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Neuroendocrine Theory of Aging Chapter 6

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.

 

Part I

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.

 

Part II

discussed how aging and stress combine to accelerate changes in the adaptive homeostat, resulting in the age-related disease, hyperadaptosis.

 

Part III

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.

 

Part IV

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.

 

Part V

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.

 

Introduction:

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.

 
LH is the primary controller of testosterone secretion by the Leydig cells in the testes. Testosterone circulates in the blood in several forms. Testosterone can be bound to both albumin and sex hormone-binding globulin (SHBG), where it is referred to as bound testosterone. It also circulates in a free (unbound) form. The free and albumin-bound forms of testosterone are the most active, while testosterone bound to SHBG is the least active form. Testosterone can exert its effects directly on the testosterone receptors in cells, or it may be converted to two active metabolites — dihydrotestosterone (DHT) or estradiol (E2). The enzyme 5 alpha reductase is essential for the conversion of testosterone to DHT, and aromatase is the enzyme which converts testosterone to estrogen (Fig. 2).

 

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).

As in the other homeostats (Adaptive, Energy, Immune, and Female Reproductive), Dilman (1981, 1994; Dilman and Dean, 1992) proposed that the major factor in the age-related dysfunction of the male reproductive homeostat (hypothalamic – pituitary – testes axis) is the progressive loss of hypothalamic sensitivity to the inhibitory effects of testosterone. This loss of hypothalamic sensitivity has been confirmed by a number of indirect studies.

Clomiphene citrate is a synthetic non-steroidal estrogen antagonist and stimulant of gonadotropins. Kulin and colleagues (1972) evaluated the amount of clomiphene citrate required to stimulate gonadotropic function in males of various ages. They found that only one mg was needed in prepubertal boys; 5 mg was adequate for young teenagers; but more than 500 mg was required in middle-aged and older men! Similar results were shown by Muta, et al (1981) and Kulin and Reiter (1972). Likewise, exogenous testosterone was found to be ineffective in reducing plasma LH in old male rats, compared to the response in young animals (Gruenwald and Matsumoto, 1991). Also, although testosterone levels show little change in most men through their forties, LH and FSH levels progressively rise throughout the lifespan (Fig. 3). This further suggests that there is a progressive decrease in the sensitivity of the hypothalamo – pituitary – gonadal axis to negative feedback. Additional confirmation of the hypothalamic involvement in dysregulation of testosterone is a link between age-related hyperinsulinemia (high blood levels of insulin) and decreasing levels of testosterone (Simon, et al, 1992). This lends further support to Dilman’s theory, as well as suggests another potential approach to improving male hormonal profiles — i.e., by restoring tissue sensitivity to glucose and insulin. Other scientists attribute the decline in testosterone production with age to a testicular defect, caused by impaired androgen synthesis and decreased Leydig cell responsiveness to LH (Swerdloff, et al, 1992). It is likely that this loss of Leydig cell activity is due to a desensitization of sex hormone receptors due to prolonged hyperstimulation by chronically elevated levels of LH (primarily) and FSH (both of which are due to the previously-mentioned loss of hypothalamic sensitivity). Another cause of the declining testosterone levels in men — both SHBG-bound and bioavailable (albumin-bound and free) — is that SHBG levels increase with age (Vermeulen and Verdonck, 1972) and albumin levels decrease with age. This results in a decline in bioavailable testosterone. Notably, the decline in bioavailable testosterone is even greater than the decline in total circulating testosterone. Wise (1998) emphasized that a principal cause of menopause in women is the disruption of regular circadian rhythms. The same may be true for men, although perhaps not to the same degree as for women, whose reproductive homeostat operates on a regular monthly cycle. An obvious chronobiological rhythm in both men and women is our daily sleep-wake cycle. Many people past 40 have increased difficulty sleeping. And the sleep they do get is of poorer quality. Sleep can also be disturbed by stress and other factors. Disturbance of the sleep wake cycle is itself a stressor, with adverse effects on other biological rhythms. In addition to the lower overall production of testosterone with aging, and the even more significant reduction of bioavailable testosterone, is a dramatic shifting of the circadian rhythmicity of testosterone production. Testosterone levels in young men are highest in the evening and early morning. However, this rhythmicity is greatly attenuated in older men (Fig. 4). Therefore, maintaining a regular sleep-wake cycle is a reasonable approach to reducing stress and normalizing other chronobiological cycles.

 

Delaying and Reversing Age-Related Changes in the Male Reproductive Homeostat

 

1. Maintain normal circadian rhythms

 

a. Melatonin

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.

 

b. GHB

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).

 

b. Melatonin

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.

 

c. DHEA

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.

 

d. Pregnenolone

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.

 

b. Yohimbe

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).

 

Conclusion

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.

 

References:

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

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