Yes, vasectomy does shorten spontaneous sexual frequency by up to 7 years in men and maybe testosterone level as well3.

Why had the topical 1- 2% testosterone gels failed me after just 6 months? The answer can be found in an article published in 1972 in Nature by CW Burke and DC Anderson4: “SHBG is an Oestrogen Amplifier.” This article showed that the Free Androgen Index (F.A.I.), the true measure of bio-available testosterone, was calculated by dividing the total testosterone by the SHBG. Estrogen increases SHBG. So when testosterone cream or gel was applied to my skin, the skin aromatized a significant percentage of testosterone to estrogen. The estrogen triggered the liver to make more SHBG, and the net effect was that my bio-available testosterone, the Free Androgen Index (F.A.I.) dropped after 6-months to where it was before applying topical testosterone.

But, the fact was the surgery was done and I was a testosterone deficient male as traumatized as much as one of my young women patients who had been castrated and made estrogen deficient at hysterectomy with bilateral oophorectomy. I replaced her hormones and they did well. Why not replace my testosterone?

Why had I felt better with the testosterone pellets? The answer is that placing testosterone below the skin surface by injection or implant avoids the aromatization for a long period of time. In my case, my F.A.I. ratio stayed youthful for 15 years.

The three internists who I consulted had no idea what my problem was before the laboratory confirmation of low testosterone. They were even more puzzled after reviewing the laboratory tests. My urologist admonished me that “we don’t replace testosterone” and “are you not afraid of prostate cancer when you are 80?” My response was simple; find another doctor. So, I found a doctor who had focused his medical practice on replacing testosterone in men. His use of compounded testosterone cream did offer a rapid rebound of my strength, my sexual performance and my exercise endurance in just days. But after 6-months of treatment, that surge of energy was gone so I repeated my blood work to see if I could understand what was going wrong. The laboratory tests shows that the testosterone cream had doubled my total serum testosterone, but it had also increased my estradiol and this protein called Sex Hormone Binding Globulin (SHBG). While search-

But 25 years later, medical treatment for hypogonadism is changing. We now have medications that can block the aromatization of testosterone to estrogen: tamoxifen, anastrozole, letrozole and toremifene. Each Selective Estrogen Receptor Blockers (SERM) is unique and may have importance for men’s health. Tamoxifen is a SERM that is approved for treating breast cancer in men as well as women; it received FDA approval in 1990. Men found that tamoxifen had the effect of reducing breast enlargement called gynecomastia when triggered by androgen replacement. It also may decrease some of the symptoms associated with bilateral prostate hypertrophy. Twenty milligrams of tamoxifen daily significantly increase FSH, LH, sperm count and testosterone level especially in the group with the most normal, low FSH5. Therefore, men who wish to counteract the sperm lowering effects of testosterone may do so successfully by adding back 20mg of tamoxifen6. The decrease in scrotal and testes size on testosterone replacement may reverse as

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well, making the use of human chorionic gonadotro- ol, increased HDL-cholesterol and did not effect tripin for this condition, unnecessary. However, tamox- gylcerides.13 Toremifene citrate is so powerful that it ifen increases SHBG7. will lower estradiol levels in a menopausal woman. [Editor] A subsequent article will show that higher Whether similar results will be observed in men is yet SHBG in men is associated with a number of chronic to be studied.

diseases. The editor considers SHBG to be as impor- So, if you are a physician who is only comfortable in tant as low testosterone to the concept of anti-aging as prescribing with topical gels, the compounding pharlow testosterone. macist can add zinc and saw palmetto to the preparaThe second SERM is anastrozole. In a study at Mayo tion. You can prescribe these aromatization blockers clinic8, anastrozole was able to reduce serum estradi- restricting them to tamoxifen and anastrozole safely. ol concentrations by 50% and elevate mean LH lev- The key is to repeat the serum hormone assays of toels two-fold. But, anastrozole could not increase total tal testosterone, estradiol, and Sex Hormone Binding testosterone concentrations of molar testosterone to Globulin. The F.A.I. (0.7-1.2) and SHBG (5-15 nmol/ SHBG ratio [F.A.I.] or LH release patterns. When mL) should be within the normal range (of Burke high estradiol levels are noted in men on testosterone and Anderson) previously referenced; and estradiol replacement, anastrozole can be routinely added espe- should be less than 20- 25pg/ml. But if patients fail to cially if there are complaints of gynecomastia and/or find comfort with topical testosterone treatment, the prostate issues. The end point is whenever the patient next step is to learn to insert testosterone pellets or reports satisfaction; from a laboratory perspective, the learn about the mixtures of anabolic steroids that is testosterone/SHBG ratio, or F.A.I. should be ideally, superior to the 3-month injection of testosterone undeconate (not available in the United State but availgreater than 0.7-1.2. able in Europe) has sustained hundreds of men for Letrozole is approved for treatment of breast cancer. these last 20 years. But testosterone undeconate also Less than 2.5mg of letrozole per week can raise tes- negatively increases SHBG.14 tosterone and free testosterone levels to physiological levels9. A study in the Netherlands used doses of 7.5 Men’s testosterone is under attack. Men in their early to 17.5mg per week resulting in a decrease of serum 20’s are requesting for Viagra™ and Cialis™. Ulcerative estradiol by half (120 to 70), LH increased (4.5 to 14.8) colitis, diabetes and cancer are occurring in too many and SHBG remained unchanged while the testoster- men under the age of 35. What is wrong? Their seone level tripled10. Concern is raised in one study that rum laboratory tests will confirm their bio-available showed that the addition of letrozole to testosterone testosterone is often in the same range as symptomatic injections caused a significant drop in bone density in men over 50 years of age. just one year11. So, although the testosterone level has Anti-aging medicine for men starts with adequate levincreased the pituitary FSH and LH see the testoster- els of bio-available testosterone. This article has outone level as not bio-available and that may explain the lined a number of treatment options and the potential observed bone loss. for present and future oral SERM intervention. The Exemestane although approved for the treatment of key is laboratory testing: treatment must maintain adbreast cancer as a SERM, has the unique effect of de- equate serum levels of total testosterone, low levels of creasing SHBG and increasing testosterone, DHEAS SHBG, and suppress levels of FSH, LH (less than 2.5 and FSH levels. It is structurally similar to androsten- miu/mL) and Estradiol to normal range. edione. The dose to lower estradiol levels by 30% is small7. Experience with exemestane is limited but, the initial study showed that 2.5mg of exemestane in an aging male dropped his estradiol levels below measurable levels and caused a profound depression relieved only by taking additional testosterone injections.

The next article will explain the environmental links that may explain what is called ‘environmental aging’ with resultant low testosterone, high SHBG, estradiol, LH and FSH. There exists a direct link between environmental toxins and diseases such as diabetes. The effective treatment may start right here with available The newest SERM is toremifene citrate 12. It is ap- treatment that will maintain adequate bio-available proved under the name Fareston™ for the treatment of testosterone for men and women. advanced breast cancer but is in trials as a preventa- References: tive for prostate cancer under the name Acapodene™. 1. Colborn, Theo. Our Stolen Future. 1996. The study in women showed toremifene but not ta2. Coniff J. Testosterone Under Attack. Men’s Health. 2007 moxifen decreased total cholesterol, LDL-cholesterLifespan Medicine Journal 2014 - Page 38

3. Mo ZN, et.al. Early and late long-term effects of vasectomy on serum testosterone, dihydro-testosterone, luteinizing hormone and follicle-stimulating hormone levels. J Urol 1995 Dec; 154(6): 20659. PMID: 7500459. 4. Burke CW, Anderson DC. SHBG is an Oestrogen Amplifier. Nature 1972:240(5375); 38-40. PMID: 4120573 5. Kadioglu TC. Oral tamoxifen citrate treatment is more effective in normogonadotropic patients who have follicle-stimulating hormone levels within the lower half of normal. Int Urol Nephrol 2009 Dec; 41(4):773-6. PMIDâ&#x20AC;? 19381855 6. Adamopoulos DA, et.al. Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia. Fertil Steril 2003 Oct; 80(4):914-20. PMID: 14556812 7. Hadji P, et.al. Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German sub--study. Climacteric 2012 Oct; 15(5): 460-6. PMMI: 22321061 8. Ingle Jn. Overview of adjuvant trials of aromatase inhibitors in early breast cancer. Steroids 2011 Jul; 76(8): 765-7. PMIKD: 21382394]

May; 158(5):741-7. PMID: 18426834 10. de Boer H, et.al. Letrozole normalizes serum testosterone in severely obese men with hypogonadotropic hypogonadism. Diabetes Obes Metab 2005 May; 7(3):211-5. PMID: 15811136 11. Merriggiola MC, et.al. Effects of testosterone undecanoate administered alone or in combination with letrozole or dutasteride in female to male transsexuals. J Sex Med 2008 Oct;5(10):2442-53. PMID: 18624972 12. Price N, Sartor O, Hutson T, Mariani S. Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer 2005;3:211-4. 13. Tominaga T, Kimijima I, Kimura M, Takatsuka Y, Takashima S, Nomura Y, Kasumi F, Yamaguchi A, Masuda N, Noguchi S, Eshima N. Effects of Toremifene and Tamoxifen on Lipid Profiles in Post-menopausal Patients with Early Breast Cancer: Interim Results from a Japanese Phase III Trial. Jpn J Clin Oncol. 2010 Apr 8. 14. Giqulli VA, et.al. The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadoptropic hypogonadism. J Sex Med 2011 Dec; 8(12): 3471-8. [PMID: 21995803]

9. Loves S, et.al. Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol 2008

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New Randomized study comparing Dessicated Thyroid Extract with Levothyroxine Dr Henri Knafo, MD, M.Sc, B.Sc

Thyroid hormones are produced by the thyroid gland, located in the neck. Its function is to regulate the body’s metabolism. There are two major thyroid hormones circulating in our bodies: T3, which is the active form and T4, which is not active but have excellent transportation capabilities throughout the body1. Thyroid is one of the most important anti-aging hormones. As we age, our metabolism decreases and hypothyroidism becomes increasingly common. Hypothyroidism affects about 5% of people over the age of 60 years2. Jacque Hertoghe MD pointed out in his lectures that a 1957 article in the New England Journal of Medicine revealed that nearly half of all mid-western Americans have untreated hypothyroidism. In recent years, others have pointed out that at least 20% of women over the age of 60 have subclinical hypothyroidism that is not treated3. Hormonal replacement therapy is a fundamental part in the management of this disease. There are two main categories of hormones available for treatment: synthetic and desiccated natural hormones. Levothyroxine, the most commonly used synthetic thyroxin form, is a stereoisomer of physiological thyroxin, which is metabolized more slowly. There has been a great controversy in regard of which treatment is the best. Many patients claim they do not feel as well when switching from DTE (desiccated thyroid extract) to L-T4 therapy but there has not been any randomized double-blind studies comparing the effectiveness of synthetic L-T4 with DTE4. An article recently published in the Journal of Clinical Endocrinology & Metabolism tried to compare DTE and Levothyroxine in patients suffering from hypothyroidism5. The goal of the article was to access symptoms, cognitive function, and sense of general well-being after being treated with either DTE or L-T4. 78 patients (18-65 years) were enrolled in this prospective, randomized, double blind, crossover study. The inclusion criterion was a diagnosis of hypothyroidism with a stable dose of L-T4 for at least 6 months. Exclusion criterias were: pregnancy, coronary artery disease, COPD, malabsorption disorder, GI surgery, significant liver/renal dysfunction, seizure disorders, any active cancer, uncontrolled psychosis, psychotropic medications, corticosteroids, amiodarone, iron supplements, sucralfate, proton pump inhibitors and cholestyramine intake. Patients were randomized to receive either DTE or

L-T4 in identical capsules. A physician not involved in randomization maintained the concealed randomization list and all study participants and investigators were blinded throughout the study. Patients underwent memory testing, a thyroid symptom questionnaire and a quality of life general questionnaire. Physical examination, ECG, Serum TSH, free T4, total T4 and T3, T3 resin uptake, rT3 SHBG and a lipid panel was done at baseline and after 16 weeks of treatment. After 6 weeks on the study TSH levels were checked and adjusted. Out of 78 patients enrolled, 70 patients completed the study. 50% of patients had autoimmune hypothyroidism. The mean dosage of L-T4 was 112.4 µg/d. Overall patients showed no difference in symptoms scores, general health questionnaire or neuropsychological testing. However, there was a trend toward improvement in GHQ-12, TSQ and auditory memory index with patient taking DTE. There was a decrease in 2.89 pounds in weight during DTE therapy compared to L-T4 (172.9_36.4 lb vs 175.7_37.7 lb, P= .001). DTE patients had higher levels of serum total T3 and TSH but lower levels of T4. At the end of the study, 49% of patients preferred DTE compared to only 19% who preferred L-T4. 33% of patients had no preferences. Preference for DTE over L-T4 was statistically significant (χ2 [1] = 9.38; P = .002). The interesting part comes from analyzing subgroups

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of patients that preferred DTE. Those patients had an average of 4lb weight loss compared to L-T4 and their subjective symptoms such as concentration, memory, sleep, decision making capability, happiness and energy levels were significantly increased as measured by the general health questionnaire-12 and thyroid symptom questionnaire (P < .001 for both). Auditory memory also improved in these patients during the DTE treatment period (P = .041). Those who preferred DTE did better in their neuropsychological measures compared with their baseline. TSQ (thyroid symptoms questionnaire) was the best predictor for clinical preference for DTE over L-T4. No adverse effects were reported with both treatments.

such drugs. It is important nevertheless to acknowledge the fact that natural hormone therapy is an important therapeutic option. As thyroid hormonal replacement becomes an important part of anti-aging therapy, it is reasonable to question ourselves on which is the best treatment for our patients. As more and more physicians become aware of therapeutic options, we can predict that DTE will become an important part of the treatment plan. 1. Marsili A, Zavacki AM, Harney JW, Larsen PR. Physiological role and regulation of iodothyronine deiodinases: a 2011 update. J Endocrinol Invest. 2011 May;34(5):395-407. 2. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Evans JG, Hasan DM, Rodgers H, Tunbridge F, Young ET 1995 The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 43:55â&#x20AC;&#x201C;68

Previously, many studies had compared L-T4/T3 therapy to L-T4 monotherapy. 3. Villar HC, Saconato H, Valente O, Atallah AN. Thyroid horIt is unclear if studies comparing DTE to L-T4 can be mone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007 Jul 18;(3): extrapolated to these previous studies. This study is the first randomized study comparing DTE and L-T4 therapy. It suggests that DTE can be beneficial in many if not most patients.. Synthetic levothyroxine holds an undisputed literature pertaining to its beneficial usage in hypothyroidism. Most clinicians are well trained in prescribing and managing

4. Grozinsky-Glasberg S - Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab - 01-JUL-2006; 91(7): 2592-9 5. Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study. J Clin Endocrinol Metab. 2013 Mar 28

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http://thyroid.eci2012.net

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HDL-C: the good cholesterol: bad for the nervous system? Dr Sus Herbosch, Meise (B) Introduction Interpretation of serum lipid levels is entirely overwhelmed by the possible influence of these lipid levels on the cardiovascular system. Artificial and inadvertent lowering of cholesterol by means of statins (anti-cholesterol drugs) has come under increasing critique, especially regarding primary prevention. Undesirable negative side effects on the nervous system are hence well documented1. Analysis of very large demographic samples must be oriented toward new goals for serum lipid levels, taking into account their differences such as sex and age. Without a doubt these are important factors in anti-aging approaches. Over 30 years of experience with the C.E.I.A. functional proteomic profile has been an eye-opener in this field, resulting in a complete new reading of HDL-C (the so-called “good” cholesterol) as a “witness for the prosecution” in the matter of neurological and neuropsychological toxicity or damage. Among the complete range of C.E.I.A. tests, lipoprotein parameters are certainly the most fascinating group and exclusive to the C.E.I.A. methodology. They offer an objective, measurable, and reproducible approach for diagnostic and therapeutic orientation in diseases with altered nervous system reactivity. Their interpretation is based upon a stringent empiricism, brought together by a vast network of physicians with C.E.I.A.-method experience (± 1.500 physicians across Europe), and confirmed by a growing number of scientific publications.

so by the general public. The number of researchers is nevertheless growing; they represent a diverse segment of the medical scientific community. According to Michel de Lorgeril: “Le cholestérol est une molécule fondamentale du cerveau! Faut pas qu’il en manque!6 (cholesterol is a fundamental molecule to our brain! Don’t be short of it!)”. One could even go back in time to find authors who already supported this hypothesis: “Le monde médical doit transformer ses idées à propos des lipides: notre mémoire, c’est de la graisse7 (doctors have to change their ideas about lipids: our memory is grease)” (Pierre Magnin, 1995). Although the brain represents only 2% of our total body weight, it contains 25% of our total cholesterol, most of it present in the myelin sheaths that protect nerve cells and fibres.

Research published by Mauch8 in 2001 has identified cholesterol as the substance produced by the protective cells of the nervous system (glial cells), responsible for the neuronal capacity to create novel networks of interconnections over synaptic junctions. Thought, memory, learning, and all other mental functions dePublications on cholesterol and the nervous system pend on the ability to form these synapses. Age-relatNumerous publications have refuted the perception of ed neuronal loss in the brain starts at the end of adcholesterol as the number one public enemy, with dis- olescence. However, the ability to form new synapses astrous influences on cardiovascular morbidity and can be preserved to very old age. mortality. They all try to correct this largely dissem- Whereas cerebral cholesterol reduction will hinder inated misinformation. The book2 by Michel de Lor- memory and other cognitive functions, raising one’s geril, cardiologist and CNRS (France), is one of the serum cholesterol will not have any effect on intellimost fascinating, next to the books of Uffe Ravnsk- gence. Since cholesterol does not pass through the ov3 4, a pioneer in this crusade, as well as the English blood-brain barrier, there is no relation between alistandard work of Malcolm Kendrick5. mentary ingested cholesterol and cerebral functions. A second kind of publication is devoted to research However, cholesterol-lowering drugs do pass this baron lipid functions in and for the benefit of the nerv- rier, resulting in the known disastrous effects such as ous system. Unfortunately, this research is very little all kinds of cognitive impairment. acknowledged by health professionals and even less

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Demographical data

• Increase and decrease with aging are absent; values To understand physiological and pathological mech- remain unchanged, meaning that the age- correlated anisms in coping with lipid metabolism, one should rise and decrease of total cholesterol can essentially be start by analysing the demographical distribution of attributed to LDL-changes. the different parameters observed. For this purpose, • Mean value for men is 53 mg% (1,37 mmol/L). Mean we collected a set of data over the period 2004–2011, value for women is 66 mg% (1,70 mmol/L). provided by MEDINA9, the laboratory where our GP • The mean value of standard deviations for HDL-C is group practice (three doctors) has its patient samples remarkably smaller than the one for total cholesterol analysed. This collection contains 970,000 male and (TC), signifying that a small, even hidden, variation over 1,100,000 female analyses. These huge figures of- in HDL-C nevertheless can have a very real meaning fer us the possibility to draw very reliable biostatistical or impact. analyses concerning their distribution. Study of the total cholesterol (TC) reveals a number of characteris- • The mean value for the female population is 13 mg% (0,34 mmol/L), higher than the male population, cortics, depending on sex and age: responding to ± 1 entire standard deviation. This is • There is a progressive rise in cholesterol levels, start- a very important argument in understanding the feing at adulthood (men from 20 years of age, women male supremacy in pathology related to HDL-C. from 30 years of age) until ± 50 years of age, with a Consequently, a decrease of the risk factor (total chosymmetrical decrease toward old age. lesterol divided by HDL-C: if the denominator raises, • The actual universal imposed (by the lipid clubs) the fraction decreases) will be meaningful in evaluupper limit of 190 mg% (4,91 mmol/L), without con- ating the functional status of the nervous system. sideration of sex and age, in no way corresponds to Classical medicine takes this risk factor only into acthe physiological reality: the mean value for adult count when it arises. They do not tell patients about its men is 192 mg% (4,96 mmol/L), and 201 mg% (5,20 meaning when it decreases. mmol/L) for adult women. Clinical data • Applying the technique of one standard deviation across the respective mean values will lead us to defi- A primary analysis during 2004–2005 performed on nitions of individual target levels: following this logic, patient records of our GP group practice led to an 200 mg% (5,17 mmol/L) will define the upper limit for initial insight into the problem. In a random group a 30-year-old man, but the lower limit for a 55-year- of 1,473 patients (41% ♂/59% ♀), we found 37 cases with HDL‑C > 100 mg% (2,58 mmol/L). The cutold woman. off level of 100 mg% was chosen as merely symbolic. We were astonished to ascertain that this group of 37 patients counted 35 women for only two men. Even more striking was the common denominator between the listed diagnostic keywords: stress, overworking, burn-out, insomnia, alcohol abuse, relational troubles, suicide attempts. This so-called “good” cholesterol was not so gratifying. This observation was striking, the HDL-C fraction of the serum lipids is to be considered from a totally different point of view: its reading as a mere cardiovascular protector is too limited. Two considerations since then are always taken into account when reading HDL-C: • The female population is by far in the majority of all HDL-C increased situations. • This increase is indubitably linked to diseases of the The same type of analysis applied to HDL cholesterol nervous system. (the “good” one) reveals a totally different and sur- More recently, we have repeated our calculations on a larger patient sample from our GP group practice, covering the prising dynamic evolution: Lifespan Medicine Journal 2014 - Page 44

period 2004–2011: 6,344 analyses (2,587 ♂ / 3,757 ♀). In this population, we have isolated all patients with HDL-C > +1,5 standard deviation above mean value and the risk factor (TC/HDL‑C) < -1,5 standard deviation below the mean (for both sex and age). In both categories, women are dominant by over 60%. Combining both characteristics (HDL-C > +1,5 sd and RF < -1,5 sd) leads to 104 cases out of 6,344 analyses, assignable to 70 patients who logically should represent the nec plus ultra among this population, giving us a clue in trying to define the relevant pathology. The almost equal division of those 70 patients between ♂ and ♀: 32/38 (= 46/54%) is troublesome: female supremacy in this extreme segment seems to be apparently less prominent. When analysing the patient records, we found 76 keywords among male diagnostics, and 113 among female. A first striking piece of evidence beyond any doubt is alcohol intoxication—the top of the male “hit parade” in 12 records, among which were four with liver cirrhosis, and in two cases there were fatal outcomes. Because it is well known that regular alcohol intake raises HDL‑C to a significant degree10, is not this the most convincing argument to rename HDL-C as a marker for neurological toxicity? Subsequently, the lot of these diagnostic keywords are immersed into the neuro-ectodermal realm (issued out of the ectoderm, one of the three embryonic germ layers that among other organs forms the nervous system). A vast majority of approximately 80% of all keywords belong to this class, be it in a direct way as neurological (e.g., neuralgia, epilepsy), psychiatric (e.g., anxiety), and psychosomatic diseases (e.g., insomnia), or be it indirectly with pain and asthenic syndromes.

decline is objectively correlated with the decompensation of one or more nervous features, from fatigue and neurasthenia to depression. These observations offer a totally different view and interpretation of the serum lipids, as opposed to the sole impetuous and relentless hunt for cholesterol. By combining several C.E.I.A. parameters into an HDL/LDL index, we have developed a simple estimation tool to assess the vital and essential balance between “good and bad” cholesterol. This index can be inserted in a combined reading of total cholesterol and HDL-C (taking into account the correct limits for corresponding sex and age, not the arbitrary limits imposed by the cholesterol lobby) on the one hand, and the positions of the functional C.E.I.A. parameters on the other. Such a combined reading will then reveal itself as an incomparable aid for objective evaluation and follow-up of neuro-vegetative, psychosomatic, and other functional perturbations of the nervous system. Taking into account: 1. the importance of a well balanced HDL-C / LDL-C for the benefit of neural functions 2. the age-correlated rise/decrease of LDL-C; and 3. the unvarying level of HDL-C with aging,

we must unavoidably come to the consideration that an immutable high level of HDL-C (in women) in Cholesterol and the C.E.I.A. functional proteomic combination with a lowering LDL-C (with aging) profile will contribute to neurological (neurocognitive and/ Parallel to the quantification of serum lipids, the or neuropsychological) problems. Using statins in the C.E.I.A. profile contains a number of lipoprotein tests elderly population will therefore add insult to injury. that are indicators for the activity level of different Not only will statins decrease LDL-C, but also they types of lipoproteins. They give us insight into the hi- raise HDL-C by 10–15%. erarchy of lipid-based and lipid-correlated functions This path of investigation will we hope lead us to a better of the organism. In this hierarchy, the liver is the cen- comprehension of the role of “good” HDL-C in neurologitral level in which lipoprotein synthesis takes place. cal and neuropsychological diseases. The bottom line is that The LDL level (the so-called “bad” cholesterol) corre- the nervous (over)burden, be it asthenia or agitation, can sponds mainly to pre-hepatic and hepatic levels. The almost be accurately predicted on the basis of the HDL-C HDL level (the so-called “good” cholesterol) corre- level. Hence the question is: is this “good” cholesterol really sponds essentially to the post-hepatic level, chiefly the that good, or could it not be so good? In an extreme high range, could it be the sign, perhaps even the cause, of nervnervous system. ous system damage?

Expression of nervous system reactivity through these “good” cholesterol-linked tests can easily be ascer- Dr Sus Herbosch - CV (abstract) Dr Herbosch has studied medicine at tained in neurological and neuropsychiatric diseases, the University K.U.Leuven (1967-1974) but most commonly in daily practice in all kinds of in Belgium, practised as a full-time GP very frequent neuro-vegetative and psychosomatic from 1975 until 1980 in a country-based syndromes. This reactivity can be observed in two GP group (4) practice near Brussels, ways: either as hyperactivity (e.g., agitation) or as hythen started over with an independent poactivity (e.g., fatigue). A drop in reactivity is at least GP practice, integrating family mediequal to, if not more frequent than, its increase. The Lifespan Medicine Journal 2014 - Page 45

cine with complementary biotherapeutical-oriented medicine (acupuncture and biopuncture, homotoxicology, complex homeopathy and related biotherapies, and C.E.I.A. methodology). Since 2002, he has engaged again in an association with a group practice in natural medicine with two fellow doctors with the same biotherapeutical orientation. He took part in local as well as international courses, seminars, and congresses for acupuncture (BVGA-school), C.E.I.A. methodology (Dr Eric Reymond), and neuro-embryological homeopathy (Dr René-Jacques Bourdiol). In addition to his patient-related work, he acts as a consultant doctor for C.E.I.A.-Benelux: he is a regular teacher for this particular biotherapeutical method in Belgium as well as abroad (Holland, Canada, France, Germany-Medizinische Woche Baden-Baden). He emphasises the complementarity between several biotherapeutical approaches, especially the convergence between homotoxicology (Dr Hans-Heinrich Reckeweg), serocytotherapy (Dr Jean Thomas) and C.E.I.A methodology.

2006. Short-term memory loss associated with rosuvastatin. Pharmacotherapy 26(8):1190–1192. Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy. lgalatti@unime.it 2 de Lorgeril, M. 2008. Cholesterol, mensonges et propagande. Vergèze, Thierry Souccar Editions, ISBN-10 : 2916878173. 3 Ravnskov, U. 2000. The cholesterol myths: exposing the fallacy that saturated fat and cholesterol cause heart disease Washington, CD: New Trends Publishing Co., ISBN 0-9670897-0-0. 4 Ravnskov, U. 2010. Ignore the awkward: how the cholesterol myths are kept alive. CreateSpace, ISBN-10: 1453759409 | ISBN13: 978-1453759400. 5 Kendrick, M. 2008. The great cholesterol con: the truth about what really causes heart disease and how to avoid it. London, John Blake, ISBN 978-1-8445-4610-7. 6 de Lorgeril, M. 2010. Le cerveau adore le cholesterol: ne l’en privez pas avec des médicaments inutiles! Available from: http:// michel.delorgeril.info/index.php?post/2010/11/25/LE-CERVEAUAIME-LE-CHOLESTEROL 7 Magnin, P. 1995. Avatars du métabolisme des lipides – Conférence au FDNR Cannes, avril 1995. 8 Mauch D, Nägler K, Schumacher S, Göritz C, Müller E, Otto A, Pfrieger F. 2001. CNS Synaptogenesis Promoted by Glia-Derived Cholesterol. Science 9 November 2001: Vol. 294 no. 5545 pp. 13541357 - DOI: 10.1126/science.294.5545.1354.

His search for truth and authenticity in medicine is reflected in his passion as a performer of ancient mu- 9 Medisch Labo Medina. Dendermonde - Hoogveld 10 B-9200 DENDERMONDE – Available at: www.medina.be sic on authentical instruments. (Endnotes) 1 Galatti L, Polimeni G, Salvo F, Romani M, Sessa A, Spina E.

10 Thornton J, Symes C, Heaton K. 1983. Moderate alcohol intake reduces bile cholesterol and raises HDL cholesterol. Lancet; ii: 819–822.

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Complementary diagnosis Personalized complementary therapy suggestions Patient follow-up tool Prevention

The functional proteomic profile (CEIA method) www.ceia.com Contact and information: C.E.I.A. - Bd Saint-Michel 119 - 1040 Brussels - Belgium Tel: +32 2 736 04 58 - Fax: +32 2 736 58 02 - E-mail: info@ceia.com

Nitric Oxide and its significance to Cardiovascular Disease by Jorge D. Flechas MD, MPH Cardiovascular disease is America’s and world wide the number one cause of death. It kills more people in America, yearly than the next nine leading causes of death combined. Cardiovascular research has understandably been the focus of a great deal of interest in both the scientific community and in the public at large. Over fourteen million Americans suffer from coronary artery disease, with another 60 million considered to be at risk. This means that approximately one of every four adults either has active coronary artery disease or is at risk for coronary artery disease. In American society we tend to focus on breast cancer as a major cause of death among women; however, cardiovascular disease has long surpassed breast cancer as the leading cause of death in women. In fact, heart disease kills more American women in the United States than any other single cause.’ The American Heart Association has identified as chronic inflammation, hypertension, hyperlipisix factors that are risk indicators for the develop- demia (such as hypercholesterolemia), diabetes and ment of heart disease:2’ 3 environmental factors such as the use of tobacco products and exposure to air pollution.8’ 9 1. Diabetes ’

2. Smoking (past or present) 3. High blood pressure 4. High cholesterol 5. Obesity (six of every ten people in the United States are considered obese) 6. Family history of heart disease

Endothelial dysfunction is thought to be a key component in the development of atherosclerosis and can predate clinically obvious vascular pathology by many years.”’ 12 Endothelial dysfunction has been shown to be of significance in predicting vascular events including stroke and he ar t att ack.” When t he endothelium becomes dysfunctional, it is associated with reduced anticoagulant properties, increased adhesion molecule expression, chemokine and other cytokine release, and reactive oxygen species production from the endothelium.14’18 All of these processes have been shown to play important roles in the development of atherosclerosis. A key and quantifiable feature of endothelial dysfunction is the inability of arteries and arterioles to dilate fully in response to a stimulus, such as nitric oxide, that stimulates the release of vasodilators from the endothelium. Nitric oxide is a gas produced by the endothelial cells, and low or nonexistent levels of this gas are commonly associated with endothelial dysfunction.19-2I In the presence of endothelial dysfunction, there will be impaired nitric oxide production by the endothelium and/or increased inactivation of nitric oxide by reactive oxygen species.

Forty-two percent of all deaths in the United States are directly related to circulation disorders. Medicine has focused in on fat as a primary source of the problem of atherosclerosis. A new paradigm in medicine has emerged over the last few years that suggests atherosclerosis is not the result of an accumulation of lipids in the bloodstream but rather is the result of endothelial dysfunction, a system-wide pathological state of the endothelium. 4-7 The endothelium is the inner lining of our blood vessels. Endothelial dysfunction can be broadly defined as an imbalance between vasodilating and vasoconstrictive subst ances pro duced by or ac te d up on by t he endothelium. The functions of the cells that line the blood vessels include mediation of coagulation, platelet adhesion, immune function, and control of volume and electrolyte content of the intravascular and extravascular spaces. Research done over the last 12 years has shown Endothelial dysfunction can result from things such that nitric oxide has anti-inflammatory and anti-proLifespan Medicine Journal 2014 - Page 48

liferative effects and, therefore, helps inhibit atheroslerosis.22-24 Since endothelial dysfunction implies a low nitric oxide state, one can see how endothelial dysfunction may contribute to future adverse cardiovascular events. As the nitric oxide content of the arteries and arterioles goes down, the blood vessels become less elastic, and arterial stiffness increases.

L-arginine is generally marketed as a dietar y supplement, and the Food and Drug Administration (FDA) restricts claims to those associated with supporting a healthier cardiovascular system. Medical studies of L-arginine’s role in the management of e x i s t i n g c a rd i ov a s c u l a r c o n d i t i o n s p rov i d e substantiation in support of these suppleEndothelial function can be improved signifi- ment claims. Discussion of some of these studies is cantly by exercise and proper diet. A study pub- intended solely to describe the substantiation unlished in 2005 shows that a positive relationship derlying dietary supplement claims. exists between the c onsumpt ion of t rans fats Daily, hundreds of women in the United States are ( t r ans fat s o c c u r in hydrogenated prod- seen in the emergency room for chest pain. When ucts such as margarines) and the de velopment these patients receive a full medical work up, many of endot helia l dysf unc tion. 25 ’ 26 Endothe- are found to have no coronary artery disease. The vast lial function can also be improved by smoking majority of women who fall into this category do, howcessation, weight loss, and treatment of hyperten- ever, show evidence of microvascular dysfunction.51 A sion and hypercholesterolemia. Studies have also study done on these women showed no significant found thatntioxidant and L-arginine supplemen- associations identified between flow velocity reverse tation can be used to restore impaired endothelial dys- and lipid and hormone levels, blood pressure, and function.27-34 left ventricular ejection fraction. In the last study The scientific community has studied L-arginine’s vast quoted, the authors concluded that coronary miarray of health benefits for many years, and, in crovascular dysfunction is present in approximately p a r t i c u l a r, L - ar g i n i n e’s ro l e i n m ai nt ai n i n g one half of women who show up in the emergency cardiovascular health has been the object of intense room with chest pain in the absence of obstructive study. In fact, in 1998, a team of researchers and coronary artery disease, and this microvascular dysdoctors won the Nobel Prize in medicine for their function cannot be predicted by risk factors for athresearch in L-arginine-derived nitric oxide. When eroslerosis nor by hormonal imbalances. Therefore, Larginine is given, it stimulates the production of ni- the diagnosis of coronary microvascular dysfunctric ox i d e, w h i ch has many b e ne f ic i a l ef fe c ts tion should be considered in women with chest pain not attributable to obstructive coronary artery on cardiovascular health. disease. It is felt that women with microvascular Nitric oxide as a molecule is produced in the body dy sf unc t ion have problems w it h endot hel i by its conversion from L-arginine, and nitric oxide a l dysfunction. More recent studies show that perhelps keep the blood vessels open, elastic and func- sistent chest pain predicts cardiovascular events in tioning properly. L-arginine is most well known for women without obstructive coronary artery disease.52 its role in cardiovascular health, but its importance does not stop there. L-arginine derived nitric oxide The vascular endothelium is a critical regulator of has been cited in the medical literature as having the vascular function and homeostasis. Nitric oxide is an important paracrine substance released by the following benefits: endothelium to regulate vasomotor tone.53-56 Risk 1. Controlling high blood pressure and improving factors that have been looked at with atheroslerosis in heart function35-37 mind are associated with endothelial dysfunction and 2. Reducing serum cholesterol and plaque forma- decreased bioavailability of nitric oxide. Endothelial dysfunction is integral to the pathogenesis of tion38’39 atheroslerosis.57 Endothelial dysfunction relates to an 3. Promoting release of the anti-aging human growth increased risk of adverse cardiovascular outcomes. hormone40’ 41 Endothelial cells make an enzyme called endothe4. Helping immune system cells to kill infections lial n it r i c ox i d e s y nt h a s e ( E NO S ) . 5 8 L- arg i and stop some cancer cells from dividing42 n i ne supplementation has been shown to help the blood vessel to produce nitric oxide. 59 L-arginine 5. Improving memory function43-45 helps improve endothelial function in both animal 6. Stimulating erections in men with erectile models and in humans with hypercholesterolemia dysfunction46-56 and with atheroslerosis. 6 ” 5 Clinical trials to date Lifespan Medicine Journal 2014 - Page 49

support potential clinical application of L-arginine in the treatment of coronary artery disease and peripheral artery disease as well as in the prevention of in stent restenosis.66’ 67 In the year 2000, a paper was published in The Journal of Nutrition showing that enteral or parenteral administration of L-arginine reverses endothelial dysfunction associated with major cardiovascular risk factors (hypercholesterolemia, smoking, hypertension, diabetes, obesity/insulin resistance and aging).68,69 L-arginine ameliorates many common cardiovascular disorders (coronary and peripheral artery disease, ischemia/reperfusion injury, and heart failure).65 It was felt by some scholars that dietary L-arginine supplementation may represent a potential novel nutritional strategy for the treatment of cardiovascular disease.7°A new paradigm in the treatment of heart disease is developing. In the early 1990s, approximately 70 research articles were published per year on endothelial dysfunction. By the year 2006, over 7000 articles per year were being published on this topic. The use of Larginine offers an effective new tool in the treatment of cardiovascular disease.7I-73 In todays world much emphasis has been given to the role of testosterone and estrogen. Studies have now shown that that these two hormones stimulate the making of nitric oxide .74 References 1) Zhang Y. Cardiovascular diseases in American women. Nutr Metab Cardiovasc Dis 2010;20(6):386-393. 2) Kereiakes DJ, Antman EM. Clinical guidelines and practice: in search of the truth. J Am Coll Cardiol 2006;48(6):1 129-1 135. 3) Dollery CT. Risk predictors, risk indicators, and benefit factors in hypertension. Am J Med 1987;82(1A):2-8. 4) Anderson TJ, Gerhard MD, Meredith IT et al. Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol 1995;75(6):71B-74B. 5) Burkhard-Meier C, Schneider TI, Baer FM. [Is endothelial dysfunction of practical relevance?]. MMW Fortschr Med 2004;146(31-32):38-40. 6) Conger JD. Endothelial regulation of vascular tone. Hosp Pract (Off Ed) I994;29(10):117-6. 7) Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004;109(23 Suppl 1):11127- 11132. 8) Fields CE, Makhoul RG. Vasomotor tone and the role of nitric oxide. Semin Vasc Surg 1998;11(3):181-192. 9) Guerci B, Kearney-Schwartz A, Bohme P, Zannad F, Drouin P. Endothelial dysfunction and type 2 diabetes. Part 1: physiology and methods for exploring the endothelial function. Diabetes Metab 2001;27(4 Pt 1):425-434. 10) Zhang WZ, Venardos K, Chin-Dusting J, Kaye DM. Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress. Hypertension 2006;48(2):278-

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Chitosan 3% added to NACL (symbiosal®) decreases its hypertensive effect : results from a double-blind, randomized, crossover, controlled clinical trial conducted versus placebo in mild or moderate hypertensive patients F.A. Allaert Head of the Chair of Health Claim Medical Evaluation ESC & Cen Nutriment Dijon France (from International Angiology, February 2013 ; vol 32 n°1 : 94-101.) One of the main difficulties in reducing salt intake is that the single largest source is in industrially processed food, which has become so prominent in the modern diet. Any change will require the active involvement of the food industry. Even so, cutting down on the amount of salt we add to our meals must not be viewed as a negligible way of reducing hypertension. For patients with borderline hypertension this is an important part of the changes they must make to their lifestyle and diet before resorting to any pharmacological treatment.

and G.Y. Kim [3] in experimental conditions in rats. It reportedly inhibits the increase in ACE induced by an acute salt intake.

All these results suggest that adding chitosan could be an effective way to lower the hypertensive effect of a restricted but hardly avoidable consumption of NaCl by hypertensive patients. The primary objective of this cross over randomised double blind placebo controlled clinical study was to investigate whether, when it is used in conjunction with lifestyle alterations and with equal levels of compliance in restricting added salt to 3 g per day, chitosan salt developed by a specific process (Symbiosal) might contribute to The main difficulties in cutting down on salt are resist- a greater reduction of SBP and DBP than standard sea ance because of gastronomic culture and the unavoid- salt (NaCl) and therefore to better control over hyperable repercussions on the patient’s family meals. An tension, thereby averting or postponing any need for alternative to salt reduction has long been to propose antihypertensive treatment. a substitute for NaCl salt. Because the predominant Methods and results opinion used to be that pressor ‘sensitivity’ to NaCl Forty outpatients were screened and randomized in depends essentially on its Na+ component, KCl was the trial in France (13 centres). The study was concommonly proposed as a substitute. However, recent ducted according a cross over plan including two pework on the effect of Cl- in rats [1] challenges the pre- riods of eight weeks separated by a by a two-week vious theory, suggesting on the contrary that the Cl- washout period As a result of random attribution, 19 component of NaCl could be the main determinant subjects received the salt shakers containing NaCl in of salt sensitivity and thereby its possible phenotypic the first period and salt shakers containing Symbiosal expression by inducing renal vasoconstriction. There- in the second period (NaCl-first group) while 21 subfore an alternative would be to keep NaCl but to add jects received the salt shakers containing Symbiosal in to it a component capable of blocking or counteract- the first period and the salt shakers containing NaCl ing the hypertensive effect of Cl-. in the second period (Symbiosal-first group).. The Chitosan could be an effective candidate here. Chitosan is a polysaccharide derived from chitin, which is a major component of shellfish like shrimp and crab. It is obtained by deacetylation of the N-acetylglucosamine bond to beta 1-4glycoside.

patients were 58.6 ± 12.0 years old (32–81 years) and 60.0% of them were female. SBP and DBP were comparable between salt groups and the baseline value of SBP was 149.7 ± 4.6 mm Hg in the NaCl-first group and 149.2 ± 4.9 mm Hg in the Symbiosal-first group The effect of chitosan in reducing SBP and its relation (p= 0.7302). The baseline value of DBP was 93.3 ± 3.4 with the Cl- ion has been described by S.H. Park [2] mm Hg in the NaCl-first group and 93.4 ± 3.0 mm Lifespan Medicine Journal 2014 - Page 53

Hg in the Symbiosal-first group (p=0.9352). The con- are twice as high as with standard NaCl. According to text for discovery of hypertension was comparable be- the results of this study, recommending chitosan salt tween the treatment groups. to 2.5 patients would avoid one drug prescription. The results of this controlled, double-blind, randomized study show that, in conjunction with cardiovascular lifestyle changes such as taking physical exercise and losing weight, a reduction in salt intake to a daily dose of 3g/day of Symbiosal (NaCl + 3% chitosan) significantly contributes to reducing patients’ blood pressure and to maintaining blood pressure under control when compared with patients taking the same daily quantity of standard NaCl sea salt. The differences in the effects produced by Symbiosal and standard sea salt are significant with respectively 8.7 ± 10.8 mm Hg vs 3.2 ± 8.5 mm Hg (p=0.0156) for SBP and 7.2 ± 8.0 mm Hg vs 3.7 ± 7.4 mm Hg (p=0.0285) for DBP leading to higher percentages of blood pressure control (SBP < 140 mm Hg and DBP < 90 mm Hg): 76.2% vs 36.8% (p=0.0119) as early as the first period of the cross over (figure 1). These results also underline that cutting salt intake to 3 g per day results in the control of HBP for one-third of patients with mild HBP but that the effects obtained with Symbiosal

Conclusion Replacing traditional NaCl by Symbiosal may contribute to bringing patients’ blood pressure under control and may therefore postpone the prescription of antihypertensive drugs. Références 1) O. Schmidlin, M. Tanaka, A.W. Bollen, S.L. Yi, R.C. Morris. Chloride dominant salt sensitivity in the stroke-prone spontaneously hypertensive rat. Hypertension; 2005; 45; 867-73. 2) S.H. Park, N.K. Dutta, M.W. Baek, D.J. Kim, Y.R. Na, S.H. Seok, B.H. Lee, J.E. Cho, J.H. Park. NaCl plus chitosan as a dietary salt to prevent the development of hypertension in spontaneously hypertensive rats. J. Vet. Sci 2009, 10(2), 141-146. 3) G.T. Kim, J.H. Jng, S.K. Kim, J.E. Cho, J.M. Lee. The effects of endurance exercise and chitosan salt on blood pressure in normotensive rats. The Korean Journal of Exercise Nutrition, (2004), 8(2), 199-206.

Figure 1 Percentage of patients with blood pressure under control at the end of first period.

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DIHYDROQUERCETINE: What do you do for the health of your capillary vessels? By V Kozlov et al Indeed, this antioxidant from the family of flavonoids presents many advantages. Its origin is natural and its qualities numerous : defense against free radical attacks, stimulation of the immune system, facilitating the assimilation by the body of vitamins C and E, it’s rich in vitamin B3 or PP, and a genuine normalizing effect on cholesterol. As a result of these properties, dihydroquercetin has the ability to « clean » the deep vascular system throughout the 100 000km length of the micro-vessels that supply our bodies. The following article demonstrates this perfectly. USE OF Dihydroquercetin for THE TREATMENT of microcirculatory disorders

Through this randomized, double-blinded trial, we were able to monitor microcirculation in patients receiving dihydroquercetin. The following methods were used to assess microcirculation:

• Computerised measurement of the skin capillaries of the lower limbs. This method measured the diameter Article from Mensuel Scientifique des Médecins June of the capillaries, the length and width of the capillary 2006 loops and the distance between the capillaries. Monitoring changes to these coefficients gave the necessary Kozlov, Azizov, Britov, Gourova information on the lability of the microcirculatory Peoples’ Friendship University of Russia system, its adaptation options and the condition of The study of blood flow in the capillaries and vessels the morphological substrate of the microcirculation. is particularly useful for understanding tissue ex- • Computerised microscopy of the bulbar conjunctiva change mechanisms. It is very important for detecting vessels. Based on the study of certain indices, the folindividual differences in the pathogenesis of various lowing parameters were calculated: the BMI conjuncblood disorders and determining the sensitivity of pa- tival microcirculation index, which gives an integral tients to different drugs. characteristic of the changes in the microcirculatory Changes in blood microcirculation play an important system, and the proportion of structural and funcrole in the pathogenesis of many diseases; thus, it is tional changes to assess the percentage of essential innow crucial to find new medical preparations to im- dicators causing general microcirculatory disorders. prove microcirculation. Amongst these preparations • The Ultrasonic Doppler Flowmeter (LDF). This are those containing in their composition the vasoac- technique is based on the non-intrusive, optical meastive bioflavonoid dihydroquercetin1. urement of fluid by a monochromatic signal and an The objective of this trial is to study the influence of analysis of the frequency spectrum of mobile erythdihydroquercetin on the microcirculation of patients rocytes. During the examination, we recorded and calculated the microcirculation coefficient (MC) and with hypertension. its mean squared deviation (MSD) and the blood flow Materials and methods of the clinical trials index (BFI), which determines the proportion of low We examined 42 patients aged 50-76 years (15 men and high frequencies in the LDF. We analysed the and 27 women) with chronic hypertension (stages frequency and amplitude of the very low frequency I-II), atherosclerosis, ischemic heart disease (func- (VLF), low frequency (LF), high frequency (HF) and tional class III and IV), diabetes mellitus or other dis- characteristic frequency (CF) vibrations in the blood eases. flow. We evaluated the relationship of the different Twenty-eight patients with hypertension were includ- rhythmic components as a percentage of their spectral ed in the group receiving dihydroquercetin. During power within the broad spectrum of blood flow. treatment, they took 0.75 g of the preparation three We carried out an occlusion test to determine the retimes per day. Fourteen others received a placebo. activity of vessels as well as the functional capillary Lifespan Medicine Journal 2014 - Page 58

flow reserve (CFR).

the microcirculation. The BFI reflected the ratio of active and passive modulation of the microcirculation Treatment of patients (...) by dihydroquercetin as 1.33 ±0.07 (normally, this coefficient is more than In all patients (100% of cases), we discovered mi- 2.0). crocirculation disorders. During biomicroscopy, we noticed a structural change of the vessels as well as The occlusion test was used to assess the CFR in permeability disorders of the histogenetic barrier and the patients examined. On average, this reserve was rheological disorders. The degree of circulatory insuf- 114.2±7.7, which is 2.5 to 3 times lower than the norficiency is directly linked to the extent of hyperten- mal value. sion and other intercurrent diseases. Two basic forms Table 1 presents the analysis of the microcirculation of microcirculatory disorders were revealed: patients parameters at each stage of the disease. We found that with stage II hypertension generally had spastic and microcirculatory disorders worsened with each stage atonic disorders and during vascular contractions of of the disease and with diabetes mellitus (...) the microcirculatory network, significant changes in the venous circulation were revealed with a predominance of passive stagnation; in patients with stage III, rheological disorders predominated. During clinical trials, the conjunctival microcirculation index was conventionally 1.13± 0.04, and individual coefficients ranged from 0.56 to 1.5. In terms of structural and functional changes, structural (29.7±0.8% patients) and rheological (34.1±1.0%) changes in the microcirculation predominated. Dilation and unequal venular diameters, and increased vessel tortuosity were found most frequently. Rheological disorders were characterised by a sudden circulatory slowdown, increased granularity and aggregation of red blood cells at the point where the capillary flow stopped (focal stasis). The LDF signal increased from 1.5 to 2 times (in 91% of cases) that of healthy persons and a change in the rhythmic structure was observed in 100% of cases. The microcirculation coefficient (MC) was 23.3±0.93 perf unit (8.35 to 33.8 perf unit). The increase in the MC is linked to the increasing stagnant phenomena in the tissues causing an increase in tissue haematocrit. According to the MSD data, the BFI in these patients decreased by 40 to 45% reaching 1.68 ±0.14 perf unit, showing significant changes in the rhythmic structure of the blood tissue vibrations. From the LDF graphics, we can see clearly the decrease in the amplitude of LF vibrations (vasomotor) and an increase in the amplitude of the HF and CF vibrations. Frequency and amplitude analysis showed that the ratio of VLF in the total power spectrum of the flowmeter was 47.5±1.4% vibrations, LF is 37.7±1.0%, HF is 9.0±0.8% and CF is 5.8±0.8%. Normal VLF is generally over 50%, LF is over 40% and the contribution of HF and CF does not exceed 5% and 1%, respectively. Data from clinical trials revealed a slowdown of the “active” modulation of blood flow in tissues and strengthening of the “passive” regulatory influence on

We observed (...) an increase in rheological disorders. Thus, their impact on the conjunctival microcirculation was 33±1.5% in patients with stage II ATH, but 37.6±2.1% in patients with stage III ATH. (…) Recurrent examination of the patients after a course of dihydroquercetin (for 3 to 3.5 months) showed positive changes in blood flow. Microscopy of the bulbar conjunctiva vessels revealed an improvement in the rheological index. Blood flow velocity in the vessels increased and the granularity of erythrocytes and their aggregation decreased. In general, focal stasis points disappeared. As a result, the haemodynamic status improved: increased amount of functioning capillaries, decreased arteriole spasms, normalization of the proportion of arteriolar and venular diameters2. Structural changes of the microvessels remained, but in some cases, dilation of the capillaries and small veins decreased and their unequal diameters along the microvessel disappeared, emphasising a weakening of the stagnant phenomena. (... ) Table 2 shows the comparative characteristics of the dynamic microcirculation coefficients. Clearly, dihydroquercetin normalised microcirculation coefficients, increased the CFR and activated vasomotor mechanisms modulating the flow to the tissues. Dihydroquercetin produced a vasotropic effect, which was supported by the positive dynamic microcirculation coefficients3.

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crovessels, and activation of metabolic processes in the tissues. Dihydroquercetin treatment improves the rheological capacity of blood and intensifies the active vasomotor mechanisms of microcirculation regulation, which contributes to elimination of the stagnant phenomena in the blood network. (…) 1. Project Director S.K. Sarsania, M.D., Prof. Effects of dihydroquercetin on physical work capacity on top athletes practicing cyclic sports. Federal State Educational Institution of Higher Professionnal Training, Russian State University of Physical Education, Sport and Tourism, Sport Research Institute.

Conclusion According to our trials, dihydroquercetin has a vasotropic effect, protects the capillaries, stimulates blood flow to the tissues, stabilises the protective function of microvessels and slightly decreases capillary wall permeability4. Microcirculation activation is caused by a weakening of neurogenic influences and the regulation of mi-

2. T.Y. Il’yuchenok, A.I. Khomenko , L.M. Frigidova, and others. Immune regulation (anti-allergy effect) and anti-inflammatory activity. Pharmacology and Toxicology 1975 ; 38 (5) : 607. 3. Haraguchi H, Ohmi I, Fukuda A, et al. Inhibition of aldose reductase and sorbitol accumulation by astilbin and taxifolin dihydroflavonols in Engelhardtia chrysolepis. Biosci Biotechnol Biochem. 1997 Apr;61(4):651-4. 4. V.H. Kolkhir, N.A. Tynkavkina, V.A. Bykov and others. Dihydroquercetin – new antioxidant and capillary protector. Chemical and pharmaceutical periodical, 1995, 9 : 61-4.

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Swedish scientists unveil breakthrough finding: Kisel-10 study shows 3x Stronger hearts and less risk of dying with new treatment By Bjorn Falk Madsen A small village in Sweden has written medical history by demonstrating a method that reduces elderly people’s risk of dying of heart disease by over 50%. In June 2012 a historical event took place in a little village called Kisa in the southeast part of Sweden. A handful of leading Swedish cardiologists, professors, and doctors, presented the results of the highly unusual Kisel-10 study which they have conducted on a cross section of 443 elderly town villagers. Normally, a relatively large percentage of senior citizens in any Western population are expected to die of cardiovascular disease, the leading cause of death, but the Swedish researchers tested a whole new type of intervention that has literally defied the statistics by reducing the number of heart-related deaths by over 50%. This has never been seen before. “We are actually quite surprised ourselves,” said lead researcher, Urban Alehagen, a renowned cardiologist from Linköping University, while presenting figures to the many journalists who had turned up to hear how a village of just 4,000 inhabitants had virtually cheated the Black Reaper. How they did it “What we have done here,” Alehagen continued, “is to test a combination of two natural compounds called selenium and co-enzyme Q10. We knew from the available literature that both compounds play a role in heart health but no one has ever studied the combined effect of these two nutrients,” he said.

signs of improvement after being treated with supplements of co-enzyme Q10 (typically in the range of 100-400 mg/day). Selenium is a so-called trace element, a natural substance that is required in trace (extremely small) quantities for the upkeep of human health. It supports at least 25-30 different proteins in the human body. These selenium-dependent proteins (selenoproteins) are involved in various body functions ranging from immune defense to fertility and fighting off inflammation. • Research has demonstrated an inverse correlation between selenium status and cardiovascular disease For a little more than five years, the volunteers were randomly assigned to daily supplements of 200 micrograms of selenium (SelenoPrecise, Pharma Nord) and 200 mg of co-enzyme Q10 (Bio-Q10, Pharma Nord), or identical placebo pills, in addition to their normal heart medicine. RESULTS: Three times stronger hearts The results of this unorthodox intervention was a 54 % lower risk of cardiovascular mortality among the selenium and co-enzyme Q10-treated men and women and the researchers even observed other improvements.

Those given the active treatment had 30% lower blood levels of NT-proBNP, which is a marker of a “stressed heart”. In other words, something indicated that their hearts worked more efficiently. This was underpinned by a third surprising finding. The scientists discovered by means of ultrasound (echocardiography) that the EF, ejection fraction, significantly improved. In other words: the heart muscles in the supplemented elderly people worked better. The treatment had quite simply • A number of published studies have shown that pa- made their hearts stronger. tients with chronic heart failure (CHF) show distinct Coenzyme Q10 – also known as ubiquinone – is a vitamin-like compound that is present in all human cells. It is a vital element of cellular energy metabolism, a process in which fat, carbohydrate, and protein are converted into ATP (adenosine triphosphate) in the mitochondria (cellular powerhouses). ATP is energy stored in its molecular form, ready for use in various energy-dependent processes in the body.

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More research needed Although the researchers were positively surprised with their findings, they do realize that it is too early to break out the champagne. Professor Ulf Dahlström, Linköping University, who is one of Sweden’s most experienced cardiologists and part of the research group that undertook the Kisel_10 Study said: “We would like very much to repeat this study on a much larger group of people, possibly even on individuals who are slightly younger. We cannot draw final conclusions from one study only so it is necessary to conduct more studies in the future.” Over 400 elderly Swedish men and women took part in a highly untraditional study, headed by a handful of professors and doctors. A significant reduction by 54% of cardiovascular mortality in the Q10/Se-group (5.9% vs. 12.6%; P=0.015).

Source: Alehagen U, et al. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and co-enzyme Q10 supplementation. Int J Cardiol. 2012. E-pub ahead of print.

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See a video on the quality of Pharma Nord Q10 at http://youtu.be/XvvSeXQ4dlA Lifespan Medicine Journal 2014 - Page 64

Safe and Effective Weight Loss with the Protein Diet By Dr Ignacio Sajoux The Protein Diet is defined as a Very-Low-Calorie Diet, which reduces carbohydrate and fat intake, while maintaining the level of protein the organism needs; this avoids loss of muscle mass during slimming. Its efficacy and safety for weight loss have been evaluated in a study conducted by the Gregorio Marañón Hospital in Madrid coordinated by Dr. Basilio Moreno, Head of Endocrinology and Nutrition and National Coordinator of the NAOS Strategy (Strategy for Nutrition, Physical Activity and the Prevention of Obesity). The main objective of the study was to evaluate the differences in weight loss among obese patients following a multidisciplinary method based on a protein diet compared to those on a low-calorie diet. The information obtained after twelve months confirms that with the Protein Diet, patients lose nearly three times more weight and waist circumference than with a low-calorie diet. Equally as important, the Protein Diet helps patients to maintain this weight loss in the long term. Introduction to the Study The Study is an open, controlled, randomized (1:1), prospective (2 years of patient monitoring), single centre clinical trial to evaluate the effectiveness of the Protein Diet (PD group) vs. a low-calorie diet (LCD group) for weight loss in obese patients. Patients who had completed the first 12-month monitoring period (27 patients for the PD group and 26 for the LCD group were analyzed). Patients attended 8 control visits (baseline, 15 days, 2, 4, 6, 8, 10 and 12 months). At each visit, in addition to measuring weight and related parameters (waist circumference, BMI), the doctor evaluated the patient’s body composition using DEXA (Dual-Emission X-ray Absorptiometry), checked blood pressure and discussed possible adverse effects and the degree of adherence to the prescribed diet. At the 15-day and at the 2-, 4-, 8- and 12-month check-ups, lab tests were done including blood sugar levels, glycated haemoglobin (HbA1c), lipids and an ionogram. During the 6- and 12-month visits, the patients rated their degree of satisfaction with the diet on a scale of 1 to 5 (1=very dissatisfied, 2=dissatisfied, 3=indifferent, 4=satisfied, 5=very satisfied). The evolution of clinical and analytical parameters were studied for each group using Student’s t-test for related samples, and results between groups were compared using Student’s t-test for unrelated samples.

Weight Loss at the Expense of Fat Mass Weight loss throughout the study was statistically significant as compared to the baseline values of the group treated with the Protein Diet (PD), beginning at the 2-month control visit, while weight loss in the LCD group was insignificant compared to the baseline. At each control visit, observed weight loss was significantly superior in the group being treated with PD (p<0.001 vs. LCD).

The total amount of weight lost after 12 months was nearly three times greater for the PD group, with a loss of -19.92 kg vs. -7.02 kg for the low-calorie diet group (LCD) (p<0.001 between groups). In determining changes in body composition using DEXA, it was found that only 7.35% of the weight lost by the PD group was lean mass, while this figure was as high as 22.05% for the LCD group. This means that the PD group lost a total of 18.44 kg of fat mass, vs. 5.48 kg for the LCD group. These results corroborate the hypothesis that the weight lost by patients treated with the Protein Diet is to a large extent fat mass, and lean mass is preserved almost in its entirety. This weight loss led to a BMI reduction which situated the PD group outside the range of obesity (BMI>30) after two months of treatment. The baseline value for

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the PD group was 35.11 and for the LCD group, 35.18. Following one year of treatment, the average BMI for the PD group is 28.06, while the LCD group registers an average of 32.51, still well above the obesity threshold.

Greater Reduction in Waist Circumference With a baseline value of 111.31 cm for the PD group and 108.25 for the LCD group, waist circumference reduction was statistically superior in the PD group at each control visit. This group saw an average reduction in waist circumference of -18.42 cm (92.89 cm waist circumference) after 12 months of treatment, compared to the average -7.02 cm lost (101.23 cm) by the LCD group (p<0.001 between groups). Given that with the PD the loss of fat mass is far greater than the reduction of lean mass, the significant reduction in waist circumference proves that this treatment attacks primarily the intra-abdominal fat, which is metabolically active and harmful to our bodies.

High Level of Satisfaction This clinical trial also evaluated the level of patient satisfaction with the treatment they received. Patients rated their level of satisfaction on a scale of 1 to 5 during their 6 and 12-month control visits. The Protein Diet obtained better results than the low-calorie diet in this area as well. After one year in treatment, 26.7% of LCD patients said they were “very satisfied” and 61.54% ”satisfied” with their diet. In the PD group, the percentage of patients who were “very satisfied” reached 40.74%, with 51.85% of PD patients stating that they felt “satisfied”. Only 7.41% of PD patients were indifferent about the results obtained with the Protein Diet, and no one claimed to be “unsatisfied” or “very unsatisfied”. The Study has also taken account of the safety and tolerability of treatment with the Protein Diet for obese and overweight patients, and it has been observed that side effects are mild and transitory. Scientific Publication The results of the Study describe the Protein Diet as a highly useful therapeutic tool for the treatment of obesity and overweight and associated problems. The study has been presented in several international forums with the aim of demonstrating the available scientific evidence.

This was the case at the 19th European Congress of Obesity (ECO), held from 9 – 12 May in the French The lipid profile of patients in the PD group has city of Lyon, with the participation of experts and aualso improved significantly as compared to the LCD thorities in overweight and obesity. group. Starting with an average baseline total cholesterol count of 207.15 mg/dL, the PD group reduced The aim of this year’s conference, which was attended their count to 193.24 mg/dL. Patients in the LCD by more than 2,500 doctors from 80 countries, was group reduced their cholesterol count from a starting to present and debate new perspectives in addressing average of 185.88 mg/dL to 183.96 mg/dL one year overweight and obesity in Europe, as well as the prevlater. Further, regarding this average reduction of to- alence of associated comorbidities. It was here that Dr. tal cholesterol (6.71% in the PD group and 1.03% in Maria Dolores Saavedra, a researcher with the Obesity LCD group), LDL-c lab tests show an average re-duc- Unit at Gregorio Marañón General University Hospition of 11.49% for the PD group, with a mere 1.75% tal in Madrid and trainer in the PronoKal® Method, reduction for the LCD group. HDL-c increased by gave a conference in which she presented these initial 12.88% for the PD group, while the increase for the results to the scientific community. LCD group was only 4.40%. Similarly, in the latest edition of the congress (ECO Average baseline triglyceride values for the PD in- 2013 held in Liverpool) the results of a yearlong study creased by 12.88% for the PD group, while the increase were presented. Improved Laboratory Test Results

for the LCD group was only 4.40%. Average baseline triglyceride values for the PD group dropped from 96.77 mg/dL to 87.96 mg/dL, a reduction of 9.10%, while the LCD group reduced their values from 137.7 mg/dL to 89.36 mg/dL one year later, a 35.11% decrease.

Conclusions of the Study: After 12 months

End weight varied significantly between the two groups, with a greater decrease in the group treated with the Protein Diet: •Average weight loss of the PD group: 19.88 kg

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•Average weight loss of the low-calorie diet group: 7.02 kg As a percentage of total weight loss, lean mass represents: •Only 7.38% for the PD group •22.05% for the LCD group And in fat mass this means: •92.62% for the PD group •Only 77.95% for the LCD group

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Testosterone therapy in women: Myths and misconceptions Rebecca Glaser a, b, Constantine Dimitrakakis c, d Millennium Wellness Center, 228 E. Spring Valley not increase aggression, T is breast protective, and the Road, Dayton, Ohio 45458 USA safety of T therapy in women is under research and b Wright State University Boonshoft School of Med- being established. a

icine, Department of Surgery, 3460 Colonel Glenn Abandoning myths, misconceptions and unfounded Highway, Dayton, Ohio 45435 concerns about T and T therapy in women will enable c 1st Department of Ob/Gyn, Athens University Med- physicians to provide evidenced based recommendaical School, 80 Vas. Sophias Street, 11528, Athens, tions and appropriate therapy. Greece

1.0

National Institutes of Health, NICHD, Bldg 10, 10 Center Drive, Bethesda, MD 20892-1103

Introduction

RG rglaser@woh.rr.com, rglasermd@gmail.com CD dimitrac@ymail.com Corresponding author Rebecca Glaser 228 E. Spring Valley Road Dayton, Ohio 45458 USA

Testosterone (T) therapy is being increasingly used to treat symptoms of hormone deficiency in pre and postmenopausal women. Recently, especially with the advent of the T patch, additional research has been, and is currently being conducted on the safety and efficacy of T therapy. However, particularly in the United States (U.S.), there still exist many misconceptions about T and T therapy in women. This review addresses and provides evidence to refute some of the most common myths.

A major source of misconceptions regarding T therapy in women arises from epidemiological studies Keywords: Testosterone, implants, women, therapy, implicating elevated (endogenous) T levels with cersafety, misconceptions tain diseases. This data is misleadingly delivered to Abbreviations: Testosterone (T), Estradiol (E2), dihy- produce a pathogenic model of these diseases without drotestosterone (DHT), United States (U.S.), Andro- enough evidence, or plausibility, to support a causative role. False conclusions repeated often enough, esgen receptor (AR), Estrogen receptor (ER), pecially when supported with anecdotal observations, Abstract create â&#x20AC;&#x2DC;mythsâ&#x20AC;&#x2122; that become widely accepted, even in Although testosterone therapy is being increasingly the absence of any biological or physiological rationprescribed for men, there remain many questions and ale. concerns about testosterone (T) and in particular, T Another source of confusion concerning the safety therapy in women. A literature search was performed of T therapy in both men and women is the extrapto elucidate the origin of, and scientific basis behind olation of adverse events (e.g., mental status changmany of the concerns and assumptions about T and T es, aggression, cardiac and liver problems, endocrine therapy in women. disturbances, abuse potential) from high doses of This paper refutes 10 common myths and misconcep- oral and injectable anabolic-androgenic steroids to tions, and provides evidence to support what is phys- T therapy, despite a lack of evidence. In this review, iologically plausible and scientifically evident: T is the testosterone (T) refers only to bio-identical (human most abundant biologically active female hormone, T identical molecule) testosterone, not to oral, synthetic is essential for physical and mental health in women, androgens or anabolic steroids. T is not masculinizing, T does not cause hoarseness, In England and Australia, T is licensed and has been T increases scalp hair growth, T is cardiac protective, used in women for over 60 years. However, as of 2013, parenteral T does not adversely affect the liver or inin the U.S. there is no licensed T product for women crease clotting factors, T is mood stabilizing and does PH: 937 436-9821

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and human/bio identical T is regulated as a ‘schedule 3’ drug and included as a ‘class X’ teratogen. 2.0 ‘Top 10’ myths about testosterone use in women 2.1 Myth: Testosterone is a ‘male’ hormone

women and aging men, may experience symptoms of androgen deficiency including dysphoric mood (anxiety, irritability, depression), lack of well being, physical fatigue, bone loss, muscle loss, changes in cognition, memory loss, insomnia, hot flashes, rheumatoid complaints, pain, breast pain, urinary complaints, incontinence as well as sexual dysfunction. These symptoms of androgen deficiency are becoming increasingly recognized in women, and treated with T therapy [5,6,7]. Rating scales for symptoms of androgen deficiency have been developed in an effort to standardize severity of symptoms and to measure treatment effectiveness. Functional, biologically active, ARs are located throughout the body in both sexes: to assume that androgen deficiency does not exist in women, or that T therapy should not be considered in women, is unscientific and implausible.

Even in scientific publications, T has been referred to as the ‘male hormone’. Men do have higher circulating levels of T than women; however, quantitatively, T is the most abundant active sex steroid in women throughout the female lifespan (Fig. 1) [1]. T is measured in 10 fold higher units than estradiol (E2), i.e., nanograms/dl or micromolars compared to picograms/ml or picomolars for E2. In addition, there are exponentially higher levels of proandrogens: dihydroepiandrosterone sulfate (DHEAS), dihydroepiandrosterone (DHEA) and androstenedione, supplying significant amounts of T to the androgen receptor (AR) Fact in both sexes. In fact, the measured ranges of andro- Testosterone is essential for women’s physical and gen precursors are similar in men and women. mental health and wellbeing Despite any clear rationale, estrogen was assumed to 2.3 be the hormone of ‘replacement therapy’ in women. However, as early as 1937, T was reported to effectively Myth: Testosterone masculinizes females treat symptoms of the menopause [2]. From a biolog- It has been recognized for over 65 years, that T effect ic perspective, women and men are genetically simi- is dose dependent and that in lower doses, T ‘stimular, having both functional estrogen receptors (ERs) lates femininity’ [8]. Although pharmacologic doses and functional androgen receptors (ARs). Interesting- of T and supra-pharmacological doses of T used to ly, the AR gene is located on the X chromosome. T, treat female to male transgender patients, may result in balance with lower amounts of E2, is equally im- in increased facial hair growth, hirsutism, and slight portant for health in both sexes. In addition, T is the enlargement of the clitoris; true masculinization is not major substrate for E2 and has a secondary effect in possible. Unwanted androgenic side effects are reversboth sexes via the ER. ible by lowering the T dose: however, because of the dose dependent beneficial effects of T, many women Fact prefer to treat the side effects rather than lower the Testosterone is the most abundant biologically active dose [9,10]. hormone in women As previously mentioned, in the U.S. androgens are 2.2 listed as a ‘class X’ teratogen. Although 400-800 mg/d Myth: Testosterone’s only role in women is sex drive of danazol, a potent synthetic androgen, can result in clitoromegaly and fused labia (without long term efand libido fects) in some female fetuses; there is no evidence that Despite many recent publications, T’s role in sexuT, delivered by pellet implant (i.e., a daily dose of 1-2 al function and libido is only a small fraction of the mg) or topical T has any adverse effect on a fetus, even physiologic effect of T in women. Functional AR’s in animal studies [11,12]. Animal studies have shown are located in almost all tissues including the breast, that virilization of a female fetus requires extremely heart, blood vessels, gastrointestinal tract, lung, brain, high doses of T (> 30 times normal maternal levels, > spinal cord, peripheral nerves, bladder, uterus, ova50-500 times ‘human’ T doses) administered over an ries, endocrine glands, vaginal tissue, skin, bone, bone extended period of time [12,13,14]. marrow, synovium, muscle and adipose tissue [3,4]. There is a significant rise in (endogenous) maternal T Testosterone and the pro-androgens decline gradually levels during pregnancy, up to 2.5 to 4 times non-pregwith aging in both sexes. Pre and post-menopausal nancy ranges. However, the placenta buffers hormone Lifespan Medicine Journal 2014 - Page 70

diffusion and is a source of abundant aromatase, which metabolizes maternal T [15,16]. T stimulates ovulation, increases fertility and has been safely used in the past to treat nausea of early pregnancy without adverse effects [8].

2.5 Myth: Testosterone causes hair loss

There is no evidence that T or T therapy is a cause of hair loss in either men or women. Although men do have higher T levels than women, and men are more Fact likely to have hair loss with age, it is unreasonable to Outside of supra-pharmacologic doses of synthetic assume that T, an anabolic hormone, causes hair loss. androgens, testosterone does not have a masculiniz- Hair loss is a complicated, multifactorial, genetically ing effect on females or female fetuses. determined process that is poorly understood. Dihydrotestosterone (DHT), not T, is thought to be the ac2.4 tive androgen in male pattern balding. Female ‘androMyth: Testosterone causes hoarseness and voice genic’ alopecia refers to a (male) pattern of hair loss in changes. women, rather than the etiology. Hoarseness is common, affecting nearly 30% of per- Although some women with PCOS and insulin resons at some point in their life, with 6.6% of the adult sistance have higher T levels, and do have hair loss, population affected at any given time. Hoarseness is this does not prove causation. Hair loss is common in more prevalent in women than men. Most common both women and men with insulin resistance [20,21]. causes of hoarseness are inflammatory related chang- Obesity and insulin resistance increase 5-alpha rees due to allergies, infectious or chemical laryngi- ductase, which increases conversion of T to DHT in tis, reflux esophagitis, voice over-use, mucosal tears, the hair follicle [22]. Also, obesity, age, alcohol, medmedications and vocal cord polyps. There is no ev- ications and sedentary lifestyle increase aromatase idence that T causes hoarseness. In addition, there activity, lowering T and raising E. Increased DHT, is no physiological mechanism by which T could be lowered testosterone, and elevated estradiol levels can expected to do so. T deficiency is listed as a ‘cause’ contribute to hair loss in genetically predisposed men of hoarseness [17]. Physiologically, this is consistent and women; as can many medications, stress and nuwith the anti-inflammatory properties of T. tritional deficiencies. Although a few anecdotal case reports and small Approximately one third of women experience hair questionnaire studies have reported an association loss and thinning with aging, coinciding with T debetween 400-800 mg/d of danazol and self-reported, cline. We have previously reported that two thirds of subjective voice ‘changes’ [17,18]; a prospective, ob- women treated with subcutaneous T implants have jective study demonstrates the opposite. 24 patients scalp hair re-growth on therapy. Women who did not receiving 600 mg of danazol therapy daily were stud- re-grow hair on testosterone were more likely to be ied at baseline, 3 months and 6 months. The authors hypo or hyperthyroid, iron deficient or have elevatreported that there were no vocal changes that could ed body mass index. In addition, none of 285 patients be attributed to the androgenic properties of danazol treated for up to 56 months with subcutaneous T ther[19]. This is consistent with the findings of our cur- apy complained of hair loss, despite pharmacologic rent, 1 year, prospective study examining voice chang- serum T levels on therapy [10]. es on pharmacologic doses subcutaneous T implant Fact therapy in women (under publication). Although high doses of anabolic steroids in female Testosterone therapy increases scalp hair growth in rats can cause irreversible vocal cord changes, there is women

no evidence that this is true for T replacement doses 2.6 in humans. If a patient experiences voice changes or Myth: Testosterone has adverse effects on the heart hoarseness on T therapy, a standard workup should be performed. Men have higher levels of testosterone than women: men have a higher incidence of heart disease; howevFact er, it is illogical to assume that T causes or contributes There is no conclusive evidence that testosterone to cardiovascular (CV) disease in either sex. Unlike therapy causes hoarseness or irreversible vocal cord anabolic and oral, synthetic steroids, there is no evchanges in women idence that T has an adverse effect on the heart. In Lifespan Medicine Journal 2014 - Page 71

addition, it is not physiologically plausible.

2.8

There is overwhelming biological and clinical evidence that T is cardiac protective [23]. T has a beneficial effect on lean body mass, glucose metabolism and lipid profiles in men and women; and has been successfully used to treat and prevent CV disease and diabetes [24]. T acts as a vasodilator in both sexes, has immune-modulating properties that inhibit atheromata, and has a beneficial effect on cardiac muscle [25-27].

Myth: Testosterone causes aggression

Low T in men is associated with an increased risk of heart disease and mortality from all causes [28,29]. In addition, low T is an independent predictor of reduced exercise capacity and poor clinical outcomes in patients with heart failure. Similar to men, T supplementation has been shown to improve functional capacity, insulin resistance and muscle strength in women with congestive heart failure [30]. Testosterone is a diuretic. However, T can aromatize to E2, which can have adverse effects including edema, fluid retention, anxiety, and weight gain. Medications, including statins and anti-hypertensives, increase aromatase activity and elevate E2, indirectly causing side effects from T therapy. Fact There is substantial evidence that testosterone is cardiac protective and that adequate levels decrease the risk of cardiovascular disease 2.7 Myth: Testosterone causes liver damage Although high doses of oral, synthetic androgens (e.g. methyl-testosterone) are absorbed into the entero-hepatic circulation and adversely affect the liver; parenteral T (i.e., subcutaneous implants, topical patch) avoids the entero-hepatic circulation and bypasses the liver. There are no adverse affects on the liver, liver enzymes or clotting factors [31]. Non-oral T does not increase the risk of deep venous thrombosis or pulmonary embolism unlike oral estrogens, androgens and synthetic progestins. Despite the concern over liver toxicities with anabolic steroids and oral synthetic androgens, there are only 3 reports of hepatocellular carcinoma in men treated with high doses of oral synthetic methyl testosterone. Even benign tumors (adenomas) were exceedingly rare with oral androgen therapy. Fact Non-oral testosterone does not adversely affect the liver or increase clotting factors

Although anabolic steroids can increase aggression and rage, this does not occur with T therapy. Even supra-pharmacologic doses of intramuscular T undecanoate do not increase aggressive behavior [32]. As previously mentioned, T can aromatize to E2. There is considerable evidence in a wide variety of species, that estrogens, not T, play a major role in aggression and even hostility through action at ER alpha [33,34]. In women, we previously reported that subcutaneous T therapy decreased aggression, irritability and anxiety in over 90% of patients treated for symptoms of androgen deficiency [5]. This is not a new finding: androgen therapy has been used to treat PMS for over 60 years. Fact Testosterone therapy decreases anxiety, irritability and aggression 2.9 Myth: Testosterone may increase the risk of breast cancer As early as 1937 it was recognized that breast cancer was an estrogen sensitive cancer; that T was ‘antagonistic’ to estrogen and could be used to treat breast cancer as well as other estrogen sensitive diseases including breast pain, chronic mastitis, endometriosis, uterine fibroids and dysfunctional uterine bleeding [8]. However, some epidemiological studies have reported an association between elevated androgens and breast cancer. Notably, these studies suffer from methodological limitations, and more importantly, do not account for associated elevated E2 levels and increased body mass index. In addition, the ‘cause and effect’ interpretation of these inconsistent observational studies conflicts with the known biology of T’s effect at the AR. AR signaling exerts a pro-apoptotic, anti-estrogenic, growth inhibiting effect in normal and cancerous breast tissue [35,36]. Clinical trials in primates and humans have confirmed that T has a beneficial effect on breast tissue by decreasing breast proliferation and preventing stimulation from E2 [37,38]. It is the T/E2 ratio, or the balance of these hormones that is breast protective. T does not increase, and likely lowers the risk of breast cancer in women treated with estrogen therapy [39]. Although T is breast protective, it can aromatize to E2 and have a secondary, stimulatory effect via estrogen

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receptor (ER) alpha. T combined with an aromatase inhibitor (subcutaneous implant) has been shown to effectively treat androgen deficiency symptoms in breast cancer survivors and is currently being investigated in a U.S. national cancer study as potential therapy for these symptoms; as well as, aromatase induced arthralgia [40,41]. Fact Testosterone is breast protective and does not increase the risk of breast cancer 2.10 Myth: The safety of testosterone use in women has not been established There are many excellent reviews on the safety of parenteral T therapy in women [6,7]. Testosterone implants have been used safely in women since 1938. Long-term data exists on the efficacy, safety and tolerability of doses of up to 225 mg in up to 40 years of therapy [9,42]. In addition, long term follow up studies on supra-pharmacologic doses used to ‘female to male’ transgender patients report no increase in mortality, breast cancer, vascular disease or other major health problems [43,44]. Many of the side effects and safety concerns attributed to T are from oral formulations, or are secondary to increased aromatase activity, subsequent elevated E2 and its effect at the ER. Aromatase activity increases with age, obesity, alcohol intake, insulin resistance, breast cancer, medications, drugs, processed diet and sedentary lifestyle. Although often overlooked or not addressed in clinical studies, monitoring aromatase activity and symptoms of elevated E2, is critical to the safe use of T in both sexes. Fact

Figure 1. Throughout the female lifespan, testosterone (T) is the most abundant active steroid. T levels are significantly higher than estradiol (E2) levels, adapted from ref. [1]. References Dimitrakakis C, Zhou J, Bondy CA. Androgens and mammary growth and neoplasia. Fertility and sterility. 2002;77:26-33. Salmon, UJ. Effect of testosterone propionate upon gonadotropic hormone excretion and vaginal smears of human female castrate. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, NY). 1937;3:488-91. Takeda H, Chodak G, Mutchnik S, Nakamoto T, Chang C. Immunohistochemical localization of androgen receptors with mono-and polyclonal antibodies to androgen receptor. J Endocrinol. 1990;126:17-25. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Molecular and cellular endocrinology. 1996;120:51-57. Glaser R, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas. 2011;68:355-61. Maclaran K, Panay N. The safety of postmenopausal testosterone therapy. Women’s Health. 2012;8:263-75. Davey DA. Androgens in women before and after the menopause and post bilateral oophorectomy: clinical effects and indications for testosterone therapy. Women’s Health. 2012;8:437-46. Loeser AA. Male hormone in gynaecology and obstetrics and in

The safety of non-oral testosterone therapy in wom- cancer of the female breast. Obst & Gynec Surv. 1948;3:363-81. en is well established, including long-term follow up Glaser R, Kalantaridou S, Dimitrakakis C. Testosterone im3.0 plants in women: Pharmacological dosing for a physiologic effect. Maturitas. Article in Press, p.6.

Conclusion Adequate T is essential for physical, mental and emotional health in both sexes. Abandoning myths, misconceptions and unfounded concerns about T and T therapy in women will enable physicians to provide evidence based recommendations and appropriate therapy. Figures

Glaser RL, Dimitrakakis C, Messenger AG. Improvement in scalp hair growth in androgen-deficient women treated with testosterone: a questionnaire study. British Journal of Dermatology. 2012;166:274-8. Brunskill PJ. The effects of fetal exposure to danazol. BJOG.1992;99:212-215. Tarttelin MF. Early prenatal treatment of ewes with testosterone completely masculinises external genitalia of female offspring but has no effects on early body weight changes. Acta endocrinologica. 1986;113:153-160. Wolf CJ, Hotchkiss A, Ostby JS, LeBlanc GA, Gray LE. Effects of prenatal testosterone propionate on the sexual development

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of male and female rats: a dose-response study. Toxicological Sciences. 2002;65:71-86. Hotchkiss AK, Lambright CS, Ostby JS, Parks-Saldutti L, Vandenbergh JG, Gray LE. Prenatal testosterone exposure permanently masculinizes anogenital distance, nipple development, and reproductive tract morphology in female Sprague-Dawley rats. Toxicological sciences. 2007;96:335-345. Mizuno M, Lobotsky J, Lloyd CW, Kobayashi T, Murasawa Y. Plasma androstenedione and testosterone during pregnancy and in the newborn. Journal of Clinical Endocrinology & Metabolism. 1968;28:1133-1142. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clinical pharmacokinetics. 2004;43:487-514.

coronary heart disease. Heart. 2010;96:1821-1825. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. Journal of Clinical Endocrinology & Metabolism. 2008;93:68-75. Iellamo F, Volterrani M, Caminiti G et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. Journal of the American College of Cardiology. 2010;56:1310-1316. Handelsman DJ, Conway AJ, Howe CJ, Turner L, Mackey MA. Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. Journal of Clinical Endocrinology & Metabolism. 1996;81:4113-4121.

Schwartz SR, Cohen SM, Dailey SH et al. Clinical practice guideline: hoarseness (dysphonia). Otolaryngology-head and neck surgery. 2009;141:S1-S31.

O’Connor DB, Archer J, Wu FCW. Effects of testosterone on mood, aggression, and sexual behavior in young men: a double-blind, placebo-controlled, cross-over study. Journal of Clinical Endocrinology & Metabolism. 2004;89:2837-2845.

Pattie MA, Murdoch BE, Theodoros D, Forbes K. Voice changes in women treated for endometriosis and related conditions: the need for comprehensive vocal assessment. Journal of voice. 1998;12:366-371.

Trainor BC, Kyomen HH, Marler CA. Estrogenic encounters: how interactions between aromatase and the environment modulate aggression. Frontiers in neuroendocrinology. 2006;27:170179.

Nordenskjöld F, Fex S. Vocal effects of danazol therapy. Acta Obstetricia et Gynecologica Scandinavica. 1984;63:131-132.

Giammanco M, Tabacchi G, Giammanco S, Di Majo D, La Guardia M. Testosterone and aggressiveness. Medical science monitor: international medical journal of experimental and clinical research. 2005;11:RA136.

Arias-Santiago S, Gutiérrez-Salmerón MT, Castellote-Caballero L, Buendía-Eisman A, Naranjo-Sintes R. Androgenetic alopecia and cardiovascular risk factors in men and women: a comparative study. Journal of the American Academy of Dermatology. 2010;63:420-429. Matilainen V, Laakso M, Hirsso P, Koskela P, Rajala U, Keinänen-Kiukaanniemi S. Hair loss, insulin resistance, and heredity in middle-aged women. A population-based study. European Journal of Cardiovascular Risk. 2003;10:227-231. Tomlinson JW, Finney J, Hughes BA, Hughes SV, Stewart PM. Reduced glucocorticoid production rate, decreased 5α-reductase activity, and adipose tissue insulin sensitization after weight loss. Diabetes. 2008;57:1536-1543. Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis. 2009;207:318. Møller J, Einfeldt H. Testosterone Treatment of Cardiovascular Diseases: Principles and Clinical Experience. Springer-Verlag; 1984;1-83. Rosano GMC, Leonardo F, Pagnotta P et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation. 1999;99:1666-1670. Worboys S, Kotsopoulos D, Teede H, McGrath B, Davis SR. Evidence that parenteral testosterone therapy may improve endothelium-dependent and-independent vasodilation in postmenopausal women already receiving estrogen. Journal of Clinical Endocrinology & Metabolism. 2001;86:158-161. Malkin CJ, Pugh PJ, West JN, van Beek EJR, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. European heart journal. 2006;27:57-64. Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with

Hickey TE, Robinson JLL, Carroll JS, Tilley WD. Minireview: The Androgen Receptor in Breast Tissues: Growth Inhibitor, Tumor Suppressor, Oncogene? Molecular Endocrinology. 2012;26:1252-1267. Eigėlienė N, Elo T, Linhala M, Hurme S, Erkkola R, Härkönen P. Androgens Inhibit the Stimulatory Action of 17β-Estradiol on Normal Human Breast Tissue in Explant Cultures. Journal of Clinical Endocrinology & Metabolism. 2012;97:E1116-E1127. Hofling M, Hirschberg AL, Skoog L, Tani E, Hägerström T, von Schoultz B. Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women. Menopause. 2007;14:183-190. Dimitrakakis C, Zhou J, Wang J et al. A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause. 2003;10:292-298. Dimitrakakis C, Jones RA, Liu A, Bondy CA. Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause. 2004;11:531-535. Glaser R. Subcutaneous testosterone-anastrozole implant therapy in breast cancer survivors. American Society of Clinical Oncology Breast Cancer Symposium. 2010:D:221. A221102, Randomized Double-Blind Placebo Controlled Study of Subcutaneous Testosterone in the Adjuvant Treatment of Postmenopausal Women with Aromatase Inhibitor Induced Arthralgias Gambrell Jr RD, Natrajan PK. Moderate dosage estrogen-androgen therapy improves continuation rates in postmenopausal women: impact of the WHI reports. Climacteric. 2006;9:224233. Traish AM, Gooren LJ. Safety of Physiological Testosterone Therapy in Women: Lessons from Female‐to‐Male Transsexuals (FMT) Treated with Pharmacological Testosterone Therapy.

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The journal of sexual medicine. 2010;7:3758-3764.

Bethesda, MD 20892-1103

Van Staa TP, Sprafka JM. Study of adverse outcomes in women using testosterone therapy. Maturitas. 2009;62:76-80.

RG rglaser@woh.rr.com, rglasermd@gmail.com

Authors Rebecca Glaser a, b, Constantine Dimitrakakis c, d Millennium Wellness Center, 228 E. Spring Valley Road, Dayton, Ohio 45458 USA a

Wright State University Boonshoft School of Medicine, Department of Surgery, 3460 Colonel Glenn Highway, Dayton, Ohio 45435 b

1st Department of Ob/Gyn, Athens University Medical School, 80 Vas. Sophias Street, 11528, Athens, Greece c

National Institutes of Health, NICHD, Bldg 10, 10 Center Drive,

CD dimitrac@ymail.com Corresponding author Rebecca Glaser 228 E. Spring Valley Road Dayton, Ohio 45458 USA PH: 937 885-4555 Competing interest none Funding: none was secured or received for writing the review

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“A synthesis on the toxicities of GMO’s and Roundup – Studies from Prof Séralini’s group” by J.Spiroux de Vendômois & G.E Séralini University of Caen, CRIIGEN and Network on Risks, CNRS, esplanade de la Paix, 14032 Caen cedex France. criigen@unicaen.fr Abstract: Our recent studies have demonstrated hepatic, renal, and endocrine toxicity of Roundup and 19 GMOs. We also demonstrate the extreme weakness of scientific protocols and toxicological tests used by biotech and pesticide companies and safety agencies. Introduction:

of toxicity according to sex and the non-linearity of responses as a function of dose or time. This is very important for endocrine pathologies2.We followed this up by studying again 3 GMOs3, and showed variable effects according to sex, mainly hepatic and renal different for the three GMOs and lesser effects: cardiac, adrenal, spleen and haematopoietic probably due to pesticides specific to each GM maize. An international debate has begun on the health risks of dietary GMOs4, which are pesticide-plants as they are configured to tolerate herbicides or to produce insecticidal toxins. The three potential causes of health risk are the possible effects of insertional mutagenesis, interferences with metabolism or the action of pesticide residues. Toxicology tests for GMOs are not mandatory, they last only three months, are confidential and trade secrets.

For 50 years we have been seeing a considerable increase in chronic illnesses: cancers, sterility, reduction in sperm-count, hormonal, reproductive and neuro-degenerative diseases…. Could this be linked to the xenobiotic substances dumped in great quantities onto the planet for the last 70 years? We have chosen to concentrate on the impact of pesticides and agricultural GMOs which tolerate, or produce, their own pesticides. This has allowed us to demonstrate the flaws in current toxicological tests on these products. This debate questions the capability of international regulation to predict and guard against deleterious Independent expertises of industry data effects by GMOs and pesticides on health5. The apA lawsuit at the German (Munich) Court of Appeal praisal of health risks cannot omit a thorough bioin June 2005 allowed us to obtain all the biological chemical study of the blood of mammals that eat these data from toxicological tests carried out by Monsanproducts during sub-chronic and chronic tests (entire to and accepted by agencies on rats fed for 90 days life-span). At the conclusion of legal actions, we have with MON863 maize1. We analysed these data inobtained the raw data of numerous toxicology tests of dependently adding to it appropriate statistics, such 28 to 90 days on rats on a GMO diet1,3. We have had as a multivariate analysis of growth curves, and for a very close look at these tests from a biological and the biochemical parameters of comparisons between bio-statistical perspective. Through the study of our rats fed on GMOs and the control group fed with an results and the analysis of 19 studies carried out on equivalent diet containing no GMO then, separately, mammals fed on commercialised GM soy or maize, with six groups fed with different diet. The rats on we have been able to pinpoint their limits and posa diet of MON863 showed variations in bodyweight sibilities for improvement 6. Our meta-analysis of depending on the doses: weak yet significant for both in vivo studies has been published showing that the sexes, with a weight loss of 3.3% for males and weight kidneys are particularly affected, grouping together gain of 3.7% for females. The biochemical study re43.5% of all the modified parameters in males, whilst vealed signs of hepatorenal toxicity which differed bethe liver is more specifically affected in females (30.8% tween the sexes. of all abnormal parameters). Ninety-day tests are We saw that at the time of the regulatory toxicology therefore insufficient to track down chronic illnesses. studies prior to the commercialisation of pesticides or There exists no current minimum duration for these GMOs, the sum total of statistically significant biolog- tests and we suggest the imposition of two-year tests ical results is not taken into account: e.g. differences as solely capable of highlighting chronic or endocrinal Lifespan Medicine Journal 2014 - Page 76

pathologies. It is a major gamble with public health 2 μg/L were detected in him and in one of his chilarising from the lack of traceability and epidemiology dren, who lived some way from the fields, two days of GMOs. after spraying. Respiratory or skin absorption could All this has conducted us to undertake a 2-year study explain these results. Stricter instructions for use are giving rats a diet of a GM maize tolerant to Roundup necessary. (in the ratio of 11, 22, 33%), grown with or without Roundup, or given Roundup alone (dose of 0.1ppb, 400ppm, 0.5%) in drinking water to see if pre-clinical signs that show up in 90 days become pathologies7. Results for females: mortality 2 to 3 times greater and earlier manifestation than with the control group; more frequent and earlier appearing mammary tumours, the pituitary gland being the second most affected organ; sexual hormone balance disrupted by GMO and Roundup. For males: more frequent and earlier mortality in GMO groups; progressive chronic kidney disease, confirmed by light and electron microscopy 2.5 – 5.5 times more than the control group. For both sexes chronic renal failure has been biochemically confirmed, and this is highly discriminant from a statistical point of view. Endocrinal disruption due to Roundup or the over-expression of the GMO transgene could explain these results. This publication is the most detailed one in the world produced over two years for a GMO and its associated pesticide consumed in its complete formulation with its additives and in doses used in the environment. Within 48 hours vehement criticism appeared from scientists, most of whom have links to agrochemical business. From January 2013 we have answered all these criticisms8. This debate is distorted because companies’ toxicology tests are considered to be industrial secrets and therefore confidential, allowing no contradictory research. But how does all this affect humans? A farming family was spreading 1.3 tonnes of pesticides annually. They had three boys, one of whom showed stunted growth and a small atrial septal perforation; the other has a hypospadias, a micro-penis, an anal atresia and a total deficiency of growth hormone9. These observations are rare and put together with other symptoms under the name Stratton-Parker syndrome. An environmental origin (pesticides) disrupting embryogenesis cannot be ruled out. Is any other means of poisoning possible beyond the food chain? To follow this up, we tested the presence of glyphosate in the urine of all members of this family, by chromatography and mass spectrometry, the day before, on the day and the day following spraying10. The glyphosate reached a peak of 9.5 μg/L in the farmer, after spraying, and

Conclusion:

These studies show the insufficiencies and flaws in current toxicology as well as in the system for appraisal of pesticides and GMOs. Furthermore, toxicology studies should become independent of companies as a matter of urgency, and transparent to enable opposing points of view to be presented. To the bacterial hygiene of the 20th century we must add a chemical hygiene capable of protecting human and world environmental health. References: (1) Séralini, G.E., Cellier, D., Spiroux de Vendômois, J., 2007. New analysis of a rat feeding study with a genetically modified maize reveals signs of hepatorenal toxicity. Arch. Environ. Contam. Toxicol. 52, 596–602. (2) Séralini, G.E., Spiroux de Vendômois, J., Cellier, D., Sultan, C., Buiatti, M., Gallagher,L., Antoniou, M., Dronamraju, K.R., 2009. How subchronic and chronic health effect scan be neglected for GMOs, pesticides or chemicals.Int. J. Biol. Sci.5, 438-443. (3) Spiroux de Vendômois, J., Roullier, F., Cellier,D., Séralini, G.E., 2009. A comparaison of the effects of three GM corn varieties on mammalian health. Int. J. Biol. Sci.5, 706-726. (4) Spiroux de Vendômois, J., Cellier, D.,Velot,C., Clair,E., Mesnage,R., Séralini,G.E., 2010. Debate on GMOs health risks after statistical findings in regulatory tests. Int. J. Biol. Sci. 6, 590598. (5) Séralini,G.E., Spiroux de Vendômois,J., Cellier,D., Mesnage,R., Clair,E., 2010. Genetically modified crop consumption at large scale: Possible negative health impacts due to holes in assessment. Overview of the safty studies of GMOs performed on mammals. Editors : Breckling, B. and Verhoeven,R. Theorie in der ökologie 16. (6) Séralini,G.E., Mesnage,R., Clair,E., Gress,S., Spiroux de Vendômois,J., Cellier,D., 2011. Genetically modified crops safety assessments : present limits and possible improvements. Env. Sci. Europe 23, 10-20. (7) Séralini,G.E., Clair,E., Mesnage,R., Gress,S., Defarge,N., Malatesta,M., Hennequin,D., Spiroux de Vendômois,J., 2012. Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize. Food Chem. Tox. 50, 4221-4231. (8) Séralini,G.E., Clair,E., Mesnage,R., Gress,S., Defarge,N., Malatesta,M., Hennequin,D., Spiroux de Vendômois,J., 2013. Answers to critics: Why there is a long term toxicity due to a Roundup-tolerant genetically modified maize and to a Roundup herbicide. Food Chem. Toxicol. 53,461-468. (9) Mesnage,R., Clair,E., Spiroux de Vendômois,J., and Séralini,G.E., 2010. Two cases of birth defects overlapping Stratton-Parker syndrome after multiple pesticide exposure. Occup. Environ. Med. 67, 359. (10) Mesnage,R., Moesch,C., Le Grand,R., Lauthier,G., Spiroux de Vendômois,J., Gress,S., Séralini.G.E., 2012. Glyphosate exposure in a farmer’s family. J. Env. Protect. 3,1001-1003.

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Testosterone and Prostate Safety Claude Schulman, MD1, PhD and Abraham Morgentaler, MD, FACS2 1. Professor and Honorary Chairman, Department of Urology, Clinic Edith Cavell, University of Brussels, Belgium 2. Associate Clinical Professor of Surgery (Urology), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

“The great enemy of the truth is very often not the lie…. but the myth, persistent, persuasive and unrealistic.” John F. Kennedy Key words: hypogonadism, testosterone, prostate can- CONCLUSIONS: Despite the long-held belief that T cer, prostate therapy may pose an increased risk of prostate cancer, the available evidence strongly suggests that T therapy Running title: Testosterone and prostate safety is safe for the prostate. Given that the population at Corresponding author: risk for hypogonadism overlaps with the population at risk for prostate cancer, it is strongly recommendProf. Claude Schulman ed that men undergoing T therapy undergo regular Edith Cavell Clinic monitoring for prostate cancer. 32 Edith Cavell Street Introduction 1180 Brussels One of the major issues with testosterone ( T ) therBelgium apy (TTh) is the fear that raising serum T concentrations will result in an increased risk of prostate cancer profschulman@gmail.com (PCa) or will convert an occult cancer into a clinical Abstract one [1]. This fear arises from the original work by OBJECTIVE: To review the safety of testosterone (T) Huggins and Hodges, who showed in 1941 that severe therapy with regards to the prostate, with special em- lowering of T by castration or estrogen therapy resultphasis on the controversial association between tes- ed in regression of advanced PCa, and who reported also that T administration caused “enhanced growth” tosterone and prostate cancer. of PCa [2]. This work by Huggins established the anMETHODS: We reviewed the existing scientific and drogen-dependence of PCa, and later earned him the medical literature pertaining to the impact of T treatNobel Prize. ment on the prostate. To this day, androgen deprivation therapy (ADT) reRESULTS: No large-scale, long-term controlled studmains a mainstay of treatment for men with advanced ies of T therapy versus placebo have yet been perPCa, with rapid observable reductions in the serum formed to document prostate safety. However, there marker, prostate specific antigen (PSA). In addition, is a wealth of evidence from smaller clinical trials as it is well-recognized that restoration of testosterone well as population-based longitudinal studies that concentrations, such as by discontinuation of ADT fails to demonstrate any signal suggesting that T therduring intermittent treatment (IADT) results in a apy in hypogonadal adult men poses an increased rise in PSA in a substantial number of men. From risk of prostate cancer. New evidence indicates that these two current, clinical observations it is easy to exogenous T does not raise intraprostatic T or dihyunderstand why clinicians would be concerned that drotestosterone concentrations. Indeed, there is acT therapy might pose an increased risk of PCa. Curicumulating evidence that low serum T is associated ously, clinical experience and scientific research fail to with increased risk of prostate cancer, and that these demonstrate an increased risk. cancers may have more worrisome aggressive clinical features. In addition, multiple studies have failed Nevertheless, most patients dying from metastatic to show that T therapy causes worsening of voiding PCa have castrate levels of T., symptoms due to benign prostatic hyperplasia. We will review the available evidence regarding the relationship of T and the prostate, with special attenLifespan Medicine Journal 2014 - Page 78

tion to safety issues regarding PCa. Although there are as yet no large-scale, long-term controlled studies of T therapy to document its safety, there does exist a substantial literature examining this relationship, and providing a rationale for why ADT causes PCa to regress but T therapy does not appear to cause PCa to progress. Testosterone trials In the absence of any single large study on T therapy, one must examine the results from smaller studies, many of which have examined PSA changes and PCa detection rates in trials of 12 months to 3.5 years.

0.5 ng/ml or less [4]. There were also 14 men with a PSA increase greater than 0.5 ng/ml, but 12 men with a decline in PSA. No apparent differences in age, baseline T concentrations, or baseline PSA were noted between men with a PSA increase >0.5 ng/ml and men whose PSA declined. To put these studies and their results in perspective, it is important to note that the observed PSA changes in multiple studies of approximately 15-20% is not much greater than the 13% increase noted over one year in 50-60 year old men participating in the placebo arm of an unrelated study [7]. In addition, the annual cancer rate of approximately 1% that shows up repeatedly in T therapy trials compares favorably to cancer detection rates in men undergoing prostate cancer screening [8].

One of these was a 12 month study of 371 men on T gel therapy [3]. Over the course of one year three cancers were detected, by a rise in PSA ( < 1 % ). In this study the mean rise in PSA was 0.4 ng/ml. This increase was noted at 3 months, and PSA remained Perhaps most importantly, two studies involving more than 400men in total have shown that hypogonadal unchanged over the next 9 months. men with PSA of 4.0 ng/ml or less have a biopsy-deOther studies have revealed a similar rate of cancer tectable cancer rate of approximately 15% [9,10]. If detection in T therapy trials. In a review of nine sep- one in seven men with low T has PCA, and if raising arate T therapy trials involving 579 men and ranging T truly caused PCa to grow more rapidly, logic would from 3 to 36 months, seven cancers were identified, suggest that T therapy trials should be associated with representing a cancer detection rate of 1.2% [4]. a much higher rate of prostate cancer. Wang et al [5] performed one of the longest T therapy Longitudinal studies trials. In this study 163 men with a mean age of 51 yr received T gel for 42 months. Over this time the mean The relationship of T and other sex hormones to subPSA increased from 0.85ng/ml at baseline to1.1 ng/ sequent development of PCa has been extensively ml at 6 months, and then did not change significantly studied, in at least 16 population-based longitudinal over the next three years of the study. Three men were studies [11-16]. In these studies, a health history is diagnosed with prostate cancer, representing a cancer obtained, and blood samples at baseline are then frozen for the duration of the study, in some cases up to rate of less than 1% per year of treatment. twenty years or longer. At the end of the study, men Finally, prostate cancer rates were investigated among who have developed PCa are identified, and a matched men with and without the prostatic precancerous le- set of men without PCa serve as controls. sion represented by high-grade prostatic intraepithelial neoplasia (PIN). In this 12-month study 75 men A total of greater than 430,000 men have been includwith hypogonadism received T therapy, including 55 ed in these studies, including 1400 men with PCa, men with benign pre-treatment prostate biopsy, and and 4400 men identified as controls. Not one study 20 men with biopsy revealing PIN [6]. A similar 12 has shown a direct correlation between total testosmonth increase in PSA of 0.3 ng/ml was seen in both terone levels and PCa. Isolated associations have groups, corresponding to a 15% rise. A single can- been reported with some measures and PCa: minor cer was detected, in the PIN group, representing an androgens in one [14], calculated free testosterone in overall cancer rate of 1.3%. The 5% cancer rate among another [15], and with quartile analysis of hormone men with PIN compares to a 25% risk over 3 years in ratios or controlling for multiple variables in a third this population, suggesting no significantly increased [16]. None of these positive associations have been supported by later studies. It is worth noting that the cancer risk. largest study of this type actually noted reduced PCa One study that examined the effect of T therapy on risk in men with higher T levels [13]. PSA found that the overall change was mild, and the individual response varied considerably. Among 58 The importance of these studies is that they provide men who underwent T therapy for one year, the ma- a sophisticated method of investigation to determine jority (32 men) demonstrated a mild PSA increase of the long-term effects of endogenous hormone levels, especially testosterone, on the subsequent risk Lifespan Medicine Journal 2014 - Page 79

of development of PCa. Although such studies cannot entirely replace the value of a prospective longterm controlled study of T therapy, they do address the question as to whether high levels of T (or other hormones) predispose men to a greater risk of later development of PCa. On this question these prospective longitudinal studies provide two uniform and convincing answers- first, that men who develop PCa do not have higher baseline T levels, and second, men with higher T levels are at no greater risk of developing PCa than men with lower T concentrations. Resolving the paradox How is it possible that androgen deprivation and its discontinuation can have such a powerful effect on advanced prostate cancer growth, yet T therapy trials appears to have little impact on PCa risk or even PSA? The answer is provided by a recent landmark study by Marks et al [17]. In this randomized, placebo-controlled, double-blind trial, 40 men with hypogonadism underwent prostate biopsy and comprehensive evaluation at baseline and after 6 months of injections of T or placebo every two weeks. Despite large changes in serum T concentrations, the intra-prostatic concentrations of both T and dihydrotestosterone (DHT) did not change significantly. Furthermore, no changes were noted in expression of androgen-related genes or genes associated with prostatic proliferation. These results indicate that substantial changes in serum androgens are not reflected within the prostate, and do not appear to induce biological changes within prostate tissue.

As clinicians have begun to let go of the old belief that raising T would necessarily increase PCa risk, there has been a coincidental recognition that low T may itself represent a risk factor for PCa. There is now emerging data that testosterone deficiency is associated with greater risk of PCa, high Gleason scores, worse stage at presentation, and worse survival [20]. A study of 345 men with hypogonadism and PSA levels of 4.0 ng/ml or less found that the group of men in the lowest tertile of total T had more than double the risk of cancer on biopsy compared with men in the highest tertile (OR, 2.15; 95% CI, 1.01-4.55) [10]. In another study of 326 men who underwent radical prostatectomy, pre-treatmenT concentrations correlated with the likelihood of organ-confined disease [21]. In addition, there is now evidence correlating high Gleason scores with low T [22]. What these findings mean is that there is growing evidence that men with low T diagnosed with prostate cancer are more likely to have positive margins in their prostate specimens and higher Gleason grades, and men with higher T were more likely to have negative margins and less aggressive disease. Testosterone therapy after diagnosis of prostate cancer

The growing number of men who appear to be cured from PCa after definitive therapy has created pressure to consider T therapy in those men who are symptomatic from testosterone deficiency. Although this has been a longstanding taboo, clinical experience with T therapy together with the scientific evidence reviewed This study provides scientific evidence supporting the in this chapter suggests this may be far less risky than concept of saturation of the prostate androgen recep- had previously been assumed. Results from several tors with regards to T, as proposed recently [18]. In small studies suggest that T therapy may be used, with this saturation model, at the extreme low end of T caution and in a carefully selected population, after concentrations there is a profound influence of T on PCa has been successfully treated. prostate growth, yet at higher T concentrations this in- The first of these was a small series of 7 cases in which fluence appears to be marginal, if present at all. Fowl- T therapy was provided to symptomatic hypogonadal er and Whitmore lay the groundwork for this model men who had undergone radical prostatectomy and in their 1981 report detailing the effect of T adminis- who had an undetectable postoperative PSA [23]. No tration in men with metastatic PCa [19]. They noted recurrences were noted in these men despite 1 to 12 that T administration resulted in rapid and near-uni- years of T therapy in these men. versal PCa progression in men who had undergone A second study reported similar reassuring results in prior androgen ablation, but not in men without prior 10 men who had also undergone radical prostatechormonal manipulation of metastatic PCa. The au- tomy with undetectable PSA [24]. Mean total T inthors concluded that naturally occurring endogenous creased from 197 ng/dl to 591 ng/dl, and symptoms of T concentrations may be sufficient to produce â&#x20AC;&#x153;near hypogonadism improved. Most importantly, no PCa maximal stimulationâ&#x20AC;? of PCa. This concept is sup- recurrences were noted with a median follow-up of 19 ported by the study of Marks et al [17], and describes months. the essence of the saturation model. A third study reported results in 31 men who received Low T and prostate cancer T therapy after PCa treatment with brachytherapy Lifespan Medicine Journal 2014 - Page 80

[25]. In this group the median duration of treatment was 4.5 years with a range of 0.5 to 8.5 yrs. Total T concentrations rose from a median of 188 ng/dL to 498 ng/dL. No recurrences or PCa progression was noted, and all men remained with PSA less than 1.0 ng/ml at the end of the study.

also under androgenic control. However, all available data indicates that any negative clinical impact on the benign prostate is minor and infrequent [5,8]. Multiple studies have shown that T therapy is associated with only a mild increase in prostate volume as measured by transrectal ultrasound. In addition, studies The largest series to date of TTh in men after radical consistently show no changes in uroflow rate, postprostatectomy was reported by Pastuszak et al, who void residual urine, and no changes in mean voiding evaluated 103 hypogonadal men (77 low/intermediate symptoms as measured by the International Prostate risk and 26 high-risk) who received TTh after RP and Symptom Score [5,8]. compared biochemical recurrences to 49 eugonadal Conclusion controls (35 low/intermediate risk and 15 high-risk) Although we still lack a large-scale controlled study to [26]. High risk was defined as GLâ&#x2030;Ľ8, positive mar- definitively assess the safety of T therapy, it is becomgins, and positive lymph nodes. After a median of ing increasingly clear that this treatment poses little 27.5 months of follow-up, there were 4 biochemical clinical risk of PCa in the short- to mid-term. The recurrences (4%) in the TTh group versus 8 (16%) in reasons for the historical concern that T therapy may the non-TTh group. cause PCa progression are easy to understand given A number of reports have provided information regarding the outcomes of TTh in men with PCa after radiation treatment. Sarosdy et al reported no biochemical recurrences among 31 men treated with TTh after brachytherapy, with a median duration of treatment of 4.5y (25). Two published studies have reported results in which TTh was offered after external beam radiation for PCa. Morales et al. reported no biochemical recurrences in five men with up to 27 mo follow-up.[27] Pastuszak et al reported no recurrences in 13 additional men with median follow-up of 29.7 months [28]. Perhaps most provocative of all is the use of TTh in men with untreated PCa, such as men undergoing active surveillance for low-risk PCa. Morgentaler et al reported on TTh in 13 such men, with mean duration of treatment of 2.5y. All men underwent follow-up prostate biopsies, an average of two sets of biopsies per individual. No change with TTh was noted for mean serum PSA or prostate volume, and none of the men demonstrated cancer progression. Follow-up biopsies revealed no cancer in 54% of cases.

the androgen-dependence of PCa and the dramatic effect of ADT in advanced metastatic prostate cancer although most men dying from PCa have castrate levels of T. yet this concern is belied by clinical experience and scientific investigations. Specifically, T therapy trials of up to 42 months as well as more than a dozen longitudinal population-based studies have consistently shown no increased PCa risk associated with higher T levels.

The explanation for the lack of PCa progression with higher T appears to be that prostate tissue is saturated with regard to T at a relatively low serum T concentration, and additional T beyond this saturation point is not reflected by intra-prostatic concentrations of androgens. Recent small studies suggest that T therapy may even be a reasonable treatment for men who have undergone definitive treatment for localized prostate cancer, a group for whom such treatment was considered taboo only a few years ago. The longstanding belief that higher serum androgen concentrations cause ever-increasing rates of PCa growth, termed the androgen hypothesis, can no longer be accepted in the face of large amounts of contradictory evidence. In its place, we see that PCa is indeed sensitive to changes in serum T at the very low end of the range of T concentrations, and becomes indifferent to changes in serum T at higher concentrations ([30].

These clinical series provide some reassurance to physicians who wish to relieve the symptoms of hypogonadal men with T therapy following definitive treatment of localized prostate cancer. However, determination of the true safety of this approach will require time and much larger studies [29]. On the other hand, there is now growing awareness Effects of testosterone therapy on the benign that low T may itself be a risk for PCa, and may portend worrisome consequences once PCa is diagnosed. prostate It will be fascinating to see what other changes come In addition to concerns regarding PCa, there have to pass over the next few years in this rapidly changing also been concerns that T therapy may cause exacer- field. bation of lower urinary tract symptoms due to growth of the benign prostate, since the benign prostate is References Lifespan Medicine Journal 2014 - Page 81

1. Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol. 2006;50:935-939 2. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297. 3. Dean JD, Carnegie C, Rodzvilla J, Smith T. Long-term effects of Testim 1% testosterone gel in hypogonadal men. Rev Urol 2004; 6:S22-29. 4. Rhoden EL, Morgentaler A. Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy. Int J Impot Res 2006; 18:201-5. 5. Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone density in hypogonadal men. JCEM 2004; 89:2085-98. 6. Rhoden EL, Morgentaler A: Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol 2003;170:2348-51. 7. Dâ&#x20AC;&#x2122;Amico AV, Roehrborn CG. Effect of 1 mg/day finasteride on concentrations of serum prostate-specific antigen in men with androgenic alopecia: a randomised controlled trial. Lancet Oncology 2007;8:21-5. 8. Rhoden EL, Morgentaler A: Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350:482-92. 9. Morgentaler A, Bruning CO, III, DeWolf WC: Incidence of occult prostate cancer among men with low total or free serum testosterone. JAMA 1996; 276:1904-6. 10. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen of 4.0 ng/ ml or less. Urology 2006; 68:1263-7. 11. Hsing AW. Hormones and prostate cancer: whatâ&#x20AC;&#x2122;s next? Epidemiol Rev 2001;23:42-58. 12. Eaton NE, Reeves GK, Appleby PN, Key TJ. Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies. Br J Cancer 1999; 80:930-4. 13. Stattin P, Lumme S, Tenkanen L, et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int J Cancer 2004; 108:418-24. 14. Barrett-Connor E, Garland C, McPhillips JB, Khaw KT, Wingard DL. A prospective, population-based study of androstenedione, estrogens, and prostatic cancer. Cancer Res. 1990;50:169-73. 15. Parsons JK, Carter HB, Platz EA, Wright EJ, Landis P, Metter EJ. Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Canc Epidemiol Biomarkers

Prev 2005; 14:2257-60. 16. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88:1118-26. 17. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 2006; 296:2351-61. 18. Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin N Am 34:555-63, 2007. 19. Fowler JE, Whitmore WF, Jr. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 1981; 126:372-5. 20. Morgentaler A. Testosterone Deficiency and Prostate Cancer: Emerging Recognition of an Important and Troubling Relationship. Eur Urol 52:623-5, 2007. 21. Isom-Batz G, Bianco FJ Jr, Kattan MW, Mulhall JP, Lilja H, Eastham JA. Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol. 2005;173:1935-1937. 22. Hoffman MA, DeWolf WC, Morgentaler A.Is low serum free testosterone a marker for high grade prostate cancer?J Urol. 2000 Mar;163(3):824-7. 23. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004;172:920-922. 24. Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol. 2005;173:533536. 25. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007;109:536-541. 26. Pastuszak AW, Pearlman AM, Lai WS et al. Testosterone Replacement Therapy in Patients with Prostate Cancer After Radical Prostatectomy. J Urol 2013 ; Feb 8 (Epub ahead of print). 27. Morales A, Black AM, Emerson LE. Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations. BJU Int 2009; 103: 62-64. 28. Pastuszak AW, Pearlman AM, Godoy G et al. Testosterone replacement therapy in the setting of prostate cancer treated with radiation. Int J Impot Res. 2013 ;25:24-8. 29. Isbarn H, Pinthus JH, Marks LS, Montorsi F, Morales A., Morgentaler A, Schulman C. Testosterone and prostate cancer : revisiting old paradigms. Eur. Urol. 2009;56:48-56. 30. Morgentaler A. Goodbye androgen hypothesis, hello saturation model. Eur Urol. 2012;62:765-7.

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Vasopressin: The antiaging, cognitive enhancing neuropeptide By Ward Dean, M.D. Vasopressin is a pituitary hormone that is best known for controlling water balance in the body. Its common name is anti-diuretic hormone (ADH), because of its property of conserving water in the body, and inhibiting urine production. Because of this property, many parents of children with bed-wetting problems find it useful, as do many men with prostate problems (BPH). Vasopressin doesn’t affect the prostate, but it does reduce urine production, resulting in less sleep interruptions13. Vasopressin as a smart drug However, vasopressin also acts as a neuropeptide in the hypothalamus, and is necessary for imprinting new information in our memories1. Not surprisingly, vasopressin content in the brain declines with age7. Consequently, vasopressin has been used to treat memory deficits due to aging, senile dementia, Alzheimer’s disease, Korsakoff ’s syndrome and amnesia6.

Drs. Sydney and Constance Friedman at the University of British Columbia2 studied the effects of posterior pituitary powder on the life spans of already-old rats (2-years old). The scientists proposed that the alterations in water and electrolytes (principally, sodium and potassium) with age resemble those of diabetes insipidus (a disease characterized by excessive urination caused by a lack of ADH). They further proposed that many other signs and symptoms of aging are similar to many features of diabetes insipidus (Findley, 1949). They had previously found that vasopressin (ADH) restored a youthful pattern of fluid distribution in rats (Friedman, et al, 1960, 1963 [b]), and improved renal function in aging men10.

Vasopressin improves attention, retention and recall (both short-term and long-term) and it is well known to enhance short-term memory in normal young adults, as well as in those with age-associated memory impairment- AAMI4, 5. In addition, it has been shown to improve both mood and memory in the el- The authors stated that; “It is a truism that in age almost all functions that can be measured will show derly and those with Alzheimer’s disease3. some decline. Since salt and water homeostasis is cerVasopressin is very useful when learning large tainly central to life itself, [effective therapy] might amounts of new information. It can increase the abil- well produce a measurable effect on life span.” ity to memorize and recall, and is especially helpful when cramming for exams, trying to memorize a To test their theory, the authors administered posterior pituitary powder, (as a source of vasopressin) to speech, or learning a script8. two year-old rats. The study was terminated after 180 One study9 demonstrated an additional, previously days. Only 8 of the original 18 controls were still alive. undocumented benefit of vasopressin-enhancement In contrast, 22 of 36 treated rats survived. The authors of slow wave sleep9. Subjects in this study used a also reported better fur condition, increased muscular dose of 40 IU/day, administered as a nasal spray (two tone, absence of age-related pituitary and adrenal ensprays at bedtime). Over a period of three months, the largement, and fewer skin lesions in the treated rats. researchers found the time spent in slow wave sleep The scientists concluded that “therapy directed at the (SWS) more than doubled. SWS is the most restful neurohypophyseal-adrenal cortical integration can kind of sleep- and it is during SWS that growth hor- exert profound effects...in the aging organism.” [Ed. mone is released. That was a profound statement in 1964]. Perras and colleagues hypothesized that in addition to Desmopressin is synthetic vasopressin11. It is indicatits direct effects as a neuropeptide, Vasopressin could ed for diabetes insipidus, as well as nocturnal eneureact by other mechanisms as well, including acting as a sis (bed-wetting), but can be taken safely by most peocorticosteroid receptor agonist (sensitizer). ple. Those with hypertension, glaucoma or prostatic hypertrophy should use Desmopressin with caution Potential antiaging effects of vasopressin and only under the care of their physician. VasopresLifespan Medicine Journal 2014 - Page 83

sin occasionally produces the following side effects: nasal congestion, runny nose, itch or irritation of the nasal passages, abdominal cramps, headache and increased bowel movements. Vasopressin has not been proven to be safe for use during pregnancy. Vasopressin comes in three forms: lysine-vasopressin (Diapid®, lypressin, VasoPRO™): l-desamino-8-D-arginine (adiuretin, DDAVP, desmopressin, Desmospray®, Minirin®) and arginine-vasopressin (argipressin, AVP, rinder-vasopressin). All forms have very similar or identical effects. The availability of vasopressin varies due to intermittent and unexplained withdrawals and reintroductions into the marketplace by the pharmaceutical companies. Because of Vasopressin’s multiplicity of benefits, I believe it is a potentially valuable antiaging, life extending agent. Even in those for whom it is relatively contraindicated (i.e., those with hypertension or glaucoma), I think long-term, low-dose use may ultimately be beneficial. References: 1. de Wied, D, van Wimersma Greidanus, TB, Bohus, B, Urban, I, Gispen, WH. “Vasopressin and memory consolidation.” Perspectives in Brain Research. New York: Elsevier Scientific Publishing, 1975.

posterior pituitary powder in aged rats. Exp Gerontol, 1964, I: 3748. 3. Gold, PW, Weingartner, H, Ballenger, JC, Goodwin, FK. “Effects of l-Desamo-8-Arginine Vasopressin on Behavior and Cognition in Primary Affective Disorders.” The Lancet, November 10, 1979, pp 992-94. 4. Laczi, F, Valkusz, Z, Laszlo, FA, Wagner, A Jardanhazy, T, Szasz, A, Szilard, J, Telegdy G. “Effects of Lysine-Vasopressin and l-Deamino-8-Arginine Vasopressin on Memory on Healthy Individuals and Diabetes Insipidus Patients.” Psychoneuroendocrinology, 1982, Vol. 7, No 2, p 185-92. 5. Legros, JJ, Gilot, P, Seron, X, Claesens, J, Adam, A, Moeglen, JM, Audibert, A, Berchier, P. “Influence of Vasopressin on Learning and Memory.” The Lancet, January 7, 1978, p41-42. 6. Oliveros, JC, Jandali, MK, Timsit-Berthier, M, Remy, R, Benghezal, A, Audibert, A, Moeglen, JM. “Vasopressin in Amnesia.” The Lancet, January 7, 1978 p43. 7. Pearson, D., Shaw, S. Life Extension, a Practical Approach. New York, Warner Books, 1982. 8. Pelton, R., Pelton, TC. Mind Food and Smart Pills. New York, Doubleday, 1989. 9. Perras, B., Pannenborg, H., Marshall, L., et al. Beneficial treatment of age-related sleep disturbances with prolonged intranasal vasopressin. J Clin Pshychopharmacology, 1999, 19: 1, 28-36. 10. Ruol, A., Menozzi, L, and Furlanello, F. J Geront Suppl 31, 1963. 11. British National Formulary, 2013

2. Friedman, S.M., and Friedman, C.L. Prolonged treatment with

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The TRH miracle! An interview with Walter Pierpaoli, M.D. In this interview, Dr. Pierpaoli discusses with Phil Micans the role of TRH (Thyrotropic Releasing Hormone) Phil: Dr. Pierpaoli, may I begin by asking you the most obvious first question? Can you please tell us what TRH is and what are its roles are considered to be- at least from the point of view of ‘mainstream’ medicine?

trapped with the misleading name at the time, and then TRH presented itself with something of an unimaginable protective power. We saw that it was able to reconstitute a thymus already made atrophic, which indicates a powerful immunoenhancing and protecting effect; it showed potent antiviral protective affects in mice infected with lethal encephalomyocarditis virus and that the activity was completely independent from the thyroid. The central role of TRH in physiology in the body was so clear and amazing that already with our first publication we depicted a slide showing how TRH must play a key role in cell physiology. I became more and more fascinated with this molecule, which is ubiquitous in the amphibians’ biological world. It is present, with thousands of other peptides of all sizes, in rice, vegetables and is highly concentrated in the skin of cold-blooded amphibians. In humans, it is present in certain parts of the hypothalamus, in the pineal gland and most importantly in the beta cells of the pancreas. I started thinking that TRH was a magic peptide containing the unstable aminoacid histidine that it must have acquired through evolution, a key role for the maintenance of temperature through oxygen-dependent glucose metabolism by regulating insulin production and release. This seems in fact to be the case. I felt like awaking from a millennia-long fog and TRH was becoming something totally different in my mind, a true ancestral and primordial life-generating molecule! This concept and the results were fundamental to organize the Fifth Stromboli Conference on Aging and Cancer in June 2010 and I’m delighted that the volume about this is going to be published in 2013 in Current Aging Science by Benthan Books.

Dr. Pierpaoli: Thank you Phil for inviting me to explain what TRH is. First of all, we are facing again a misleading name attributed to this tiny tripeptide molecule, composed as it is of three aminoacids, namely histidine, proline and glutamine. It was discovered by the Nobel Prize Roger Guillemin, whom I met many years ago at a conference. He did a gigantic/ heroic work to identify it and gave it a name which expresses an activity which, however, is negligible: Thyrotropic Releasing Hormone or TRH. The activity of TRH, found in the hypothalamus of pigs by Guillemin, is also able to stimulate a lazy pituitary gland to produce TSH, Thyroid Stimulating Hormone. Again this semantic problem and this nomenclature given to molecules, similarly to Prolactin, generates confusion and restricts the attention from much wider activities of the greater physiological relevance. It is a true disgrace that we focus on names rather than on activities. Therefore for the majority of doctors and endocrinologists TRH serves only to activate TSH in the case of pituitary dysfunction, they use it to evaluate with an injection of 400 ug to see if the pituitary gland can produce TSH and thus stimulate the thyroid to release T3 and T4. This was also my idea in 1989, when I was thinking that melatonin may act via the thyroid and, to my surprise I saw that the activity of TRH was totally independent from the thyroid. I must point out that it is in fact that in most mammals TRH has no effect whatsoever on the thyroid! Phil: And in your early animal trials what sort of Phil: So the Greek philosopher Epictetus was right results did you see? when he said; “It is impossible for anyone to start understanding what he thinks he already knows.”

Dr. Pierpaoli: What I saw in my animal experiments was truly striking. Thanks to its key role in cell metabolism, TRH, similarly but differently from melatonin, Dr. Pierpaoli: Yes! Well said. modifies all age-related values to normality. Whatever Phil: So in the course of your research, what attract- you measure after acute or chronic oral or IV or subed you to first study TRH, believing as I understand cutaneous treatment in aging mice, the modification you did, that it may have special properties? observed shows true aging-reversing effects, they can Dr. Pierpaoli: What I saw in my first experiments at- be measured via the ions, hormones, blood or immutracted my keen attention simply because I was also nological parameters. Lifespan Medicine Journal 2014 - Page 86

Phil: Very interesting, I can see why it piqued your There are molecules such as TRH which have startinterest. And in the continuing animal experiments ed the first aggregation of life in the primeval soup. I what else was uncovered? suspect that TRH was an initiator of life thanks to its Dr. Pierpaoli: I am used to capture ‘the truth’ about instability by opening and closing the primeval moleorgans and tissues and have always used light micros- cules to exchange ions. After all, we are built with ions copy/ histology from the time I was a student. I make and hormones and their interplay, namely hormonal slices of tissues, stain them and watch them under the inter-synchronization which regulates our clock in microscope. Only this is the convincing stuff for me. the brain to the day-night-seasonal cyclicity, via therQuite simply I want to ‘touch with my fingers’ what moregulation. I do believe TRH is the first building is going on after treatment in old mice. In spite of block of our extraordinary life adventure. Our aim in some previous hints that we were confronted with a not immortality, but a long healthy and disease-free life-generating molecule whose role is prominent for life and TRH is a first answer. life itself, I was almost paralyzed by shock when I saw the testes, pancreas and the kidneys of TRH-treated mice. Old mice show atrophic testes where follicles are empty of spermatozoa and generally old mice die of kidney sclerosis/ nephrosclerosis. I saw a true reversal of aging! The surprise confirmed my first suspicions from my first experiment in 1989 and confirmed the key role of TRH in the maintenance of all body functions by a mechanism which is probably essential for the genesis on life itself on our planet.

Phil: Have any other significant benefits been noted in addition to what you have already mentioned?

Dr. Pierpaoli: TRH also produces a regulation of lipid levels in the blood as we have shown with three models in a paper published in 2011. Virtually all the parameters that have been studied to date appear to normalise over several months of TRH use. For example, we’ve seen improvements to cholesterol, triglycerides, phospholipids, albumin, aminotransferases, urea, testosterone and glucose to name but a few. Plus, in the animals it helped to restore healthy organ weights of the kidneys, thymus, adrenals, testes, heart and liver. But most people become most excited when we mention the weight loss! Phil: So what reasoning is behind the ability of TRH to induce weight loss?

Figure 1: Shows on the left the testicle follicles of an old 2-year mouse with an inability for sperm production. On the right is another 2-year old mouse testicles; but here after 4 months of TRH treatment he has complete recovery of sperm production.

Dr. Pierpaoli: It is simple; TRH activates basal metabolism via regulation of anabolic hormones and proper release of insulin. Glucose is burnt and fat is not stored. Only TRH can do that without any side-effect. It must be emphasized that TRH even if injected intravenously in huge amounts, has no side effect whatsoever. This magic molecule of nature knows what to do and how to do it.

Figure 2: On the left the kidney of a 2 year old mouse showing signs of typical age related disorders. On the right another 2 year old mouse kidney but now after 4 months treatment with TRH, many signs of the rejuvenation of function are shown.

Figure 3: Shows the body weight of mice before treatment with TRH, at 13 days after treatment and then again at 30 days. An average body weight loss of 13% within a month has been seen and substantiated with another animal trial.

Phil: My goodness, so there have been significant improvements seen in animals that have implications for fertility, renal disorders and immunity- Phil: So the sixty four million Dollar question isan incredible range of functions. How is it possible what have you seen in your own patients using that ‘a hormone’ can have such widespread activity? TRH? Dr. Pierpaoli: The more I read about TRH in the lit- Dr. Pierpaoli: Fundamentally, I see always that they erature, the more convinced I am that we must open feel well and always ask for more TRH! The only probour mind to a totally new dimension of life and death. lem is the current cost. We are working on it because costs hamper higher dosage/ long term use and thus Lifespan Medicine Journal 2014 - Page 87

more clinical work is needed. But because TRH is a natural molecule and cannot be patented I do not think that the drug companies are interested.

ly whilst costs are high, in the future- as the sublingual tablets become more popular I am sure that the costs will fall, it will be a common effort for the benefit of all of us all.

Phil: Can you please tell our readers the typical dose a patient takes of TRH and how long they typically Phil: Do you think there will be more to come about take it for? the TRH research? Dr. Pierpaoli: In the course of 22 years and many trials I decided that a daily sublingual tablet of 5 mg is correct. In fact any other method would require very high and expensive treatments. The tripeptide is rapidly destroyed in the stomach, but can pass directly into the blood if the tablet is kept under the tongue in the morning for a few minutes until complete solution. One must be patient; it is an expensive but life-saving procedure- there’s no need to hurry! I suggest cycles of one month on, one month off, thus TRH is taken for six months in a year.

Dr. Pierpaoli: Undoubtedly, we’re working on the submission of a paper at the moment that shows that TRH induces insulin-producing cell proliferation; that could have great implications for diabetics. Phil: Congratulations on exposing these remarkable qualities about this hitherto relatively obscure molecule. Are there any plans to write a book about this discovery- ‘the TRH miracle’ perhaps?

Dr. Pierpaoli: I hope so. I must find a proper medical writer who wants to stay young and wants to be involved with a bestselling book. Perhaps somebody Phil: Of course I must ask- at the doses mentioned, can suggest him or her to me? I am waiting: we have have there been any side effects or contraindica- plenty of time, or maybe not? (Ha ha) tions to date in your patients? Phil: Thank you very much for your time and sharDr. Pierpaoli: No side-effects, no contraindication. Of ing your research with us today. course 5 mg is a relatively minimal dose, and currentDr. Pierpaoli: You’re welcome.

Lifespan Medicine Journal 2014 - Page 88

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