Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEA-S) in Mammalian Reproduction: Known Roles and Novel Paradigms

Steroid hormones form an integral part of normal development in mammalian organisms. Cholesterol is the parent compound from which all steroid hormones are synthesized. The product pregnenolone formed from cholesterol serves as precursor for mineralocorticoids, glucocorticoids, as well as dehydroepiandrosterone (DHEA) and its derived sexual hormones. DHEA assumes the prohormone status of a predominant endogenous precursor and a metabolic intermediate in ovarian follicular steroidogenesis. DHEA supplementation has been used to enhance ovarian reserve. Steroids like estradiol and testosterone have long been contemplated to play important roles in regulating meiotic maturation of oocytes in conjunction with gonadotropins. It is known that oocyte priming with estrogen is necessary to develop calcium (Ca²⁺) oscillations during maturation. Accruing evidence from diverse studies suggests that DHEA and its sulfate (dehydroepiandrosterone sulfate, DHEA-S) play significantly vital role not only as intermediates in androgen and estrogen formation, but may also be the probable 'oocyte factor' and behave as endogenous agonists triggering calcium oscillations for oocyte activation. DHEA/DHEA-S have been reported to regulate calcium channels for the passage of Ca²⁺ through the oocyte cytoplasm and for maintaining required threshold of Ca²⁺ oscillations. This role of DHEA/DHEA-S assumes critical significance in assisted reproductive technology and in-vitro fertilization treatment cycles where physical, chemical, and mechanical methods are employed for artificial oocyte activation to enhance fertilization rates. However, since these methods are invasive and may also cause adverse epigenetic modifications; oral or culture-media supplementation with DHEA/DHEA-S provides a noninvasive innate mechanism of in-vitro oocyte activation based on physiological metabolic pathway.