Dehydroepiandrosterone Research: Past, Current, and Future.

The discovery of "oestrus-producing" hormones was a major research breakthrough in biochemistry and pharmacology during the early part of the 20th century. The elucidation of the molecular weight and chemical structure of major oxidative metabolites of dehydroepiandrosterone (DHEA) led to the award of the Nobel Prize in 1939 to Adolf Frederick Johann Butenandt and Leopold Ruzicka. Considered a bulk androgen in the circulation, DHEA and its sulfated metabolite DHEA-S can be taken up by most tissues where the sterols are metabolized to active androgenic and estrogenic compounds needed for growth and development. Butenandt's interactions with the German pharmaceutical company Schering led to production of gram quantities of these steroids and other chemically modified compounds of this class. Sharing chemical expertise allowed Butenandt's laboratory at the Kaiser Wilhelm Institute to isolate and synthesize many steroid compounds in the elucidation of the pathway leading from cholesterol to testosterone and estrogen derivatives. As a major pharmaceutical company worldwide, Schering AG sought these new biological sterols as pharmacological agents for endocrine-related diseases, and the European medical community tested these compounds in women for conditions such as postmenopausal depression, and in men for increasing muscle mass. Since it was noted that circulating DHEA-S levels decline as a function of age, experimental pathology experiments in animals were performed to determine how DHEA may protect against cancer, diabetes, aging, obesity, immune function, bone density, depression, adrenal insufficiency, inflammatory bowel disease, diminished sexual function/libido, AIDS/HIV, chronic obstructive pulmonary disease, coronary artery disease, chronic fatigue syndrome, and metabolic syndrome. While the mechanisms by which DHEA ameliorates these conditions in animal models have been elusive to define, even less is known about its role in human disease, other than as a precursor to other sterols, e.g., testosterone and estradiol. Our groups have shown that DHEA and many of its oxidative metabolites serve as a low-affinity ligands for hepatic nuclear receptors, such as the pregnane X receptor, the constitutive androstane receptor, and estrogen receptors α/β (ERα/ERβ) as well as G protein-coupled ER (GPER1). This chapter highlights the founding research on DHEA from a historical perspective, provides an overview of DHEA biosynthesis and metabolism, briefly summarizes the early work on the beneficial effects attributed to DHEA in animals, and summarizes the human trials addressing the action of DHEA as a therapeutic agent. In general, most human studies involve weak correlations of circulating levels of DHEA and disease outcomes. Some support for DHEA as a therapeutic compound has been demonstrated for postmenopausal women, in vitro fertilization, and several autoimmune disorders, and adverse health effects, such as, acne, embryo virilization during pregnancy, and possible endocrine-dependent cancers.