Summary
The vagina has traditionally been conceived as a passive female reproductive organ that serves basically as a passageway for menstrual blood, sexual intercourse and childbirth. However, recent research, as revised by Cipriani et al. [1], has provided insights on the role of the vagina as an endocrine organ that plays a crucial role in female hormonal balance and overall health. Current evidence, taking into account the novel concept of “intracrinology”, highlights the fact that the human vagina may be considered both as a source and target of androgens. Aside from the well-known role of estrogens, androgens are also pivotal for the development and maintenance in women of healthy genitourinary tissues. During the female menopausal transition and the aging process per se, androgen and estrogen levels decline, thus exerting changes in the genitourinary system. Indeed, tissues become thinner, drier and less elastic, leading to a variety of uncomfortable and sometimes painful symptoms, clustered in the genitourinary syndrome of menopause (GSM). Due to the lack of testosterone-based or androstenedione-based products approved by regulatory agencies to treat GSM, the possibility of using intravaginal prasterone, which exerts effects by providing a local source of dehydroepiandrosterone (DHEA) to the vaginal tissues, appears to be a reasonable targeted treatment; however, further studies are needed to better assess its safety and efficacy. In this commentary I would like summarize main points revised by the authors [1].
Commentary
Recent studies allow us to say that the role of the vagina, as an endocrine organ, is crucial in the female hormonal balance and in general health. Estrogen, progesterone, and androgens play important roles in regulating the vaginal environment, including pH levels, moisture, and bacterial balance, as well as the neurovascular mechanisms that underlie the female sexual response. During the menopausal transition and beyond a decrease of sex steroids cause a negative impact on women’s genitourinary health.
Cipriani et al. [1] conducted an extensive literature search (2002-2023) of peer-reviewed publications in order to present emerging data and current confirmed evidence that support the role of the vagina as an endocrine organ, serving as a source and destination of androgens, and hence related clinical implications for the treatment of GSM, including the recently approved intravaginal DHEA.
During the reproductive years, testosterone in women is produced by the ovaries and by peripheral conversion of androstenedione and DHEAS, which are pre-androgens synthesized by the ovaries and the adrenal glands [2]. The production of androgens in women decreases as they approach menopause, although some studies indicate that the decrease does not depend per se on the menopause; however, this decrease is much slower than that of estrogens, and in a recent world consensus it was concluded that systemic administration of testosterone to postmenopausal women complaining of low libido, with the aim of maintaining premenopausal physiologic levels, is a safe and effective strategy [3].
Studies in human vagina tissue have showed androgen expression levels markedly higher in the distal vagina than in the ovary. These studies, at the enzymatic level, led to the conclusion that vaginal muscle cells express the necessary machinery to produce androgen metabolites. Androgen receptors have been identified in the vaginal mucosa, submucosa, stroma, smooth muscle, and vascular endothelium. Aromatase, the enzyme that converts testosterone to estradiol, and isotopes 1 and 2 of 5α-reductase, which convert testosterone to dihydrotestosterone, are also present in the vaginal tissue [4].
Signs and symptoms related to GSM/Vulvovaginal Atrophy are well known, which cause impaired female quality life. In the literature, the prevalence of GSM-related symptoms in postmenopausal women may range from 13% to 87%. In many cases doctors do not ask and/or patients report symptoms, hence the GSM has been underdiagnosed.
Since the female genitourinary tissue express androgen receptors, off-label topical testosterone therapies, such as local creams of bioidentical compounds have been proposed, however, this is an area that requires further research [5]. Treatment with testosterone, or with prasterone, have been used as therapeutic options in breast cancer survivors, since they trigger the activation of vaginal sex steroid receptors, without activating the estrogen receptors located in different tissues, due to the reduced expression of aromatase in the vagina [6].
As a conclusion to this commentary, we can say that although estrogens have historically been considered fundamental players in the human vagina it is also a target organ for androgens and has the ability to synthesize them. Nevertheless, further studies are needed to strengthen the current evidence that androgens can be used to improve alterations of the female genital tract caused by hypoestrogenism.
Prof. Alejandra Elizalde-Cremonte, MD, PhD
Full Professor, Chair, Department of Women and Children, Faculty of Medicine, National University of the Northeast (UNNE), Corrientes, Argentina
President of the Latin American Association of Gynecological Endocrinology (ALEG)
President of the Argentine Association of Perinatology (ASAPER)
Vice-President of the Argentine of Menopause and Andropause Society (AAMA)
Associate Member of the International Menopause Society (IMS)
References
- Cipriani S, Maseroli E, Ravelli SA, Vignozzi L. The vagina as source and target of androgens: implications for treatment of GSM/VVA, including DHEA. Climacteric. 2023 Jun 8:1-7.
https://pubmed.ncbi.nlm.nih.gov/37288964/ - Davis SR, Wahlin-Jacobsen S. Testosterone in women: the clinical significance. Lancet Diabetes Endocrinol. 2015;3(12):980-992.
https://pubmed.ncbi.nlm.nih.gov/26358173/ - Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. J Clin Endocrinol Metab. 2019;104(10):4660–4666.
https://pubmed.ncbi.nlm.nih.gov/31498871/ - Hammes SR, Levin ER. Impact of estrogens in men and androgens in women. J Clin Invest. 2019;129(5):1818-1826.
https://pubmed.ncbi.nlm.nih.gov/31042159/ - Fernandes T, Pedro AO, Baccaro LF, Costa-Paiva LH. Hormonal, metabolic, and endometrial safety of testosterone vaginal cream versus estrogens for the treatment of vulvovaginal atrophy in postmenopausal women: a randomized, placebo-controlled study. Menopause. 2018;25(6):641-647.
https://pubmed.ncbi.nlm.nih.gov/29462095/ - Davis SR, Robinson PJ, Jane F, White S, White M, Bell RJ. Intravaginal Testosterone Improves Sexual Satisfaction and Vaginal Symptoms Associated With Aromatase Inhibitors. J Clin Endocrinol Metab. 2018;103(11):4146-4154.
https://pubmed.ncbi.nlm.nih.gov/30239842/
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