Menopause Live (17 May, 2010) from IMS

Over the past 10 years, hormone preparations of dehydroepiandrosterone (DHEA) have been available over the counter and have been sold as the ‘fountain of youth’. This has raised concerns about the real clinical efficacy and the possible effects of such uncontrolled and widespread hormonal self-administration and the lack of quality control in this increasingly financially rewarding business. Susan Davis and colleagues recently reviewed the published literature on the effect of DHEA treatment in postmenopausal women [1]. The authors included only randomized, controlled trials that compared DHEA therapy with placebo in postmenopausal women not receiving other hormonal treatments. The end-points analyzed were measures of sexual function, well-being and safety such as lipids and carbohydrate metabolism. However, only nine well-designed studies are available in the literature that analyze sexual function and only seven trials that address the issue of well-being, but they differ by dose and treatment time, age of the women and measured function. More findings are available on the effects on lipid levels and insulin sensitivity, but studies still lack definitive evidence.
The authors concluded that there are little convincing data to support the use of oral DHEA in healthy postmenopausal women to improve conditions related to the aging process, such as reduced sexual function and reduced well-being.

Overview
This paper of Davis and colleagues renews the attention and the debate on one of the most attractive and controversial issues in the physiology of the aging process that is still far from being clearly defined by the scientific community. 
The most relevant aspect meriting attention is certainly the controversial finding among the studies that investigate the correlation of the endogenous DHEA sulfate (DHEAS) level, the aging process or organ illness with the results coming from studies focusing on the effects of exogenous DHEAS administration on brain function, sexuality, cardiovascular health and metabolic syndrome. 
Indeed, the marked age-related decline in serum DHEA and DHEAS has suggested that a deficiency of these steroids may be causally related to the development of a series of diseases that are generally associated with aging. The postulated consequences of low DHEA levels include insulin resistance, obesity, cardiovascular disease, cancer, reduction of the immune defense system as well as psychosocial problems such as depression and a general deterioration in the sensation of well-being and cognitive function [2].
There is also growing evidence in the literature that a low DHEAS level, representing the most abundant sex steroids in plasma in humans (more than 1000 times higher than estradiol and testosterone levels), negatively correlates with the domains of sexual function in pre- and postmenopausal women [3] to a greater extent than testosterone levels. Nonetheless, a DHEAS cut-off level for defining androgen deficiency syndrome has not been established. Similarly, in a cross-sectional study, higher endogenous DHEAS levels are independently and favorably associated with several measures of cognitive function and well-being [4]. 
As a consequence, DHEA replacement may seem an attractive treatment opportunity. Nevertheless, the analyses of clinical outcomes are far from being conclusive and many issues should still be addressed. Although DHEA preparations have been available in the market since the 1990s, there are very few definitive reports on the biological functions of this steroid, and it is still the case that its regulation is unclear and its mechanisms of action largely yet to be established. 
The great conundrum in this area is the lack of a clear mechanism of action of DHEA. It is known that this steroid serves as a precursor for estrogens and androgens, and many believe that DHEA is merely an inactive precursor pool for the formation of bioactive steroid hormones. To this extent, oral supplementation of DHEA in postmenopausal women results in the formation of significant amounts of 17β-estradiol and estrone, accompanied by increases in androstenedione, testosterone and dihydrotestosterone. This, plus the evidence that DHEA can also be converted into estrogens and other androgens within cells, supports the view that many actions of this steroid are indirect and mediated via estrogen and/or androgen receptors. However, the rate of DHEA metabolism into estrogen/testosterone in different tissues, the presence of enzyme regulators and the effect of the aging process on the intracrinology of DHEA require additional investigation. Indeed, DHEA administration in both early and late postmenopausal women directly affects the age-related changes in adrenal enzymatic pathways and steroid synthesis, including DHEA and progesterone [5]. 
There is, also, increasing evidence for DHEA acting in its own right through a dedicated, although as yet unidentified, receptor. The existence of such a receptor for DHEA has been particularly investigated in brain tissue and in vascular cells. In the brain, DHEA is a neurosteroid that acts as a modulator of neurotransmitter receptors, such as gamma aminobutyric acid type A, N-methyl-D-aspartate, and sigma-1 receptors. In vitro and in vivo documented effects involve neuroprotection, neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion, as well as anti-oxidant, anti-inflammatory and anti-glucocorticoid effects [6]. In the vessels, DHEA binds with high affinity to the endothelial cell membrane, and it is not displaced by structurally related steroids. Binding of DHEA to the cell membrane is coupled to recruitment of G proteins such as G{alpha}i2 and G{alpha}i3 that mediate the rapid activation of intracellular signaling cascades [7].
Although there is still debate on DHEA receptors, these findings corroborate the evidence that DHEA is not just a pre-hormone of the adrenals, but rather a hormone in its own right, and that it modulates a series of biological processes, with a remarkable tropism for the central nervous system.
Clinically, the spectrum of women that would benefit from DHEA therapy is not clearly defined and nor is the dosage of hormone treatment. Whether DHEA therapy could be prescribed as a general anti-aging therapy or could be an alternative treatment for women suffering from androgen deficiency syndrome remains uncertain across studies. In particular, among symptomatic women, the spectrum of symptoms responding to DHEA requires further investigation, to define the type of sexual symptoms (e.g. decreased sexual function or hypoactive sexual desire disorder) and the degree of mood/cognitive symptoms that could be responsive to hormonal treatment. Similarly, the definition of criteria for the choice of the starting dosage of DHEA to be prescribed in postmenopausal women needs further investigation: the extent of the symptoms, baseline DHEA(S) plasma levels, concomitant estrogen therapy or the combination of all the previous should be considered.
Plasma DHEA(S) levels at baseline and during treatment merit attention given that a cut-off value for DHEA(S) deficiency is not yet defined and the plasma level might not represent the rate of tissue conversion into estrogens or delta-4 androgens. This fact is also coupled with the route of administration of DHEA, given that oral, vaginal and parenteral administrations seem to induce different steroid concentrations in the plasma, with different clinical consequences and applications [8, 9]. 
All these findings may have far-reaching implications in the debate about the role of DHEA(S) in the female aging process and might reconcile discordant findings from basic science and clinical studies.


The lack of definitive evidence for biological mechanisms and the presence of only a few studies that address these emerging issues of DHEA therapy in postmenopausal women might encourage a new critical analysis of the available literature, evidencing current limits and incongruities. Concurrently, new clinical trials, specifically planned to relate to the biology of symptomatic postmenopausal women and designed for the translation of basic science into clinical practice, are now a required step to move forward the scientific debate on DHEA.


Andrea R. Genazzani
Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy

and

Nicola Pluchino
Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy

References
1. Panjari M, Davis SR. DHEA for postmenopausal women: A review of the evidence. Maturitas 2010 Jan 18. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/20089375
2. Labrie F, Luu-The V, Bélanger A, et al. Is dehydroepiandrosterone a hormone? J Endocrinol 2005;187:169-96.
http://www.ncbi.nlm.nih.gov/pubmed/16293766
3. Davis SR, Davison SL, Donath S, et al. Circulating androgen levels and self-reported sexual function in women. JAMA 2005;294:91-6.
http://www.ncbi.nlm.nih.gov/pubmed/15998895
4. Davis SR, Shah SM, McKenzie DP, et al. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008;93:801-8.
http://www.ncbi.nlm.nih.gov/pubmed/18073302
5. Genazzani AR, Pluchino N, Begliuomini S, et al. Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women. Gynecol Endocrinol 2006;22:627-35.
http://www.ncbi.nlm.nih.gov/pubmed/17145649
6. Maninger N, Wolkowitz OM, Reus VI, et al. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009;30:65-91.
http://www.ncbi.nlm.nih.gov/pubmed/19063914
7. Simoncini T, Mannella P, Fornari L, et al. Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Endocrinology 2003;144:3449-55.
http://www.ncbi.nlm.nih.gov/pubmed/12865324
8. Labrie F, Archer D, Bouchard C, et al. Serum steroid levels during 12-week intravaginal dehydroepiandrosterone administration. Menopause 2009;16:897-906.
http://www.ncbi.nlm.nih.gov/pubmed/19436226
9. Pluchino N, Ninni F, Stomati M, et al. One-year therapy with 10 mg/day DHEA alone or in combination with HRT in postmenopausal women: effects on hormonal milieu. Maturitas 2008;59:293-303.
http://www.ncbi.nlm.nih.gov/pubmed/18394829