FOCUS
Allergy Research Group ® Newsletter | SPECIAL EDITION Fall 2021
DHEA AND PREGNENOLONE
SPECIAL EDITION www.allergyresearchgroup.com | 800.545.9960
CONTENTS
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DHEA and Pregnenolone
10 In Vitro Fertilization
A Comprehensive Clinician’s Guide to the Research Behind the Parent Hormones DHEA and Pregnenolone
10 Bone Density in Special Settings
13 Mental Health
DHEA
6 Stress Protection 7 Adrenal Insufficiency
7 Aging
9 Sexual Function
14 Pregnenolone
14 Age-Related Memory Decline
15 Mental Health
16 Anti-Inflammatory Effects
Allergy Research Group® FOCUS Newsletter | Fall 2021 SPECIAL EDITION
From the Editor Many integrative health care practitioners know about DHEA (dehydroepiandrosterone) and pregnenolone, but few really know the depth of their clinical utility and importance in human health (particularly in the case of pregnenolone). These are two of my favorite hormones to use in practice—when used in appropriate clinical settings. Personally, I never like to give hormones unless I determine, via blood tests and clinical presentation, that the patient needs them. These hormones are quite safe when used judiciously. To err on the side of caution, they should be avoided with any past and present history of hormone-sensitive cancers.1,2 In this special edition of FOCUS Newsletter, we take an in-depth dive into the world of DHEA and pregnenolone and the many health benefits they offer.
Yours in Health,
Dr. Todd A. Born, ND, CNS Editor-in-Chief 1 Mayo Clinic Staff. DHEA. Feb 12, 2021. https://www.mayoclinic.org/drugs-supplements-dhea/art-20364199 2 Folkerd EJ and Dowsett M. Influence of Sex Hormones on Cancer Progression. J Clin Oncol. 2010 Sep 10;28(26):4038-44.
Editor-in-Chief Todd A. Born, ND, CNS
Executive Editor Meagan Purdy, ND
Copy Editor Katie Van Amburg
Art Editor Matt Ivan
Graphic Designer Kristin Wood
Want more educational resources? Visit our blog at www.allergyresearchgroup.com/blog for more articles, including these related articles.
The Pro-Hormone DHEA and Sexual Health
DHEA for Bones, Brains, and in the Bedroom
Pregnenolone for Memory, Mood, and Brain Health
Feed Your Brain, Part 1 of 2
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DHEA AND PREGNENOLONE A Comprehensive Clinician’s Guide to the Research Behind the Parent Hormones DHEA and Pregnenolone When we speak of hormones, we often think of those that play a role in mediating sexual function: estrogen, testosterone, and progesterone. These hormones come from the common base molecule of cholesterol, and all three have the same parent hormone pregnenolone (PREG), while estrogen and testosterone are both downstream from dehydroepiandrosterone, commonly known as DHEA. DHEA and its sulfated form DHEA-S are the most abundant steroid hormones in the human body.1 They are primarily produced in the adrenal cortex, with smaller amounts of DHEA being synthesized in the ovaries and testes.
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Data suggests that DHEA and DHEA-S are also produced in the brain.2 DHEA is a precursor to estradiol, estrone, testosterone, and 5α-dihydrotestosterone (5α-DHT).3 As an androgen, DHEA has roughly 1/20 of the androgen potency of testosterone.4 PREG is upstream of DHEA; it gives rise not only to DHEA but also progesterone, cortisol, and other intermediary metabolites. The synthesis and metabolism of PREG primarily take place in the adrenals, with the specific pathways and
Allergy Research Group® FOCUS Newsletter | Fall 2021 SPECIAL EDITION
products varying by the adrenal location.5 Smaller amounts of PREG are also made in the gonads as well as the brain.6,7,8 In postmenopausal women, hormone replacement therapy (HRT), typically estrogen in combination with progesterone, is prescribed primarily for the alleviation of menopausal symptoms, but it also may have protective effects on the bone and the brain.9,10,11 While testosterone was once only prescribed for hypogonadism, as diagnosed by clinical signs and symptoms and multiple low morning fasting serum testosterone values, testosterone prescriptions increased three-fold from 2001 to 2011, mostly being prescribed to men without this clinical diagnosis.12 Primary symptoms of hypogonadism are fatigue, loss of libido, and depressed mood, and, later, loss of muscle mass and body hair, voice changes, gynecomastia, and osteoporosis.13 With the replacement of testosterone, libido and energy levels are restored rapidly as hormone levels are normalized, typically in three to six
months.14 Testosterone replacement in hypogonadal men has been shown to have a significant impact on bone mineral density (BMD), increasing BMD by more than 20% after the first year of treatment. It also may have positive effects on mood and memory.16,17 While estrogen, progesterone, and testosterone are prescription only, PREG and DHEA are considered dietary supplements in the U.S., making them widely available for use by consumers and practitioners without prescribing rights. Much like the clinical response seen with the replacement of estrogen and testosterone, similar benefits may be derived from these hormone precursors. Additionally, both DHEA and PREG have substantial and very interesting research pointing toward a positive impact on mental health in a wide array of settings. Herein, we take a comprehensive look at the research concerning DHEA and PREG for chronic stress, hormone deficiency states, aging, sexual function, bone strength, mental health, and even pain.
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DHEA Clinical research with DHEA does not fall far from the indications for which we would consider its hormone metabolites, estrogen and testosterone. Much like estrogen and testosterone, levels of DHEA and DHEA-S decrease with age and fall to approximately 25% of their peak by age 70.2,18 Thus, we see substantial research surrounding concerns with aging: libido, skin integrity and appearance, bone health, and body composition. As a hormone that in some ways balances the action of cortisol, we also see research in the settings of stress and glucocorticoid-related bone loss. Finally, DHEA also has data for its positive effects on mental health—another issue that commonly occurs along with dysfunction of the hypothalamic-pituitaryadrenal (HPA) axis. Herein, we take a deep dive into each of these issues and clinical research with DHEA in other settings of deficiency. Stress Protection Similar to cortisol, which we speak of most often in regard to stress, DHEA and DHEA-S are adrenal hormones that fluctuate with stress. As neurosteroids, they have an impact on neurotransmitter balance and thus also affect our mental and physical responses
to stress.2 It has been suggested that DHEA may be protective against an excessive cortisol response under stress.19 Both DHEA and DHEA-S have been shown to increase with the experience of acute stressful events,20,21 although with chronic psychological stress, the DHEA response to additional acute stressors may be blunted.22 In active military subjects, higher levels of DHEA and DHEA-S have been shown to be associated with improved stress tolerance and performance and reduced dissociative symptoms during an underwater navigation exam—which is typically a very stressful event.23 Other studies suggest that a higher DHEA-S–to–cortisol ratio may be protective against the deleterious effects of stress.24 A diminished DHEA and DHEA-S response to acute psychological stress has also been shown in otherwise healthy young adults with depression.25 Collectively, these studies suggest DHEA may be beneficial as a supplement for stress protection, even at a young age, particularly if there are mood symptoms (which will be discussed at length shortly).
Collectively, these studies suggest DHEA may be beneficial as a supplement for stress protection, even at a young age, particularly if there are mood symptoms.
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Allergy Research Group® FOCUS Newsletter | Fall 2021 SPECIAL EDITION
Adrenal Insufficiency In women, DHEA conversion to testosterone by the adrenals is the primary source of testosterone; hence, with adrenal insufficiency, women often experience a decline in libido, while in men, sexual function and testosterone levels are largely preserved.26 Studies have shown that 50 mg of DHEA is a suitable dose for women with adrenal insufficiency. 27,28 When DHEA was taken at 50 mg daily for four months, the women’s levels of DHEA, DHEA-S, androstenedione, and testosterone were restored to normal levels, while serum concentration of sex hormone–binding globulin, total cholesterol, and high-density lipoprotein (HDL) cholesterol significantly decreased.28 In addition to significant improvements in well-being and anxiety and depression scores, there was a significant increase in frequency of sexual thoughts and interest. Other clinical research in men and women with secondary adrenal failure found that augmentation of growth hormone replacement and other indicated treatments with DHEA led to a significant increase in insulin-like growth factor (IGF)-1 in women (but not in men), demonstrating DHEA’s anabolic effects.29 In women with chronically low adrenal function due to various underlying causes, supplementation of 50 mg of DHEA daily for 12 weeks has also been shown to significantly improve various parameters of insulin sensitivity and decrease total, HDL, and low-density lipoprotein (LDL) cholesterol and triglyceride levels.30 DHEA also has been shown to improve alertness, stamina, initiative, and sexual interest or activity in women with hypopituitarism when added to other indicated hormone replacement therapies.31
Because of these findings, DHEA and different androgenic medications have been investigated as treatments for individuals with SLE.38 Generally, outcomes were positive or neutral, with findings of reduced disease flares and disease activity,39 improved bone mineral density, enhanced mental well-being and cognitive function, and a reduced need for corticosteroid treatment.40,41,42 The dose of DHEA was typically 200 mg/day, and a common minor adverse effect was acne, seen in up to 40% of patients, with hirsutism being observed less frequently, in approximately 10% of patients.
Generally, outcomes were positive or neutral, with findings of reduced disease flares and disease activity, improved bone mineral density, enhanced mental well-being and cognitive function, and a reduced need for corticosteroid treatment. Aging
Although the impact of adrenal insufficiency is somewhat less in men due to testosterone preservation, DHEA may still be beneficial. In a population of men and women with Addison’s disease, a randomized, double-blind, placebo-controlled trial (RDBPCT) with a crossover segment found that supplementation with 50 mg of DHEA daily for 12 weeks significantly improved self-esteem, mood, and fatigue in both sexes, with symptoms being particularly better in the evenings.32 An altered HPA axis response and low androgen levels have been implicated as possible contributors to autoimmune diseases, such as systemic lupus erythematosus (SLE).33,34 Much like other autoimmune diseases, SLE disproportionately affects women more than men.35 Low levels of DHEA have been shown in
women with SLE even at disease onset and are not just associated with long-term corticosteroid use,36 although this can also be a contributing factor. Men with hypogonadism are additionally at greater risk of developing SLE, further reinforcing the role androgens play in preventing this disease.37
In healthy seniors, age 60 to 79, supplementation of 25 to 50 mg of DHEA for eight days was shown to restore levels to those of young adults.3 On the day it was taken, supplementation of DHEA significantly increased levels of DHEA, DHEA-S, and estrone in both men and women. A significant increase in estradiol levels was seen in women, but not in men, on day 8 only. In men, DHEA supplementation increased testosterone nonsignificantly, while in women, on day 8 (but not day 1) it led to a significant and dosedependent increase in testosterone. A similar increase in testosterone was seen in the men and women but was only significant in the women, as baseline levels were less than 1/10 that of the men. In this short trial, which was a precursor to a longer, year-long investigation, no accumulation of steroids (DHEA, DHEA-S, testosterone, estradiol, and estrone) was observed, with the area under the curve at day 8 not being statistically different than day 1. Comparing hormone profiles from day 1 to day 8, in women, a
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DHEA supplementation positively affected bone health, decreasing bone turnover in women over age 70, and significantly improved most parameters related to libido.
trend toward increased estradiol and estrone levels (signifying hormone accumulation) was observed but not significant. In the follow-up RDBPCT, a population of 280 men and women from 60 to 79 years of age received 50 mg of DHEA or placebo daily for a year.18 With supplementation, DHEA-S levels were restored to “normal youthful levels” in both sexes. In men, there was no significant increase in testosterone, while in women, testosterone levels were significantly higher by month 6, exceeding the normal range of testosterone in menstruating women in 14 of the subjects. There was a significant trend of increasing estradiol levels in men at month 12, while in women, this increase was significant, with levels falling within normal ranges of the early follicular phase of menstruating women. Interestingly, in the women, despite no changes in the intervention, DHEA-S and testosterone levels were significantly lower at 12 months compared to month 6. Although these findings are important to mention, what is more interesting is the impact of DHEA supplementation on the physical changes related to aging, which were most noteworthy in the older women. DHEA supplementation positively affected bone health, decreasing bone turnover in women over age 70, and significantly improved most parameters related to libido in this more elderly group as well. In all participants taking DHEA, significant changes were seen in skin hydration, sebum production, and
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pigmentation: hydration and sebum levels increased, and facial yellowness decreased. Epidermal thickness on the dorsal hand significantly increased in the individuals having initial DHEA levels less than the lowest quartile “normal” threshold. No adverse effects associated with DHEA supplementation were noted, and there was no significant change in the prostate specific antigen levels in the men. The overall findings of the study are well summarized in the authors’ conclusion: “A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging.”18 Additional human studies in aging individuals (typically 65 years or older) have shown that longterm DHEA supplementation may decrease insulin resistance, triglycerides, and the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-α;43 enhance the effects of weight training on muscle mass; decrease arterial stiffness; improve BMD;46 decrease visceral and subcutaneous fat;47 and improve cognitive function in women with mild to moderate cognitive impairment.48 Interestingly, a study of middle-age practitioners of tai chi found that these individuals had significantly higher levels of DHEA-S and lower levels of cortisol, shedding light on potential mechanisms by which this practice enhances longevity.49
Allergy Research Group® FOCUS Newsletter | Fall 2021 SPECIAL EDITION
Somewhat surprisingly, supplementation with DHEA has also been shown to enhance sexual arousal in postmenopausal women acutely as well. In a RDPBCT with crossover, oral administration of 300 mg of DHEA significantly increased both the mental and physical arousal response to viewing an erotic video 60 minutes later.54 However, a similarly designed study did not show a significant effect in premenopausal women.55
In addition to DHEA being a testosterone precursor, its demonstrated anti-inflammatory effects and action of enhancing vasodilation further suggest it may be useful for the treatment of ED. Sexual Function In addition to the research in women age 70 and older, DHEA has been shown to possibly enhance libido in younger individuals as well. In postmenopausal women age 50 to 60, DHEA at a dose of only 10 mg a day for 12 months was shown to significantly improve sexual function and frequency compared to the control intervention (400 IU of vitamin D).50 In a population of men and women with hypoactive sexual desire disorder, at a dose of 100 mg/day for six weeks, treatment with DHEA significantly improved sexual arousal and satisfaction in women; however, in men, no improvements were seen.51 In women taking oral contraceptives (OC), the addition of 50 mg of DHEA daily significantly improved numerous markers of sexual function that had declined with initiation of the OC medication.52 Libido was also improved in men and women with HIV in an open-label trial with supplementation of DHEA at a considerably higher dose of 200 to 500 mg/day for eight weeks.53
Multiple population studies have shown an inverse relationship between DHEA levels and the incidence of erectile dysfunction (ED).56,57 In addition to DHEA being a testosterone precursor, its demonstrated anti-inflammatory effects and action of enhancing vasodilation further suggest it may be useful for the treatment of ED.58 There is not a preponderance of evidence for DHEA as a tool for the treatment of ED, although two studies have demonstrated a positive impact. In one small prospective study without placebo, supplementation with 50 mg of DHEA for six months was shown to improve ED in two populations of men naïve to HRT and treatment for ED.59 Both the men with hypertension and those having ED without organic etiology saw significant improvements in multiple International Index of Erectile Function (IIEF-5) subscores after treatment, while those with diabetes mellitus and neurological disorders did not see any change. In a RDBPCT of men with ED without subclassification of etiology, treatment with 50 mg of DHEA/day for six months was associated
Somewhat surprisingly, supplementation with DHEA has also been shown to enhance sexual arousal in postmenopausal women acutely as well.
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with significantly higher scores on all IIEF domains compared to placebo;60 however, the study had a fairly high dropout rate, especially in the placebo group, due to an insufficient response to treatment. Multiple studies have shown that intravaginal preparations of DHEA also improve dyspareunia, vaginal tissue atrophy, and related genitourinary symptoms in postmenopausal women.61,62,63 Longterm treatment with intravaginal preparations at doses of up to 13 mg/day have been shown to be very effective for these local tissue-related complaints, with little to no change of serum sex steroid levels.64 In Vitro Fertilization The vast majority of research with DHEA concerning fertility is concentrated in the arena of infertility due to diminished ovarian reserve. Studies in rats suggest that DHEA reduces follicular atresia; that is, the process by which follicles not selected for maturation involute and become part of the parenchyma.65 By doing so, the total number of follicles that can later potentially grow into larger, mature oocytes that are viable for fertilization increases. However, when the period of DHEA supplementation was doubled from 15 to 30 days (roughly equivalent to going from 1.5 to 3 human years66), a follicle-reducing effect was seen, suggesting that DHEA may not be appropriate as a very long-term intervention.67 Human studies have similar findings. In women who were poor responders to in vitro fertilization (IVF), the majority of whom were of advanced age or diagnosed with low ovarian reserve, supplementation of DHEA at a dose of 75 mg/day for three months prior to ovarian stimulation led to a highly significant improvement in four of the five oocyte parameters assessed.68 With IVF, there was a 31% clinical pregnancy rate, and a live birth rate of 19%. Additional subgroup analysis found that there was a significant increase in high-quality embryos in the patients less than 38 years of age and in those who became pregnant following DHEA treatment. In a randomized, placebo-controlled study of women who previously had a poor response to ovarian stimulation, DHEA was also provided at 75 mg a day for a period of six weeks prior to ovulation induction and IVF procedures.69 Those receiving DHEA were observed to have significantly improved embryo quality as well as a significantly higher live birth rate versus controls (23.1 vs. 4%). 10 10
Those receiving DHEA were observed to have significantly improved embryo quality as well as a significantly higher live birth rate versus controls (23.1 vs. 4%).
In addition to the positive findings seen with extensive reproductive assistance, one study reports of the positive impact DHEA had on spontaneous pregnancy. The women were enrolled in a study with a design much like the others previously described; however, after taking 75 mg of micronized DHEA daily for a period of time, a substantial amount of the women spontaneously became pregnant.70 In fact, of the women taking DHEA, in the 39 women under age 40 who had previously been poor responders to IVF, there were 10 spontaneous pregnancies, while in women age 40 and older, 21% of those taking DHEA became pregnant. There was not a control group for comparison with the women under age 40, but in those over 40, the women in the control group not receiving DHEA only had a spontaneous pregnancy rate of 13%. Many other clinical studies have also assessed the impact of DHEA on female infertility due to diminished ovarian reserve, with mostly positive findings.71,72,73,74 Clearly, this represents yet another category of anti-aging effects that this prohormone that will increasingly be investigated for, particularly as maternal age continues to rise. Bone Density in Special Settings In addition to the studies already mentioned, DHEA has been studied as a supplement to support bone health in other unique settings associated with hormonal imbalance: anorexia nervosa and long-term glucocorticoid therapy. Anorexia nervosa (AN) is well known as a mental health condition associated with substantial weight loss and malnutrition. Most women experience amenorrhea, while both men and women who struggle with AN have a dysregulated hypothalamicpituitary-adrenal (HPA) axis response.75 The resulting imbalance typically seen is that of estrogen and testosterone deficiency and cortisol excess: a
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hormonal recipe for substantial bone loss, worsened by chronic and substantial malnourishment.76,77 Although there are numerous factors at play in this population that cannot be well controlled and that possibly impact bone health (such as nutritional intake, exercise levels, weight restoration, and other therapeutic interventions), there are multiple long-term clinical trials investigating the impact of hormone replacement including DHEA. In one RDBPCT that lasted 18 months, the combination of 50 mg of DHEA with OC (combination of 20 µg ethinyl estradiol/0.1 mg levonorgestrel) was shown to stabilize femoral bone density in women age 13 to 27, with bone density decreasing in the placebo group.78 The bone cross-sectional area and cortical thickness were also improved. In another study, the impact of these two therapies was compared.79 In this study, there was no placebo, and the intervention period lasted one year, during which both groups had significant weight gain as a part of treatment. With both interventions, bone resorption significantly decreased; however, only the DHEA group had a significant increase in bone-specific alkaline phosphatase and osteocalcin by six and nine months. Improvements in validated psychological tools for assessing eating disorder–related parameters as well as anxiety scores were seen in the DHEA group only. A three-month study in a small population of women with AN also assessed the impact of DHEA doses, comparing 50, 100, and 200 mg potencies.80 The 50 mg dose was adequate to restore DHEA, testosterone (total and free), and estrogen levels to roughly the middle of normal ranges. With all doses, osteocalcin levels were increased from their very low normal baseline. Perhaps most significant was the finding that 53% of subjects had at least one menstrual cycle during the three months of treatment—prior to starting DHEA, the mean duration of amenorrhea was 20.9 months.
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Long-term use of glucocorticoids is well recognized to have adverse effects on bone in addition to a multitude of other metabolic consequences. This can be particularly detrimental in the menopausal years when other hormone levels significantly decline. There are several mechanisms by which DHEA may have anti-glucocorticoid effects,81 while it simultaneously has anti-inflammatory effects, suggesting that it could be useful to co-administer DHEA with glucocorticoid treatments for chronic inflammatory diseases like rheumatoid arthritis.82
However, other parameters, such as mental and sexual well-being, did improve at the lower doses. A trend to decreased SLE disease flares has also been shown with the addition of 200 mg of DHEA to prednisone treatment,86 while in another study, 51% of those taking DHEA at this dosage were able to decrease their prednisone for a prolonged period, maintaining stable or reduced disease activity.42
There are several mechanisms by which DHEA may have anti-glucocorticoid effects, while it simultaneously has anti-inflammatory effects, suggesting that it could be useful to co-administer DHEA with glucocorticoid treatments for chronic inflammatory diseases like rheumatoid arthritis. In one study of postmenopausal women (age 50 and over) taking an average of 7.5 mg of prednisone for three years, long-term supplementation with 25 to 50 mg of micronized DHEA/day significantly increased IGF-I and BMD in the femoral neck and lumbar spine.83 Significant increases in IGF-I and osteocalcin were seen as early as six weeks, while the improvement in BMD was seen at both the six- and 12-month evaluation periods. A study of women with SLE who were taking prednisone for at least six months showed that, after supplementing with DHEA at a dose of 200 mg/day for one year, there were significant improvements in the BMD of the hip and lumbar spine, while BMD in the placebo group declined.40 A follow-on, open-label study considered the impact of DHEA dosage, finding that there was a dose-dependent effect, with 200 mg having a significantly greater impact than 100 mg on spinal BMD.84 A dosage effect is further supported by the findings of Nordmark, et al., showing that 20 or 30 mg of DHEA did not have an impact on BMD in women with SLE being managed on glucocorticoids.85 12 12
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Allergy Research Group® FOCUS Newsletter | Fall 2021 SPECIAL EDITION
Fall 2021 SPECIAL EDITION
Mental Health As early as the 1950s, research pointed toward effects that DHEA may have on mental health and mood;87 and by 2018, more than 70 publications that investigated the impact of DHEA on the mental health of humans could be found.88 Studies suggest that low DHEA-S levels may be a vulnerability factor for depression and may predict depression severity or recurrence.89,90 This 2018 systemic review and meta-analysis of randomized, clinical trials found that DHEA supplementation was more effective than placebo in treating depression in patients with depression or in the depressive phase of bipolar disorder.88 In one of the studies included in this review, DHEA was studied as a treatment for midlife onset depression. In males and females ranging from 45 to 65 years of age, treatment with DHEA for six weeks (three weeks with
90 mg/day and three with 450 mg/day) significantly improved depression scores compared to placebo and baseline, with significant improvements also being seen in sexual function scores.91 Although only two clinical trials qualified for the 2018 meta-analysis, the majority of the excluded studies considered DHEA as a treatment for depression that was deemed to be secondary to other medical or psychiatric disease. From the array of studies not qualifying for this analysis due to these reasons, we see positive findings with DHEA on mood symptoms in a variety of settings including schizophrenia,92 HIV/ AIDS,93,94 heroin addicts undergoing treatment, and as an adjunctive to growth hormone replacement in individuals with panhypopituitarism.96
In males and females ranging from 45 to 65 years of age, treatment with DHEA for six weeks significantly improved depression scores compared to placebo and baseline, with significant improvements also being seen in sexual function scores.
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PREGNENOLONE
Numerous studies have investigated the effects of pregnenolone (PREG) in the brain, and its action as a neurosteroid.8 Peripherally and in the brain, PREG is metabolized to progesterone (PROG) and further converted to allopregnanolone (ALLO-P).97 Much like DHEA, PREG also exists in its sulfated form, PREG-S, throughout the body, including in the brain.98 PREG, PROG, and ALLO-P each has been demonstrated to have neuroprotective effects.99 Interactions of ALLO-P with gamma-aminobutyric acid (GABA) receptors as an allosteric agonist may be the primary mechanism of both PREG’s and PROG’s central nervous system calming effects.100,101 These findings have given rise to research investigating PREG and its metabolites as therapies for a variety of conditions associated with neuroinflammation and CNS hyperexcitability, including epilepsy,102,103 schizophrenia,104 anxiety,105 and depression.106 Age-Related Memory Decline With regards to the challenges of age-related hormonal decline, PREG and its derivatives may enhance learning and memory, reduce dementia risk, enhance locomotor activity, and promote the growth and survival of brain cells.107,108 Much like other hormones, PREG declines with increasing age after reaching its peak around 20 years of age.109,110
Memory formation and cognitive function, much like all things, rely on an appropriate balance of excitation and inhibition. In contrast to PREG and ALLO-P, PREG-S has GABA-inhibitory effects and by such may enhance processes such as memory formation.111 A significant correlation between PREG-S and cognitive performance has been shown in animal models: rats with memory impairments tend to have much lower concentrations of the neurohormone as compared to rats with normal memory, while restoration of normal levels reversed memory deficits.108 PREG-S mediates many aspects of synaptic plasticity; that is, the connections between neurons that are responsible for their communication, the learning of new skills, and the formation of memory.112 As compared with healthy controls, patients with Alzheimer’s disease (AD) tended to have lower levels of PREG and its primary products, as well as DHEA-S (another downstream metabolic product of PREG), in their brain.113,114 The sex steroids estrogen and testosterone have also been shown to be significantly lower in individuals with AD, particularly in females at an older age.115 Higher levels of the proteins ß-amyloid and hyperphosphorylated tau (proteins characteristic of AD116) are correlated with lower levels of the neurosteroids in certain regions of the brain. The neurosteroids also have been shown to reduce the damage that these proteins cause, improving cellular survival.
With regards to the challenges of age-related hormonal decline, PREG and its derivatives may enhance learning and memory, reduce dementia risk, enhance locomotor activity, and promote the growth and survival of brain cells.
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Allergy Research Group® FOCUS Newsletter | Fall 2021 SPECIAL EDITION
Although there are not studies specifically investigating PREG as a therapy for cognitive decline associated with aging, there are studies investigating its cognitive impact in other populations. In patients with schizophrenia, supplementation with PREG at escalating doses up to 500 mg/day for eight weeks was associated with significant improvements in negative symptoms, with serum increases in PREG and ALLO-P predicting improved cognitive scores.117 A subsequent study in patients with recent onset schizophrenia also found that supplementation of PREG at only 50 mg/day also improved multiple markers of attention as well as executive function.118 Medications that specifically stimulate the brain’s production of PREG, PROG, and ALLO-P are currently under investigation as a treatment or prevention strategy for AD.119
anxiety disorder (unmedicated), lower serum levels of PREG-S have been shown compared to healthy controls.124 Lower serum ALLO-P levels were also seen in the men with anxiety; however, the difference was not significant, and there was no difference in DHEA-S levels between populations. Levels of ALLO-P have been shown to be significantly lower in men and women with PTSD and were inversely correlated with PTSD and dysphoria symptoms.125
Mental Health Because of the impact neurosteroids have on CNS excitability and neural function, their role in anxiety and depression has also been studied.120 Interesting research has shown that ALLO-P and DHEA modulate amygdala connectivity and our responses to conditions that promote the emotion of fear.121 Anxiety, Depression, and Post-Traumatic Stress Disorder. In mice, it has been shown that there are lower serum levels of DHEA-S in the mice displaying a conditioned fear response, while administration of both DHEA-S and PREG-S (separately) dosedependently reduced the anxiety response to conditioned fear.122 This effect gives rise to the impact these neurosteroids may have on conditioned fears, a factor in post-traumatic stress disorder (PTSD), as well as our arousal state and response to stress. The effects of PREG on the emotional response have also been studied in humans with functional magnetic resonance imaging along with a task designed to assess emotional processing and regulation.123 When 400 mg of PREG was given two hours prior to performing the task, compared to placebo, it altered multiple brain patterns prompted by the task: it reduced activity in the amygdala and insula, increased activity in the dorsal medial frontal cortex, and increased functional connectivity between the amygdala and dorsal medial frontal cortex. These effects were associated with a reduction in selfreported anxiety. In young, otherwise healthy men with generalized
Schizophrenia and Bipolar Disorder. Schizophrenia and bipolar disorder are both particularly difficultto-treat mental health conditions, as many of the medications have substantial adverse effects, and patients often reject or discontinue the indicated mood-stabilizing medications. Because of the stabilizing impact that PREG and its downstream metabolites have on the brain, PREG has been researched in both of these settings with positive clinical findings. In a RDBPCT of patients with schizophrenia (stable on antipsychotic medications), the addition of PREG, at doses gradually escalating to 500 mg/day, was shown to lead to significant improvements in negative symptoms compared to placebo.117 Increases in serum PREG and ALLO-P levels were correlated with composite cognition scores. In another RDPBCT of schizophrenic and schizoaffective patients (also stable on medications), the addition of PREG at the low dose of only 30 mg/day significantly reduced positive symptom scores and extrapyramidal medication side effects and improved attention and working memory.126 In a RDBPCT of patients with schizophrenia (stable on antipsychotic medications), the addition of
PREG, at doses gradually escalating to 500 mg/day, was shown to lead to significant improvements in negative symptoms compared to placebo.
In another interesting RDBPCT, the pairing of 50 mg of PREG with 400 mg of L-theanine daily was investigated as an adjunctive treatment in schizophrenic patients.105 It was found that the addition of this combination significantly improved negative symptoms compared to placebo, and also significantly improved anxiety scores and
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elevated general functioning. The duration of these representative studies in the setting of schizophrenia was eight weeks, although dosage was variable over that period in dose escalation studies. In men and women with bipolar disorder, PREG, titrated to 500 mg/day and taken for 12 weeks, also positively impacted depression remission rates compared to placebo.106 In another study, PREG, given at a dose of 100 mg/day for eight weeks, positively impacted mood (but not cognition) in abstinent individuals being treated for substance use disorder, with trends toward greater improvement in scores of both manic and depressive symptoms.127 Substance Use Disorders. Studies also suggest that PREG and its metabolites may have a positive impact on alcohol use disorder (AUD). Research has shown that plasma levels of ALLO-P are markedly lower in alcoholic subjects in early stages of withdrawal as compared to control subjects.128 In an animal model of AUD, the self-administration of alcohol in rats with a preference for alcohol was significantly decreased by PREG.129 Other animal studies also suggest that ALLO-P may help reduce alcohol use,130 giving rise to interest in further study of how this research may translate to humans.131 Low levels of PREG have been shown in individuals with cocaine use disorder as well.132 Treatment with PREG, given at a dose of 100 mg/day for eight weeks, has been shown to have a positive impact on mood (but not cognition) in abstinent individuals being treated for substance use disorder, with trends toward greater improvement in
scores of both manic and depressive symptoms.129 Mental Health with Concomitant Hormonal Issues. Not surprisingly, levels of PREG and its metabolites have also been investigated in women with hormonalrelated mood disorders. In women with premenstrual syndrome, significantly lower serum levels of both ALLO-P and progesterone have been shown in the luteal phase as compared to controls.133,134 In women with postpartum depression, significantly lower levels of ALLO-P have been shown compared to control women postpartum, with levels of both ALLO-P and PREG having a significant negative correlation with Hamilton Rating Scale for Depression scores.135 One setting in which the underlying etiology suggests PREG may be worthy of a therapeutic trial is hypothalamic amenorrhea, particularly as it pertains to women struggling with or in recovery from anorexia nervosa (AN). Hypothalamic amenorrhea is more common after intense stresses of metabolic, physical, or psychological stresses, of which AN is one.136 In women diagnosed with hypothalamic amenorrhea who have a normal body weight, lower levels of ALLO-P have been shown,137 and in those specifically in recovery from AN, a low DHEA-S–to– cortisol ratio is also common.138 The positive findings with DHEA for restoring the menstrual cycle in this population,80 combined with the general anxiety- and fear-“dampening” effects of PREG and its additional downstream products, point toward overall benefits PREG also may offer. Anti-Inflammatory Effects Interesting research as early as 1950 suggested that PREG may be useful for decreasing fatigue and treating inflammatory conditions like ankylosing spondyloarthritis and rheumatoid arthritis.139,140 Physicians at the time were already aware that the more potent glucocorticoids had several unwanted effects; hence, they had great interest in PREG as an alternate anti-inflammatory treatment.141 Fast-forward to our modern, medication-laden era, and we still see research with PREG as a natural therapy for reducing pain. In fact, a 2019 study specifically details the many mechanisms by which PREG may impact pain and other inflammatory pathologies by interactions with the innate immune
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system.142 It is not an immunosuppressant, but similar to many of our other endogenous hormones, it acts to modulate inflammation and the immune response to it. ALLO-P levels have been shown to be inversely related to symptoms of pain in male veterans.143,144 The association was not limited to muscle pain and included chest pain as well. Interestingly, a very strong association was also shown between a history of traumatic brain injury and muscle soreness— suggesting some aspect of this symptomology may be centrally mediated. As the research discussed so far points to the central anti-inflammatory effects of PREG, it is no surprise that this neurohormone has been studied in this special population, especially given the concomitant issues of PTSD, for which PREG may be of benefit.125 A 2020 RDBPCT considered escalating doses of PREG (one week at 100 mg/day, one week at 300 mg/day, and two weeks at 500 mg/day) for low back pain in U.S. military veterans of the Iraq and Afghanistan wars.145 The population of veterans was approximately 90% male, and ages ranged from 18 to 65. Compared to placebo, PREG was shown to significantly reduce pain and the effects pain had on participation in other activities, including work. Both pain recall and pain diary scores progressively decreased and were significantly lower in the PREG group than placebo by the study completion. Serum PREG levels approximately doubled after taking 100 mg for one week and were almost five times greater after taking 500 mg for two weeks. ALLO-P and PREG levels increased more than 10-fold by study completion, as well. The intervention was well tolerated, with no significant adverse events being reported. Recent research suggests the PREG downstream metabolites ALLO-P and PROG may also improve neuropathic pain, another condition that is often difficult to treat.146,147 Potential Contraindications and Adverse Effects of DHEA and Pregnenolone Use With both hormone precursors, at doses typically used, adverse effects will not be seen acutely but only with prolonged use. Testing of DHEA-S levels to ensure they are not high or in the high normal range prior to therapy initiation may help prevent untoward
effects. With DHEA, adverse effects are mild and include complaints of oily skin, hair growth, acne, and body odor148,149 —things we typically associate with increased testosterone levels. However, hair loss can also be seen, as DHEA converts to more potent androgens in the follicle, which can interfere with hair growth.150 Studies suggest that some of these epidermal effects may be related to steroidal production in the skin,151 which oral supplementation additionally enhances, and which some individuals may be more sensitive to. In men, studies have not found DHEA to have an adverse effect on prostate size or markers.60 In senior women, a small, yet significant, increase in estradiol levels has been seen with daily supplementation of 50 mg of DHEA.18 In the studies discussed herein, adverse effects related to PREG use, despite the fairly high dosage, were not seen, but clinically, there are reports of dysmenorrhea and mastalgia. Again, adverse symptoms may be adverted by ensuring normal to low levels of hormones prior to initiation of treatment. It is worthwhile to mention that the doses of DHEA and PREG used in many of these studies are higher than practitioners typically use in clinical practice. Often, these therapies will be used with a low dose initially, and if there are not complaints, the dose is gradually increased to levels shown to be effective. Micronization and dissolution into a lipid matrix supports the absorption of fat-soluble substances such as these;152 hence, with such a preparation, clinical results may be seen at lower doses. Given the pleiotropic actions of these parent hormones and their metabolites, it is no surprise we see such a broad range of research. Overall, findings point to the benefits of DHEA in a state of deficiency or decline (such as aging), while both DHEA and PREG may be of benefit for mental health conditions, particularly those associated with stress. The research with PREG as an intervention for addressing pain is unique to it, and given the positive findings discussed in the 2020 publication, it is likely we will see further research in this arena. Similarly, the findings with addiction medicine are quite recent and will likely be further explored. Clearly, DHEA and PREG are worthy of consideration for many chronic conditions that are regularly seen in clinical practice.
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Allergy Research Group® FOCUS Newsletter | Fall 2021 SPECIAL EDITION
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Allergy Research Group FOCUS Newsletter | Fall 2021 SPECIAL EDITION