The Male Reproductive Homeostat
By Ward Dean, M.D.
Summary of the Neuroendocrine Theory to date, as published in previous issues of Vitamin Research News. The modern neuroendocrine theory of aging was first conceived in 1954 by the noted Russian gerontologist, Professor Vladimir Dilman. Several years ago, I had the pleasure of working with him on our book, The Neuroendocrine Theory of Aging and Degenerative Disease. In coming issues of Vitamin Research News, elements of this theory will be presented with recommendations for potential therapeutic intervention. Dilman’s theory, in essence, is that aging is caused by a progressive loss of sensitivity by the hypothalamus and related structures in the brain to negative feedback inhibition. This loss of sensitivity not only enables us to grow and develop, but is the cause of post-maturational diseases, aging and death. The neuroendocrine theory explains the cause of the major diseases of aging which contribute to over 85% of deaths of middle-aged and elderly individuals. These diseases include: (1) obesity, (2) atherosclerosis, (3) hypertension, (4) diabetes, (5) cancer, (6) autoimmune disorders, (7) metabolic immunodepression, and (8) hyperadaptosis. Two other diseases — depression and menopause — although not fatal, also occur regularly with age. Several of these diseases (hyperadaptosis, and metabolic immunodepression) have strange-sounding names, but as one gains an understanding of Dilman’s theory, these names will not seem so strange.
introduced the concept of homeostasis and how the progressive loss of hypothalamic sensitivity to inhibition by hormones and other signaling substances by the four homeostatic systems in the body results in growth, development and aging. Living organisms are characterized by their capacity to (1) reproduce, (2) adapt, (3) regulate the flow of energy, and (4) protect themselves. Consequently, these organisms have regulatory control systems (which Dilman called homeostats) that regulate and attempt to maintain homeostasis (balance) in each of these critical areas.
discussed how aging and stress combine to accelerate changes in the adaptive homeostat, resulting in the age-related disease, hyperadaptosis.
discussed the energy homeostat. Living systems are essentially energy-converting machines which run on fuel (food) to maintain their structure and activity. This section explained how dysfunction of the energy homeostat results in a decline in physical activity and metabolic rate, accompanied by subjective feelings of reduced energy, and increased fatigue, followed by the age-related diseases of (1) diabetes, (2) obesity, (3) essential hypertension, (4) atherosclerosis, (5) depression and (6) fatigue.
introduced the immune homeostat, which explains the cause of the decline of the body’s resistance to disease, how the cause of this decline is related to the neuroendocrine theory, and how immunity can be restored.
provided an overview of how the female reproductive homeostat functions, what causes it to cease functioning (resulting in menopause), what are the physiological and psychological correlates of menopause, and how we may alleviate these symptoms and adverse effects, and restore optimum functioning.
This latest installment in the Neuroendocrine Theory of Aging series will discuss how the male reproductive homeostat functions, what causes the decline in its performance with age, what adverse effects result from these changes, and how these changes may be delayed and, in some cases, reversed.
The Male Reproductive Homeostat
The male reproductive homeostat consists of: (1) the central nervous system (CNS) including the hypothalamus; (2) the pituitary; (3) the testes; and (4) the end organs where testicular steroids and peptides act (Fig.1). Gonadotropin releasing hormone (GnRH) is synthesized in the hypothalamus and is released in a pulsatile fashion into the hypophyseal-portal blood system, which connects the hypothalamus and pituitary. GnRH production and release is controlled by neurotransmitters such as norepinephrine, dopamine, and endorphins. GnRH regulates the pulsatile release of two pituitary hormones — the gonadotropins — luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH act on the testes to stimulate the secretion of testosterone and to regulate production of sperm.
Cause(s) of Age-Related Alterations of the Male Reproductive Homeostat
With age, testosterone levels begin to decline (Fig. 3). Simultaneously, a number of related physiological changes can be noted. These changes include decreasing muscle mass, increasing body fat, reduced physical energy and endurance, gradually decreasing libido accompanied by reduced frequency of sex (the senior slump) (Fig. 5), loss of bone density, and increase in cholesterol and circulatory system changes which contribute to many of the previous symptoms. The average human male begins to feel some of the signs of aging after age 40, with rapid deterioration after 50 years of age (Ottinger, 1998).
Delaying and Reversing Age-Related Changes in the Male Reproductive Homeostat
1. Maintain normal circadian rhythms
One cause of disturbed sleep as we age is the reduction in nightly release of melatonin by the pineal gland (Fig. 6). Many people have found that bedtime doses of melatonin have restored their ability to obtain a sound, restful night’s sleep.
Although GHB, and presumably its precursors GBL and BD, has now been relegated to the same classification as crack cocaine and heroin by the passage of Public Law 106-172, I remain convinced that GHB, GBL and BD are among the safest and most effective anti-aging substances known. An even stronger sleep-inducing agent than melatonin, GHB has been notoriously mis-named and unjustly vilified as the date rape drug. In addition to enhancing normal sleep, resulting in a significant release of growth hormone, GHB (and its precursors, GBL and 1,4 BD) has a number of other positive effects on health. See previous issues of Vitamin Research News (or VRP’s website — www.vrp.com) for articles on the many healthful aspects of this unique but much-misunderstood and now all-but-unavailable supplement.
2. Prevent Loss of Hypothalamic Sensitivity and Restore Sensitivity Using Cell Resensitizers
Based on his understanding of the mechanism underlying age-related hormonal alteration, Dilman researched means of reversing that mechanism using hypothalamic receptor sensitizers. Such sensitizers, he reasoned would literally rejuvenate the various homeostats. This is an extremely fruitful area for pharmaceutical and nutritional research. The following substances are believed to restore hypothalamic (central) or peripheral (end organ) receptor sensitivity to testosterone.
a. Neurotransmitter modulation
Alterations of catecholamine neurotransmitters (epinephrine, norepinephrine, dopamine), as well as a shifting balance of the catecholamine/serotonin ratio are proposed to be a principal cause of the loss of hypothalamic sensitivity (Dilman, 1981) (Fig. 7). Approaches to correcting these neurotransmitter imbalances include the administration of the selective MAO-B inhibitor, Deprenyl, as well as neurotransmitter precursors like the amino acids tyrosine, phenylalanine, L-DOPA, GABA, and 5-HTP. Dilman (1981; Dilman and Dean, 1992) presented evidence that appropriate use of these substances restores hypothalamic sensitivity to varying degrees. For a complete review of nutritional approaches to normalizing these neurotransmitter systems, see Dr. Lane Lenard’s article, Circadian Rhythm Synchronicity in the April, 1999 issue of Vitamin Research News or via VRP’s website at www.vrp.com.
b. Metformin/Goat’s Rue
Metformin is an anti-diabetic drug with profound anti-aging properties. Metformin acts to resensitize the hypothalamus to negative feedback inhibition by steroid hormones. Metformin use results in numerous beneficial effects in non-diabetic people, including lowering cholesterol and triglycerides, reducing glucose and insulin, stimulating immunity and preventing atherosclerosis. In addition, based on the previously cited work of Simon, and colleagues (1992), metformin may also increase testosterone levels by normalizing blood glucose and insulin levels. Phenformin (a less effective analog of metformin) also extended the maximum lifespan of rats and mice (Dilman, 1981). Goat’s Rue (Galega officinalis), which contains guanidine, is the herbal prototype of the biguanide class of pharmaceuticals (Metformin, Phenformin). Presumably (although the research is sparse), Goat’s Rue would act in the same manner as Metformin.
c. Puncture Vine (Tribulus terrestris)
Tribulus is an herb that has been used since ancient times in India as a treatment for both male and female sexual problems. It has been widely tested for its efficacy in enhancing sperm quality and mobility, and for increasing libido and sexual performance in experimental animals and men. It is also widely used as a body building substance. Tribulus administration results in an increase of LH levels by 72%, and free testosterone levels by 41% (Chemical Pharmaceutical Institute Product Literature). The actions of Tribulus are complex. Since it enhances spermatogenesis, it must act by enhancing the activity of FSH upon the Sertolli cells in the testes (which produce sperm), since FSH levels do not increase. However, Tribulus also seems to stimulate the hypothalamus (or perhaps, the pituitary) directly to increase the secretion of LH, resulting in an elevation of testosterone. Tribulus could also have a direct sensitizing action on the Leydig cells of the testes, which produce testosterone in response to LH.
d. Chaste Berry (Vitex agnus castus)
Chaste berry appears to act at the hypothalamic level by increasing secretion of LH and decreasing FSH. This helps to restore gonadotropin levels to a more youthful profile. Chaste berry also causes a relative increase in progesterone and a relative decrease in estrogens. Although chaste berry has traditionally been used to treat a variety of menopausal symptoms in women, I believe that it may have beneficial effects on men, as well. Experience with this herb in men is limited, however.
3. Hormone Replacement Therapy (HRT)
a. Testosterone and testosterone precursors
In humans, replacement therapy with testosterone considerably improves the quality of life in a great number of men after middle age. Replacement of testosterone may also prolong the duration of life by reducing the severity of age-associated diseases like osteoporosis and cardiovascular disease, which are among the leading causes of disability and death. Various forms of synthetic testosterone have traditionally been used. These include injectable testosterone and oral or sublingual methyltestosterone. While these synthetic hormones have been widely used with beneficial effects, there are drawbacks to their use. The injectable testosterones act over days or weeks. Consequently, this obviously eliminates the natural daily diurnal rhythm of testosterone production—high at night and early morning, and low during the day. The shortest-acting version—methyltestosterone—is fairly toxic to the liver, and is not recommended. A short-acting injectable form is so painful that it is rarely used. Recently, natural forms of testosterone have become available which have all of the benefits of the synthetic hormones, and little to none of their adverse side effects. Dr. Jonathan Wright, author of Natural Hormone Replacement for Women over 45, has also written Maximize Your Vitality and Potency for Men Over 40. Dr. Wright describes the availability of natural testosterone preparations which can be dispensed by compounding pharmacists upon request from a licensed physician. Alternatives to testosterone include the testosterone precursors androstenedione and androstenediol (Earnest, et al, 2000), which are available in oral capsules or sublingual sprays. The sublingual sprays are the most bioavailable forms of these substances, since they are absorbed directly into the blood stream, thereby avoiding the first pass inactivation by the liver. A potential adverse effect of these precursors (or any form of testosterone, for that matter) is the possibility of their conversion to estrogen, via the enzyme aromatase (Fig. 2).
As previously mentioned, melatonin levels are known to drop dramatically with age (Fig. 6). Since melatonin and FSH appear to be antagonistic in women (Fernandez, et al, 1990) — it is not unreasonable to assume that the same relationship holds true in men. It is not unreasonable to propose that melatonin may even act to normalize (lower) gonadotropin levels. Significantly, it is also one of the few substances that repeatedly has been shown to extend the maximum lifespan of experimental animals.
DHEA—an adrenal hormone—is the most abundant steroid hormone in the body. DHEA levels plummet—more than any other hormone—dramatically and predictably with age. William Regelson, M.D. (1995), reviewed the effect on male sexual function as documented in the groundbreaking Massachusetts Male Aging Study. This study investigated, among other things, sexual function and activity in men aged forty to seventy. Of the seventeen hormones measured in each of the men, only one showed a direct and consistent correlation with impotence — DHEA. As DHEA levels declined, the incidence of impotence increased. Other reported effects of increased DHEA include reduction in blood insulin and glucose, increased lean body mass and reduction in fat, increased bone density, and lowered cholesterol and blood pressure.
Although pregnenolone has not been studied as extensively as DHEA, because it is a precursor of DHEA, and because it appears to decline as rapidly as DHEA, I believe it should also be considered in a comprehensive hormonal replacement regimen. Pregnenolone is best tested for its ability to alleviate depression and improve mood, and enhance cognitive performance. It also has corticosteroid-like anti-inflammatory effects, without joint-destroying catabolic effects of corticosteroids (Regelson, 1995).
4. Prevent Adverse Effects of Hormone Therapy
a. Indole-3-Carbinol (I3C)
Several studies have demonstrated that Indole-3-Carbinol (I3C) dramatically accelerates the metabolism and excretion of estrogens in both men and women. Athletes who had problems with estrogenic conversion of testosterone and other anabolic steroids have noted dramatic alleviation of their symptoms. I3C also appears to be of benefit to cancer patients with estrogen-sensitive tumors (J Nat Cancer Inst, 1997).
b. Saw Palmetto, Pygeum, Stinging Nettle
These three herbs contain phytonutrients that block the enzyme 5 alpha reductase, which converts testosterone to its active metabolite, dihydrotestosterone (DHT). DHT is believed to be the major cause of male pattern baldness, and a contributing factor in the pathogenesis of benign prostatic hypertrophy (BPH) (estrogen is believed to be another potential cause).
5. Miscellaneous Enhancers of Male Reproductive Homeostat Function
a. Muira Puama
Muira Puama, also known as potency wood, is native to Brazil, and has long been used as a powerful aphrodisiac and nerve stimulant in South American folk medicine. Muira Puama may be effective in restoring libido and treating erectile dysfunction. In one study, 262 patients with libido and potency problems were given Muira Puama extract. Within two weeks, at a daily dose of 1 to 1.5 grams of the extract, 62% of the patients with loss of libido claimed that Muira Puama had been of benefit (Wayneburg, 1990). The mechanism of action of Muira Puama is unknown.
Yohimbe (YoconTM — yohimbine hydrochloride) is the only substance that is listed in the Physician’s Desk Reference as a potential male aphrodisiac. Yohimbe has been traditionally used to enhance male potency and libido, by its effect as an alpha adrenergic stimulant. Several studies have attested to its effectiveness (Susset, J.G., 1989; Morales, 1987).
Despite his pioneering research and far-reaching ideas, Vladimir Dilman is unfortunately largely unrecognized by modern scientists. Despite the fact that modern sophisticated analytical techniques provide continuing and increasing validation of his theories, he is rarely cited in modern literature. His recognition of the loss of hypothalamic sensitivity as a key factor in the aging process, leading to his innovative work in developing hypothalamic receptor sensitizers, are major breakthroughs in the development of techniques to retard and in some cases even reverse various aspects of aging. Dilman certainly deserves more widespread recognition and respect for his pioneering work in the field of anti-aging medicine and life extension.
1. Bremer, J. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab, 1983, 56: 1278-1281.
2. Chemical Pharmaceutical Institute, Sofia, Bulgaria. Review of scientific literature. Product Literature.
3. Dilman, V.M. The Law of Deviation of Homeostasis and Diseases of Aging, John Wright, Littleton, 1981.
4. Dilman, V.M., and Dean, Ward. The Neuroendocrine Theory of Aging and Degenerative Disease. The Center for Bio-Gerontology, 1992, Pensacola, Florida.
5. Dilman, Vladimir. Development, Aging and Disease—A New Rationale for an Intervention Strategy, 1994, Harwood Academic Publishers, 820 Town Center Drive, Langhorne, Pennsylvania 19047.
6. Earnest, C.P., Olson, M.A., Broeder, C.E., Breuel, K.F., Beckham, S.G. In vivo 4-androsene-3, 17-dione and 4-androstene-3 beta, 17 beta-diol supplementation in young men, Eur J Appl Physiol, 2000, 81: 229-232.
7. Fernandez, B., Malde, J.L