CHAPTER I
Physiology & Biochemistry of Steroid Hormones
A
ll sex hormones in men and women are chemicals that are called steroids, although other non-sex hormones are also steroids. All steroid hormones come from cholesterol. The biosynthesis of steroid hormones takes place in the testicles, ovaries, adrenal glands, and in fat cells (adipose tissue).
Biosynthesis of Cholesterol Cyclopentanoperhydrophenanthrene This is the core structure or nucleus of cholesterol and all the steroid hormones.
Cholesterol
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Biosynthesis of Cholesterol 14
1. Cholesterol from food (animal origin: meat, dairy, eggs) 2. Biosynthesis (liver, skin, brain, intestine, adrenals, gonads) P.S. The statin drugs (Lipitor, Crestor, Vytorin, etc.) act by blocking the betahydroxy betamethylglutarylCoA reductase. Red yeast rice, to a milder degree than the statins, also interferes with production of mevalonate and of cholesterol.
HISTORICAL REFLECTION Our knowledge of the pathophysiology of cholesterol is far from being complete. Cholesterol, free fatty acids, phospholipids, and triglycerides (triacylglycerol) move within the circulation connected to proteins—the combination is called lipoprotein or lipoprotein particles. These particles have different densities depending on their make up, or more specifically, depending on how many lipid components.
UNDERSTANDING THE LANGUAGE OF CHOLESTEROL • VLDL (very low density lipoprotein) has large amounts of cholesterol and phospholipids and relatively small amounts of triacylglycerol. • IDL (intermediate density lipoprotein) compared to VLDL, has a bit less cholesterol and phospholipids and a bit more triacylglycerol. • LDL (low density lipoprotein) has a lot more cholesterol and phospholipids and relatively less triacylglycerol. • HDL (high density lipoprotein) has a lot less cholesterol and phospholipids, and a lot more triacylglycerol. LDL delivers cholesterol to cells whereas HDL takes cholesterol away from the cells. The blood test for cholesterol is called cholesterol or lipid profile and is reported as: In Units Total cholesterol above 200 is high mg/dl Triglycerides above 149 is high mg/dl HDL below 40 for men and 45 for women is low mg/dl VLDL above 40 is high mg/dl LDL above 99 is high mg/dl LDL/HDL Ratio Units: 0.0-3.6
Physiology & Biochemistry of Steroid Hormones 15
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A more informative testing of lipids is called lipoprotein subparticles that gives a great deal more detail but is also more expensive. Cardiologists and other medical doctors recommend to their patients a prescription of a cholesterol lowering medication when they see an LDL-C at 120 or 130. Personally, I feel this is not a wise decision. First, it is much more important to stress the value of healthy eating and exercise, as well as correcting all hormonal deficiencies. Cholesterol medications are expensive and can have serious side effects to the brain, liver, heart, joints, muscles and kidneys. For example, there was a report on ABC News (Good Morning America) about two years ago where they cited some women and a few men taking the drug Atorvastatin™ began to have memory problems, and some began to manifest symptoms of Alzheimer ’s disease—when the drug was stopped, all symptoms ceased. My observation is that the drug most likely lowered their LDL too far. A more recent report, by the American College of Cardiology, stated that people with coronary heart disease who took a drug combination of Simvastatin™ and Ezetimbe™ did achieve lowering cholesterol levels. However, no beneficial effect for heart disease was reported. It is also well known that some people who died of coronary heart disease had normal cholesterol blood level. Therefore, my recommendation is to focus on healthy eating (including certain supplements), exercise, and hormone replacement. In the event these safe, natural measures do not correct elevated cholesterol levels, or any other health issues, then it’s appropriate to consider taking statin or other cholesterol lowering drugs.
Physiology & Biochemistry of Steroid Unfortunately, in mainstream medicine, the main focus is on Hormones
anti-cholesterol drugs. To further illustrate my experiences, the following is an account of a recent observation:
LDL CHOLESTEROL (LDL-C) • Many doctors, and the general public, call LDL-C the bad cholesterol—this is incorrect as it is one of the most important chemicals or compounds in the body. • If you lower it too much, the brain suffers; it is what the liver uses to make bile acids which help digest fats. • It is vital for cell membrane synthesis. • The gonads (testicles, ovaries) and adrenals use it to make sex hormones, and other steroids. • It is necessary for production of vitamin D. • However, when you oxidize LDL then it is turned into a substance that causes irritation to the lining of arteries, which can elicit an inflammatory response and eventually create an atherosclerotic plaque in the artery. How LDL-Cholesterol is Oxidized • By consuming fried foods, processed red meat, greasy foods, and foods that are made with transfats, (commercially prepared baked products, French fries, muffins, pies, cakes, etc.). How Oxidation of LDL-Cholesterol is Discouraged • By eating an abundance of green vegetables and fruits, preferably organic. • By supplementing with vitamin K2, according to recent research, is believed to block the oxidation of LDL-cholesterol. • In addition to antioxidants from greens and fruits, there is also benefit in taking antioxidant supplements such as vitamin C and E.
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Metabolism of Steroid (Sex) Hormones in the Ovary1 18
Cholesterol
3ß-HSD-11
0c1 7 -11 SD -H 3ß
O
HS D1
O
1
Aro P450 ma tas e
-
-1
ß-
3ß Dehydroepiandrosterone O (DHEA)
D HS
Androstenedione 17
P450c17
OH
Estrone O
OH OH
P450 3ß-HSD-11 17ß-HDS-1 StAR
Cytochrome Enzyme System Three Beta Hydroxysteriod Dehydrogenase Seventeen Beta Hydroxysteriod Dehydrogenase Steriodogenic Acute Regulatory Protein
(E1) 17ß-HSD-1
Testosterone Aro P450 ma tas e
O
7
17-OH Pregnenolone
C=O OH
O
0c1
CH3
P45
17
OH
O
17-OH Progesterone
P450c
C=O
C=O
P45
StAR cc P450s
Pregnenolone CH3
CH3
Progesterone (P)
Estradiol (E2) OH
OH
Physiology & Biochemistry of Steroid The initial step of cholesterol conversion takes place in the mitoHormones
chondrion of the cell. The cholesterol comes from the blood or from the biosynthesis in the ovary. In the mitochondria, the cholesterol conversion is under influence of StAR (Steroidogenic Acute Regulatory Protein) and the cytochrome P450 complex of enzymes. In the first half of the menstrual cycle, estradiol is produced in the ovarian follicle (Graafian Follicle). In the second half, after ovulation, the corpus luteum is now the source of estradiol and progesterone. Both phases of the cycle are under the influence of LH (leutinizing hormone) and FSH (follicle stimulating hormone) of the anterior pituitary gland.
COMMERCIAL PRODUCTION OF SEX STEROID HORMONES FOR WOMEN Synthetic sources—urine of pregnant mares 1. Estrogen a. Ethenyl Estradiol b. Premarin c. Estrace Cream 2. Progesterone a. MedroxyProgesterone 3. Estrogen/Progesterone a. Prempro 4. Birth control pills II. Natural or Bio-identical—extracted from plants (soy, yam) 1. Estrogen a. Biest (Estradiol® and Estriol®) b. Triest (Estradiol®, Esteriol®, and Estrone®) 3. Progesterone a. Progesterone 4. Birth control—Vivelle Patch* I.
*I have not been able to determine whether Yasmin birth control pill is synthetic (from horse urine) or natural (from yam or soy).
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Biosynthesis of Testosterone in the Testis2 20
Cholesterol comes from the blood (mostly LDL-C) as well as local biosynthesis in the testicles—specialized cells in the testis producing testosterone are the Leydig Cells.
Physiology & Biochemistry of Steroid Of the total testosterone circulating in the blood, most of it Hormones
is bound to proteins. SHBG- (Sex hormone binding globulin) binds testosterone very firmly. Albumin binds testosterone in a loose way (bioavailable T). Free testosterone is about 1 to 2% of the total and is the portion that does the work of testosterone in all tissues.
Biosynthesis of Steroid Hormones in the Adrenal Gland3
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Aldosterone conserves sodium through effect on the kidneys. Cortisol action (glucocorticoids in general) will be clarified in the next chapter.
PRODUCTION OF HUMAN GROWTH HORMONE (HGH) For many years, growth hormone treatment was for children who were not growing and their medical evaluation revealed they had pituitary failure at least as far as growth hormone production. The other category of children was those with idiopathic short stature. In those days, the source of the growth hormone was pituitary glands of cadavers. In addition to a limited supply, there was also the danger of developing a serious brain disorder called Creutzfeldt-Jakob Disease—a complication of using cadaveric pituitary growth hormone. This source of growth hormone, fortunately, was abandoned worldwide by the mid 1980s. Deciphering the human genome and the science of genetic engineering was the critical step for producing pure growth hormone in the laboratory. This was an example of what can be accomplished with this complicated new knowledge—leading to the special class of pharmaceutical companies called The Biotech Industry. Genentech has been one of the prominent companies in this class and has been the first to produce pure growth hormone (named Protropin®) and a close second was the Eli Lilly Company who produced pure growth hormone (naming it Humatrope®). In the 1980s and ’90s, endocrinologists began to be aware of growth hormone deficiency in adults. Then a monumental clinical observation by Dr. Daniel Rodman from Wisconsin shed light on the possibility of improving or reversing many of the changes and challenges of aging with growth hormone treatment. His scientific observations were published in the early ’90s. Then in
Physiology & Biochemistry of Steroid 1996, The Food and Drug Administration approved the use of Hormones
growth hormone for adult growth hormone deficiency. Growth hormone is a very large molecule—it’s a protein made up of 191 amino acids. At this time in the 21st century, many pharmaceutical companies produce growth hormone; the process is called Recombinant DNA Gene Technology. The pharmaceutical companies that produce human growth hormone (hGH) use different names, different packaging, and different pricing. Thus hGH made by Pfizer is called Genotropin®, hGH made by NovoNordisk is called Norditropin® or Nordiflex®. There are others with names like Omnitrope®, Tevtropin®, Saizen®, etc. ✔NOTE For sake of clarification, the following interpretations will clarify acronyms used within this book: • HGH = human growth hormone produced naturally within the body • hGH = human growth hormone produced as a pharmaceutical (man-made) • HCG = human chorionic gonadotropin produced naturally within the body • hCG = human chorionic gonadotropin produced as a pharmaceutical (man-made)
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