Adrenal Androgens in Human Physiology

Bruce R. Carr, M.D. William E. Rainey, Ph.D.

The human adrenal cortex produces aldosterone, cortisol, and the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS). Within the adult adrenal, the zona glomerulosa produces aldosterone, the zona fasciculata produces cortisol, and the zona reticularis produces both DHEA and DHEAS. The processes regulating aldosterone and cortisol synthesis are well-defined; however, the mechanisms regulating the production of DHEA continue to represent one of the most intriguing mysteries of endocrine physiology. In addition, the mechanism(s) for DHEA and DHEAS action has also proved to be illusive. Studies have shown that the administration of DHEA produces striking beneficial effects in animal models of obesity, cancer, diabetes, and atherosclerosis. This has caused scientists as well as the public to speculate on the importance of these “orphan” steroids in human aging and diseases. Progress in defining the mechanisms regulating DHEA production and action have increased in recent years, and it was our goal to ask the current and future leaders in this field to provide clinical and basic researchers with an update on what is now known concerning the physiology of these steroids.

Our issue commences with “Overview of Dehydroepiandrosterone Biosynthesis” by Dr. Auchus. He studies the regulation of steroid 17α-hydroxylase, 17,20 lyase (CYP17), which produces DHEA from pregnenolone. His insight into this enzyme as well as other factors that determine the adrenal's ability to produce DHEAS sets the stage for the other articles.

As noted earlier, it is not only the factors regulating adrenal androgen production that are not understood, but also the effects and mechanisms of action for the adrenal androgens. There has been a long and winding search for receptors that could bind either DHEA or DHEAS. Although no DHEA receptor has been genetically cloned, there is growing evidence that DHEA may act through cell surface receptors in certain tissue targets. Drs. Widstrom and Dillon provide a detailed review of the search for a receptor in their article entitled “Is There a Receptor for Dehydroepiandrosterone or Dehydroepiandrosterone Sulfate?”

The most well-documented mechanism for DHEA action is through peripheral metabolism to classic steroid hormones, such as estrogens and androgens. Dr. Labrie is the world's expert on this process, and he has coined the term intracrinology to describe the use of DHEA by peripheral target tissues for the production of other steroids. In his article, “Adrenal Androgens and Intracrinology,” he provides the most recent findings on how adrenal androgens can be used by tissues throughout the body and particularly the prostate.

Progress in defining the mechanisms that regulate DHEAS production has been hampered by the fact that adrenal secretion of DHEAS is absent or very low in all other mammals except primates. Studies on the in vivo regulation of DHEAS synthesis have therefore been limited to humans and nonhuman primates. However, even among the primates there appear to be considerable differences in the production of adrenal androgens. This has been eloquently summarized by Drs. Conley, Pattison, and Bird. Their review of the literature, entitled “Variations in Adrenal Androgen Production Among (Nonhuman) Primates,” provides important considerations, not only regarding differences in DHEA biosynthesis but also on the differences in the adrenal glands between these species.

For more than 20 years, we have had a research program directed at determining the mechanism regulating fetal adrenal DHEAS production. The primate adrenal produces large amounts of DHEA and DHEAS during fetal development that decrease rapidly after birth and remain low for the first 5 years of life. The production of fetal adrenal androgens surpasses those of the adult adrenal, and the fetal adrenal is the size of the kidney at birth. We summarize recent evidence suggesting that the fetal adrenal has the unique ability to respond to placenta-derived corticotropin-releasing hormone (CRH) and that CRH may be part of the reason the human fetal adrenal produces so much DHEAS. This evidence was present in our article with Dr. Rehman entitled “The Human Fetal Adrenal: Making Adrenal Androgens for Placental Estrogens.”

Levels of DHEA drop in infants and then begin to rise around 5 to 6 years of age and peak during the second decade of life. The process, called adrenarche, is still not understood, and to date no circulating factor has been found that might initiate the process. However, several recent studies have shown that the adrenal reticularis begins to enlarge at the time of adrenarche and that this zone expresses unique steroidogenic enzymes from the adjacent cortisol-producing tissue. Drs. Havelock, Auchus, and Rainey discuss both the biochemical and the clinical events associated with the rise in adrenal androgen production at adrenarche in their article “The Rise in Adrenal Androgen Biosynthesis: Adrenarche.”

An interesting aspect of circulating DHEAS in humans is that there are well-documented differences between the sexes, with men having higher levels than women have. This observation, which is often overlooked, is discussed in the article by Drs. Rehman and Carr. They provide what is currently known concerning these differences, as well as providing information on sex differences observed in other primate species, in “Sex Differences in Adrenal Androgens.”

Adrenal androgen production is not maintained at levels seen during early adulthood. Indeed, an age-dependent decline occurs, so that levels in octogenarians are similar to those seen in infants. Abnormally low levels of DHEAS have also been seen in serious medical illness, thermal injury, breast and ovarian cancer, hypercholesterolemia and increased cardiovascular mortality, osteoporosis, and human immunodeficiency virus (HIV) infection. Dr. Parker has dedicated a large portion of his long research career to better defining the mechanisms regulating DHEA production in the ill and aging. He summarizes what is known about these areas in two articles: “Adrenal Androgens and Aging,” coauthored with Dr. Dharia, and “Adrenal Androgens and the Immune System,” coauthored with Dr. Chen.

Finally, it is clear that DHEA is not an adrenal hormone that is necessary for life, and the role for DHEA therapy remains controversial. Dr. Arlt, who studies DHEA production and action, provides an exceptional article concerning what is currently known about DHEA replacement therapy. Her article, entitled “Dehydroepiandrosterone Replacement Therapy,” provides a fitting ending to our issue, summarizing what little is known about the function of this steroid.

We have enjoyed working with each of the authors who have participated on this project and wish to extend our thanks to them for contributing to this issue. In addition, we hope that “Adrenal Androgens in Human Physiology” provides an important resource for those in this field.

Figure caption: Bruce Carr, M.D. and William E. Rainey, Ph.D.