Androgens and aging men
Introduction
In women's life, when they are approximately 50 years old, a remarkable event occurs still at the same age as a century ago when longevity was much shorter, ovulation stops and, therefore, fertility and consequently estradiol, the archetypal estrogen, becomes very low in the blood—lower (naturally in absence of replacement administration) than it is in men and even aging men (Table 1, Vermeulen et al., 1999). In women, hormone replacement therapy, mainly with estrogen, has obtained a recognized benefit for several estrogen deficit-associated physical impairments, the XXth century was that of the discoveries of sex hormones, of their main mechanism of action at the gene expression level via nuclear receptors, and of the synthesis of synthetic active derivatives and preparations permitting relatively easy utilization, including thanks to recent specific estrogen receptor modulators (SERMs) which may display differential activity in different receptor-positive target cells.
Where are we, men of my generation whose mean life expectancy, particularly in our ‘advanced’ countries, is several years shorter than that of women, even reaching 80 years for approximately half of us? Clearly the second part of men's life is not as hormonally standardized and selective as in women, even some decline of the testicular endocrine function is always there (Tenover et al., 1988, Vermeulen and Deslypere, 1985), the decrease of blood testosterone (Fig. 1, Seidman and Walsh, 1999) and its active metabolite 5α-dihydrotestosterone (DHT; Fig. 2) is globally incomplete but variably according to individuals, whose several other health parameters may be deficient while fertility, even certainly decreased, is, however, far to be abolished, many sperm characteristics are preserved (Nieschlag et al., 1982), but Sertoli cells are functionally diminished. What is functionally much a problem in terms of quality of life has been summarized under the heading of ‘climacteric’ symptoms (Table 2; Bauer, 1944, McKinlay et al., 1989, Werner, 1946, Heinemann et al., 1999), very similar to those of women with an emphasis on the decrease of sex life components—from diminished sexual desire to several forms of impotence. If the hormonal status of menopause, even including the pre- and perimenopausal symptoms, is rather rapidly established in a few months, there is a long period—many years—during which a ‘partial Androgen Deficiency in Aging Men’, the so-called PADAM, is slowly progressing, even the precise criteria have not yet been established. It follows that it is particularly difficult to decide if the observed physical (and mental) changes in aging men are dependent on hormonal modifications, or whether the androgen deficit is consequent of age-related alterations. Consequently, one may predict that androgen substitution is difficult to rationalize and its potential beneficial effects relatively uncertain. However, currently PADAM is increasingly recognized as important for health and quality of life issue. To give approximative values exemplifying the hormonal deficit, we may cite the mean level observed in 75 years old men as 2/3rd of that of young men, sexual dysfunction in young men being observed when testosterone is ≤3 ng/ml (≤10 nmoles). The bioavailable testosterone is lower in 25% of aged men than the lowest normal young values.
Section snippets
Hormones
The basis of any scientific reasoning is to be found in publications measuring carefully hormonal and other behavioral and physical parameters. Circulating (plasma) testosterone, practically of only testicular origin, decreases each year of approximately 0.5–1% between 40 and 70 years, and this decrease of circulating testosterone is logically associated to (and probably responsible for) modest LH increase (Morley et al., 1997a, Morley et al., 1997b), with attenuation of secretory burst
DHEA(S)
In most men as in most women, there is a profound decrease of DHEA(S) correlated with age (Orentreich et al., 1984, Fig. 5). DHEA(S) means DHEA itself, the unconjugated form in a few ng/ml concentration, and DHEAS, its ester-sulfate form, principally of adrenal secretion origin and very abundant: still in more than 60 years old men, normal values are in the μg/ml range. Both forms are decreased in aging. As indicated in Fig. 6, DHEAS has to be hydrolyzed to give DHEA which itself is metabolized
A few clinically related remarks
Aging is not a synchronous process as far as its different characteristics, it is even more evident clinically than hormonally. I only write down a few remarks.
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