Localization of the Androgen-Synthesizing Enzymes, Androgen Receptor, and Sex Steroids in the Vagina: Possible Implications for the Treatment of Postmenopausal Sexual Dysfunction

Abstract

Introduction To better understand the mechanisms underlying the beneficial effects of the intravaginal administration of dehydroepiandrosterone (DHEA) observed in postmenopausal women on sexual dysfunction. Aims To identify the distribution of the androgen-synthesizing enzymes as well as androgen receptor (AR) and measure steroid levels in the monkey vagina. Methods The cynomolgus monkey (Macaca fascicularis), the closest model to the human, has been used to measure the expression levels of steroidogenic enzymes and androgen receptor by quantitative reverse transcription polymerase chain reaction (n = 4), confirmed by immunohistochemistry, and immunofluorescence (n = 3). DHEA and its androgenic metabolites were quantified by LC-MS/MS (n = 4). Main Outcome Measures The presence of SRD5A1, SRD5A2, HSD17B3, AR as well as nerve fibers (PGP 9.5) was investigated, and steroid levels were measured. Results AR is widely distributed within the vaginal epithelium and also in the lamina propria with a lower expression in the muscularis layer and blood vessel walls. Androgen-forming enzymes, on the other hand, are expressed in the vaginal stratified squamous epithelium at a relatively high level where they are uniformly distributed from the basal membrane up to the superficial keratinized cells. The enzymes are at a lower level in blood vessel walls and zona muscularis where nerve fibers are localized. DHEA and its androgen metabolites are present at biologically significant concentrations in the monkey vagina. Conclusion The enzymes responsible for androgen formation as well as AR are at the highest level in the superficial layer of the stratified epithelium and muscularis layers of the vagina. These data provide a potential explanation for the described role of androgens in regulating vaginal lubrication, smooth muscle activity, blood flow, and the neuronal activity potentially involved in the correction of sexual dysfunction.

Accurate and sensitive liquid chromatography/tandem mass spectrometry simultaneous assay of seven steroids in monkey brain

“…Indeed, our group has measured these steroids in the monkey prostate, seminal vesicles, muscle (preliminary data) and vagina [63,64]. This technology could thus open the way for studies to better understanding the role of DHEA and its unconjugated metabolites in the brain and other tissues.…”

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women

“…These interactions elicit activation of G-protein-coupled receptors and/or stimulation of intracellular kinases with concomitant increase in the synthesis of second messengers. 49,50 These nongenomic signaling events may regulate neural activity in the central nervous system, as suggested by human brain imaging studies. 56,57 However, this has not been studied directly in the context of sexual function.…”

“…48 Testosterone directly, or via its metabolism to 5adihydrotestosterone (5a-DHT) or aromatization to estradiol, modulates many biochemical and physiological pathways, thus regulating cellular metabolism (Figure 2). 49,50 Testosterone influences sexual differentiation of the genitalia and the brain, determines secondary sexual characteristics during development and sexual maturation, contributing to maintenance of their functional state in adulthood, and modulates sexual behavior. 44 5a-DHT is the most potent androgen and has the highest binding affinity to the androgen receptor (AR), 4 whereas the testosterone precursors androstenedione and dehydroepiandrosterone (DHEA) are only weakly androgenic.…”

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women

“…48 Testosterone directly, or via its metabolism to 5a-dihydrotestosterone (5a-DHT) or aromatization to estradiol, modulates many biochemical and physiological pathways, thus regulating cellular metabolism (Figure 2). 49,50 Testosterone influences sexual differentiation of the genitalia and the brain, determines secondary sexual characteristics during development and sexual maturation, contributing to maintenance of their functional state in adulthood, and modulates sexual behavior. 44 5a-DHT is the most potent androgen and has the highest binding affinity to the androgen receptor (AR), 4 whereas the testosterone precursors androstenedione and dehydroepiandrosterone (DHEA) are only weakly androgenic.…”