Neuroendocrine Theory of Aging Chapter 5

The Female Reproductive Homeostat

By Ward Dean, M.D.

Introduction: This installment provides 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 the menopause, and how we may alleviate these symptoms and adverse effects, and restore optimum functioning.

Functional Organization of the Female Reproductive Homeostat
The female reproductive homeostat is a closed-loop system that consists of the hypothalamus, pituitary, and ovaries (Figure 1). The system is often considered a homeostatic system-that is, one which is maintained in a relative state of stability by the stimulatory and inhibitory effects of various hormones and endocrine factors.

A simplified explanation of the operation of this system is that estrogen and progesterone, when present in relatively high amounts, act through feedback inhibition to suppress the release of follicle stimulating hormone (FSH) and leutinizing hormone (LH). FSH and LH, produced by the anterior pituitary, are also known collectively as gonadotropins. Likewise, when levels of estrogen and progesterone drop, the hypothalamus senses this and triggers the release of gonadotropin-releasing hormone (GnRH). GnRH is produced by the hypothalamus, and stimulates the release of FSH and LH by the pituitary. FSH and LH act in sequence on the ovary to produce the two primary female hormones, estrogen and progesterone. Other substances produced by the ovary include testosterone, inhibin, activin, and relaxin. Functions of these latter three substances are not well defined and are still under investigation.

If this system were truly homeostatic, it would remain forever in balance from the time of childhood on-i.e.., the small amount of estrogen produced in childhood would inhibit any increase in FSH and LH, thus growth and development would not take place. In 1954, Dilman hypothesized that a progressive loss of hypothalamic sensitivity to negative feedback inhibition resulted in a progressive shifting of homeostasis throughout the lifespan-and that this shifting of homeostasis was the primary cause of growth, development and aging. According to Dilmans then-revolutionary theory, it is this continued shifting of homeostasis in the various homeostats (adaptive, energy, immune, and reproductive) during adulthood that is a major cause of aging and the diseases of aging.

Menopause-Age-related Disease of the Reproductive Homeostat
Dilman (1981) defined disease as any persistent deviation from homeostasis, because such deviation increases the probability of death. Menopause, characterized by the cessation of menstruation, not only signals the end of the reproductive lifespan, but also the beginning of a multitude of profound, far-reaching alterations in hypothalamic-pituitary-ovarian relationships. That results in adverse effects on cognitive and cardiovascular function, bone density, and increased risk of many age-related diseases (Wise, 1998) (Table I).

For many years, scientists believed that menopause resulted simply from the ovaries running out of eggs. However, recent research is now confirming Dilmans theories with regard to the pathogenesis of menopause. It is now being realized that ovarian follicular exhaustion originates in the brain, rather than the ovary.

At birth, the human ovary has 300-400,000 ovarian follicles. After birth, this number decreases rapidly. The rate of loss then slows somewhat from ages 25-38, and then resumes at a rapid rate until completely exhausted sometime during a womans fifties (Gougeon, et al, 1994) (Fig. 2).

Strikingly, if the rate of follicular loss remained unchanged throughout the lifespan, the ovarian follicular reserve would not be exhausted until a woman was in her 100s! This accelerated follicular loss precedes the onset of menopausal symptoms by about nine years.

Cause of Ovarian Follicular Exhaustion
What are the factors that lead to this dramatic increase in follicular loss at such a relatively youthful age? Scientists are now beginning to agree that the brain, not the ovary, is the critical pacemaker in the sequence of events leading to reproductive senescence. Increasing evidence is now confirming Dilmans hypothesis that deterioration at the hypothalamic level is the trigger for the constellation of events that leads to menopause. Professor Phyllis Wise (1998) of the Department of Physiology, College of Medicine, University of Kentucky in Lexington, states that multiple [brain] signals are altered during aging and that the dampening and desynchronization of the precisely orchestrated circadian neural signals lead to miscommunication between the brain and the pituitary-ovarian axis. Dr. Wise believes that the increasing desynchronization of these hypothalamic signals contributes to the accelerated rate of follicular loss. Using analytical techniques that were not available to Dilman forty years ago, she has focused a great deal of research on identifying the specific hypothalamic site that is responsible for triggering menopause, locating it in the supra-chiasmic nucleus (SCN) of the hypothalamus.

As the number of active follicles decrease, levels of estrogens and progesterone decrease-because it is the ovarian follicle (and corpus luteum) where these hormones are synthesized by the body. The decreased levels of these hormones result in diminished feedback inhibition on the hypothalamus and pituitary, resulting in elevated levels of FSH and LH (Fig. 3). It is likely that the loss of hypothalamic sensitivity to the inhibiting effects of estrogen and progesterone is what causes the initial elevation and subsequent exacerbation of the progressively higher levels of the gonadotropins.

Dilman proposed that the loss of hypothalamic sensitivity-the key factor in the progressive shifting of homeostasis-is due to changes in the pattern and synchronization of a number of neurotransmitter and neuroendocrine signals. These changes begin during middle age in women (Reame, et al, 1996; Matt, et al, 1994), and are the most likely explanation for the accelerated loss of follicles that occurs during the perimenopausal period. Approaches to Delay Aging-Related Changes in the Reproductive Homeostat

1. Maintain Normal Circadian Rhythms
An obvious fact to everyone is that menopause signals the end of a womans most obvious chronobiological rhythm-the menstrual cycle. Exogenous factors like chronic or excessive stress can adversely affect a womans menstrual regularity, fertility, and can even accelerate the onset of menopause (see The Neuroendocrine Theory, Part II). Wise (1998) emphasizes that a principal cause of menopause is the disruption of regular circadian rhythms.

Another obvious chronobiological rhythm is our daily sleep-wake cycle. This cycle, too, can be disturbed by stress-and disturbance of this cycle is in itself a stressor, with adverse effects on other biological rhythms. Many people past 40 have increased difficulty sleeping, and poorer quality of what sleep they do get. Therefore, maintaining a regular sleep-wake cycle is a reasonable approach to reducing stress and normalizing other chronobiological cycles. Grandmas advice of early to bed and early to rise. appears to be sound in the light of recent research findings.

A. Melatonin
One cause of disturbed sleep as we age is the reduction in nightly release of melatonin by the pineal gland (Fig. 4). Many people have found that bedtime doses of melatonin have restored their ability to obtain a sound, restful nights sleep. (See the menopause-fighting capabilities of melatonin outlined in greater detail below.)

In addition to the endogenous causes of dysregulation of our sleep-wake cycle (i.e., age-related drop in melatonin production), we should as much as possible maintain regular hours. Frequent disturbance of normal circadian rhythms is experienced by shift workers like police officers and nurses, as well as transcontinental airline crews due to the frequent time zone/shift changes they experience. Many pilots and flight attendants complain that the frequent disruptions of their normal sleep-wake cycles cause them to age before their eyes-significantly more rapidly than their peers who maintain more normal schedules. Their symptoms of jet lag are frequently greatly reduced or completely eliminated with appropriately-timed melatonin.

B. GHB
An even stronger sleep-inducing agent than melatonin is GHB (gamma hydroxy butyric acid)-the substance that has been notoriously mis-named and unjustifiably villified 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.

All of my GHB-consuming airline pilot patients report that they are better rested and more alert when at the controls, now that they can get a solid, restful sleep during their turnarounds. See previous issues of Vitamin Research News for articles on the many healthful aspects of this unique but much-misunderstood 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 act by restoring hypothalamic sensitivity to estrogens and progesterone.

A. Neurotransmitter Modulators
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. 5). 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 and 5-HTP. Dilman (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 Lenards article, Circadian Rhythm Synchronicity in the April, 1999 issue of Vitamin Research News.

B. Metformin/Goats 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. In addition to numerous beneficial effects in non-diabetic people, including lowering cholesterol and triglycerides, reducing glucose and insulin, stimulating immunity and preventing atherosclerosis, phenformin (a less effective analog of metformin) also causes resumption of estrus (peak of the sexual cycle in animals, culminating in ovulation) in old rats (Anisimov, 1980) and extends the maximum lifespan of rats and mice (Dilman, 1981).

Goats Rue (Galega oficinalis), which contains guanidine, is the herbal prototype of the biguanide class of pharmaceuticals (Metformin, Phenformin). Presumably (although the research is sparse), Goats Rue would act in the same manner as Metformin.

C. Tribulus terrestris (Puncture vine)
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 eliminating menopause-related hot flashes, insomnia, depression, and loss of libido. It performs these function without altering ovarian hormone levels, while profoundly suppressing prolactin and gonadotropins.

D. Vitex agnus castus (Chaste Berry)
Chaste berry appears to act at the hypothalamic level, by increasing secretion of LH and decreasing FSH. This results in a restoration of gonadotropin levels (see Fig. 2) to a more youthful profile. Chaste berry also causes a relative increase in progesterone and a relative decrease in estrogens. Chaste berry has traditionally been used to treat a variety of menopausal symptoms.

E. Cimicifuga racemosa (Black Cohosh)
Black cohosh has a long history of use by American Indians to relieve menstrual cramps. Europeans use it against menopausal depression. Phytochemicals in black cohosh also decrease LH.

3. Hormone Replacement Therapy (HRT)

A. Estrogen and Progesterone
In humans, replacement therapy with estrogens and progesterone considerably improves the quality of life of a great number of postmenopausal women by ameliorating sexual and some nonsexual functions. HRT with estrogens and progesterone 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 estrogen have traditionally been used to prevent or treat many menopausal symptoms. Unfortunately, most physicians rely on these synthetics which, while providing significant relief to many women, often are accompanied by adverse effects, and their use is known to increase the risk of breast and endometrial (uterine) cancer.

Recently, natural forms of estrogen (and progesterone) have become available which have all of the benefits of the synthetic hormones, and little to none of their adverse effects (including reduced incidence of cancer). Dr. Jonathan Wright, author of Natural Hormone Replacement for Women over 45, has formulated several combinations of natural estrogens that are widely available. These hormonal preparations can be dispensed by compounding pharmacists upon request from a licensed physician. Another excellent book on the subject is David Brownstein, M.D.s The Miracle of Natural Hormones (248) 851-1600.

For information on the menopause-fighting benefits of natural progesterone, also see Natural Progesterone-the Feel Good Hormone, in the April and May, 1997 issues of VRP Nutritional News (available upon request from VRP, or on VRPs website). The definitive treatise on natural progesterone use is Natural Progesterone-The Multiple Roles of a Remarkable Hormone, by John Lee, M.D. (BLL Publishing, P.O. Box 2068 Sebastopol, California 95473).

B. Phytoestrogens
Alfalfa, soybeans, and the Chinese herb, Angelica sinensis (Dong Quai) contain high amounts of some of the most widely studied phytoestrogens. These phytoestrogens include coumestans, and the isoflavonoids genistein and daidzein, and have been previously discussed in detail (Dean, 1998)

C. Melatonin
As previously mentioned, melatonin levels are known to drop dramatically with age. Melatonin and FSH appear to be antagonistic. It has been found that the higher a womans level of FSH, the lower her levels of melatonin (Fernandez, et al, 1990). It is not unreasonable to propose that melatonin may even act to normalize (lower) gonadotropin levels. This may be the idea behind a melatonin-containing pill that has been developed to specifically treat menopausal problems.

Michael Cohen, M.D., Ph.D.,

Director of Applied Medical Research Ltd., is the developer of an experimental formula-M-Oval-designed to relieve some of the symptoms of menopause, including insomnia, hot flashes, and irritability.

The formula combines 75 mg (!) of melatonin, plus a small amount of estrogen (Reiter and Robinson, 1995). The M-Oval formula is believed to have the potential to relieve the symptoms of menopause, as well as reduce the risk of heart disease and breast cancer.

Melatonin, significantly, is also one of the few substances that repeatedly has been shown to extend the maximum lifespan of experimental animals. (Figure 7)

D. 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 potential of DHEA to alleviate menopausal symptoms. He also discussed several European pharmaceutical products that utilize DHEA. One, to alleviate menopausal hot flashes and depression, and another as a replacement for estrogen. DHEA offers many of the same benefits of estrogen without estrogens potentially harmful side effects. Other effects of DHEA that have been reported 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 has some estrogenic qualities, but 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 the joint-destroying catabolic effects of the corticosteroids (Regelson, 1995; Sahelian, 1997).

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 technique.

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