DHEA, Important Source of Sex Steroids in Men and Even More in Women

Abstract

A major achievement from 500 million years of evolution is the establishment of a high secretion rate of dehydroepiandrosterone (DHEA) by the human adrenal glands coupled with the indroduction of menopause which stops secretion of estrogens by the ovary. Cessation of estrogen secretion at menopause eliminates the risks of endometrial hyperplasia and cancer which would result from non-opposed estrogen stimulation during the post-menopausal years. In fact, from the time of menopause, DHEA becomes the exclusive and tissue-specific source of sex steroids for all tissues except the uterus.

Intracrinology, a term coined in 1988, describes the local formation, action and inactivation of sex steroids from the inactive sex steroid precursor DHEA. Over the past 25 years most, if not all, the genes encoding the human steroidogenic and steroid-inactivating enzymes have been cloned and sequenced and their enzymatic activity characterized. The problem with DHEA, however, is that its secretion decreases from the age of 30 years and is already decreased, on average, by 60% at time of menopause. In addition, there is a large variability in the circulating levels of DHEA with some post-menopausal women having barely detectable serum concentrations of the steroid while others have normal values. Since there is no feedback mechanism controlling DHEA secretion within ‘normal’ values, women with low DHEA will remain with such a deficit of sex steroids for their remaining lifetime.

Since there is no other significant source of sex steroids after menopause, one can reasonably believe that low DHEA is involved, in association with the aging process, in a series of medical problems classically associated with post-menopause, namely osteoporosis, muscle loss, vaginal atrophy, fat accumulation, hot flashes, skin atrophy, type 2 diabetes, memory loss, cognition loss and possibly Alzheimer’s disease. A recent randomized, placebo-controlled study has shown that all the signs and symptoms of vaginal atrophy, a classical problem recognized to be due to the hormone deficiency of menopause, can be rapidly improved or corrected by local administration of DHEA without systemic exposure to estrogens. In addition, the four domains of sexual dysfucntion are improved. For the other problems of menopause, although similar large scale, randomized and placebo-controlled studies usually remain to be performed, the available evidence already strongly suggests that they could be improved, corrected or even prevented by exogenous DHEA.

In men, the contribution of adrenal DHEA to the total androgen pool has been measured at 40% in 65–75-year-old men. Such data stress the necessity of blocking both the testicular and adrenal sources of androgens in order to achieve optimal benefits in prostate cancer therapy. On the other hand, the comparable decrease in serum DHEA levels observed in both sexes has less consequence in men who continue to receive a practically constant supply of testicular sex steroids during their whole life. In fact, in men, the appearance of hormone-deficiency symptoms common to women is observed at a later age and with a lower degree of severity. Consequently, DHEA replacement has shown much more easily measurable beneficial effects in women. Most importantly, despite the non-scientific and unfortunate availability of DHEA as a food supplement in the United States, a situation that discourages rigorous clinical trials on the crucial physiological and therapeutic role of DHEA, no serious adverse event related to DHEA has ever been reported in the world literature (thousands of subjects exposed) or in the monitoring of adverse events by the FDA (millions of subjects exposed), thus indicating, as expected from its known physiology, the excellent safety profile of DHEA. With today’s knowledge, one can reasonably suggest that DHEA offers the promise of a safe and efficient replacement therapy for the multiple problems related to hormone deficiency after menopause without the risks associated with estrogen-based or any other treatments.

Introduction

The unique physiological importance of DHEA in men was first recognized in the early 1980s when it was discovered that after complete medical castration achieved with gonadotropin-releasing hormone (GnRH) agonists in men suffering from prostate cancer (Labrie et al., 1980), 40–50% of active androgens were left in the prostate, thus indicating an important extratesticular source of androgens (Labrie et al., 1985). When pooling data obtained by various laboratories around the world, values of residual intraprostatic dihydrotestosterone (DHT) range from 25 to 50% for an average of 40% of DHT left in the prostate after castration (Labrie et al., 2009b). That originally surprising observation is now well explained by the transformation of DHEA into androgens and/or estrogens by specific steroidogenic enzymes in each cell type in each peripheral target tissue according to the process of intracrinology, an expression coined in 1988 (Labrie, 1991, Labrie et al., 1988, Labrie et al., 2005, Luu-The and Labrie, 2010).

While the supply of sex steroids from DHEA decreases in both men and women in a comparable fashion from the age of 30 years, men receive a practically continuous supply of testosterone, estrone (E₁) and estradiol (E₂) from the testicles during their whole life (Fig. 1) while, in women, E₂ secretion by the ovaries stops at menopause (Fig. 2). Consequently, after menopause, all estrogens and androgens are derived from DHEA which has already decreased by an average of 60% at time of menopause (Labrie et al., 2006) and continues to decrease thereafter (Fig. 3), with some women having barely detectable serum levels (Labrie, 2010). Since DHEA is the only source of sex steroids after menopause, it is reasonable to believe that such a decrease in DHEA-derived sex steroid availability, coupled with aging, is at least partially responsible for the numerous symptoms of hormone deficiency observed after menopause. These pertain to vaginal atrophy, bone loss, fat accumulation, type 2 diabetes, skin atrophy, cognition problems, memory loss and possibly Alzheimer’s disease (Labrie, 2007).

A major problem with DHEA, the only source of sex steroids after menopause, is that there is no feedback control of its secretion. In other words, there is no endogenous mechanism in either women or men to increase DHEA secretion when serum DHEA concentrations become low. Consequently, the only possibility to correct a clinically significant lack of DHEA availability in post-menopausal women is to administer exogenous DHEA in order to replace the amount of DHEA missing in these women. Such a replacement with DHEA can thus improve or even make the symptoms of hormone deficiency disappear as observed recently in women treated for vaginal atrophy, a classical consequence of hormone deficiency during post-menopause (Buster, 2009, Labrie et al., 2009a, Labrie et al., 2009b, Labrie et al., 2009c). In fact, the progressive and variable fall in serum DHEA starting in the thirties has been associated with a series of medical problems including cardiovascular mortality (Barrett-Connor et al., 1986), malignancy (Ebeling and Koivisto, 1994), osteoporosis (Sambrook et al., 1992) and a series of other medical problems to be discussed later.

Due to the marked decrease in the serum levels of DHEA starting in the thirties, a relatively long series of clinical studies have administered DHEA to women and men in order to correct various symptoms of hormone deficiency (Table 1, Table 2). One should be careful, however, about going as far as considering DHEA as the response to all problems of aging or a ‘fountain of youth’. Unfortunately, for more than 15 years, DHEA has been available over the counter and/or on the Internet, especially in the United States. This uncontrolled availability of DHEA raises serious concerns about self-administration of a series of DHEA formulations not submitted to the quality control process of pharmaceuticals required by regulatory agencies, with the result that the quantity and quality of the DHEA available in these formulations is very uncertain (Parasrampuria et al., 1998).

On the other hand, it should be mentioned that many studies reported as negative do not have the statistical power to reach any conclusion. One has always to consider that data which do not reach the statistical level of significance should not be interpreted as demonstration of an absence of effect. Critical evaluation must always be made of the design of the study, the precision of the parameters used to assess the effect(s) of treatment, the true placebo component, the population studied and, most importantly, the duration of treatment and the number of subjects investigated. As can be seen in Table 1, Table 2, the majority of studies examined the effect of DHEA in a too small number of subjects and/or the duration of treatment was too short to truly assess the potential changes induced by DHEA.

This chapter is an opportunity to briefly mention the beneficial effects of DHEA already observed in the literature and, as expected from the physiological mechanisms involved, to realize that no significant negative effect has ever been observed in any study reported, despite the high doses sometimes used. This lack of significant side effects could, up to an unknown extent, be related to the fact that a natural saturation mechanism limits the transformation of DHEA into androgens and/or estrogens in post-menopausal women at a serum DHEA concentration of about 7 ng/ml, a value well within the physiological range (Labrie et al., 2006).