Does the adrenal zona reticularis become an important androgen source after menopause?

The transition into menopause marks a profound shift in female endocrine physiology, characterized by the decline of direct ovarian steroidogenesis and an increased reliance on alternative pathways to maintain systemic androgen levels.

Cellular and molecular mechanisms

• The adrenal zona reticularis synthesizes dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) starting with the conversion of cholesterol to pregnenolone by CYP11A1, followed by CYP17A1-catalyzed 17-hydroxylation and 17,20-lyase cleavage.
• Low expression of HSD3B2 in this zone prevents intermediate diversion into the cortisol pathway, while the sulfotransferase SULT2A1 converts DHEA to DHEAS to establish a large circulating reservoir.
• In peripheral target tissues, DHEAS is desulfated by steroid sulfatase (STS) to DHEA, which is then converted into active testosterone via the sequential action of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD).

Postmenopausal clinical evidence

• Prior to menopause, women derive bioavailable androgens relatively equally from ovarian and adrenal sources. Following the depletion of ovarian follicles, direct ovarian contributions to the systemic steroid pool fall sharply.
• The adrenal glands subsequently emerge as the dominant source of circulating androgen precursors (DHEA and DHEAS) for peripheral intracrine conversion.
• This transition is highlighted clinically by the fact that bilateral oophorectomy in postmenopausal women results in a roughly 50% drop in circulating testosterone, whereas postmenopausal women with adrenal insufficiency present with virtually no circulating androgens.

Bottom line

• Bottom line: The adrenal zona reticularis-derived DHEA and DHEAS serve as the essential endocrine precursors for peripheral testosterone synthesis after menopause, becoming the dominant driver of systemic androgen levels as ovarian follicular activity ceases.