A Systematic Review of Intravaginal Testosterone for the Treatment of Vulvovaginal Atrophy

Robin J. Bell, MBBS, PhD, MPH, FAFPHM; Farwa Rizvi, MBBS, MPH; Rakabul M. Islam, MPH, PhD; Susan R. Davis, MBBS, PhD, FRACP

Disclosures

Menopause. 2018;25(6):704-709. 

In This Article

Abstract and Introduction

Abstract

Objectives: Intravaginal testosterone has emerged as a potential treatment for vulvovaginal atrophy (VVA) in women, in general, and women taking an aromatase inhibitor (AI). A systematic review of the literature was undertaken to determine whether available clinical trial data support efficacy and safety of intravaginal testosterone for the treatment of VVA.

Methods: Scopus, MEDLINE, EMBASE, and the Cochrane Library databases were systematically searched on July 26, 2017, for human studies published in English of clinical trials of intravaginal testosterone.

Results: Six separate clinical trials were identified that ranged in size from 10 to 80 participants, with either single dose, or durations of 4 to 12 weeks. Only one study incorporated a double-blind design. Three studies were of women taking an AI.

Taken together, the studies suggest that intravaginal testosterone may lower vaginal pH, increase the proportion of vaginal lactobacilli, and possibly improve the vaginal maturation index. The lack of a placebo treatment in four studies, and failure to adjust for baseline differences, resulted in uncertainty of the effect on sexual function. Safety remains uncertain because of the small number of women exposed, short study durations, and inconsistent and incomplete outcome reporting for sex steroid levels.

Conclusion: Adequately powered double-blind, placebo-controlled clinical trials of intravaginal testosterone therapy are needed to establish both efficacy and safety.

Introduction

Unless treated, all postmenopausal women will experience some degree of vulvovaginal atrophy (VVA) as a result of sex steroid depletion. VVA, which is characterized by thinning of the vaginal epithelium and an increase in vaginal pH, is manifest as vaginal dryness, irritation, itching, infection, discomfort, and dyspareunia.[1] The consequences of VVA are substantial. It has been shown to cause women to avoid intimacy (58% of affected women), and has negative effects on self-esteem and quality of life.[2] VVA is effectively treated with local vaginal estrogen therapy.[3]

Aromatase inhibitors (AIs), which are first-line adjuvant therapy for postmenopausal women with hormone receptor-positive (HR+) breast cancer,[4] cause profound estrogen depletion and VVA, which worsens with duration of estrogen deficiency.[1,5] Clinicians are reluctant to use vaginal estrogen to treat VVA in women with HR+ breast cancer taking an AI as the potential for systemic absorption exists even with ultralow-dose vaginal estrogen,[3,6,7] as evidenced by reduced bone turnover and lowered low-density lipoprotein cholesterol.[3]

Vaginal moisturizers are less effective than vaginal estrogen for the treatment of VVA.[8] Some vaginal moisturisers lower vaginal pH and may normalize vaginal cell composition, but sustained relief of symptoms has not been seen in most studies.[8] Vaginal moisturizers do not reduce urinary tract symptoms or asymptomatic bacteruria.[8] Vaginal lubricants alleviate dryness during intercourse, but do not treat the underlying pathophysiology. As VVA associated with AI therapy has been identified as an important cause of noncompliance and treatment discontinuation, affecting as many as 20% of women,[9] a safe and effective treatment option for women taking an AI, and also for women not responsive to vaginal estrogen, is needed.

Recently, intravaginal testosterone has emerged as a potential treatment for VVA in women, in general, and women taking an AI, in particular. Androgen receptors (ARs) have been identified in the vaginal mucosa, submucosa, stroma, smooth muscle, and vascular endothelium.[10] The density of ARs in these tissues declines with age, whereas vaginal AR gene expression increases with testosterone administration.[10,11] Acutely administered oral methyl testosterone increases vaginal blood flow.[12] Furthermore, intramuscular testosterone therapy has been shown to induce proliferation of vaginal epithelial cells in postmenopausal women.[13]

We therefore considered it timely to undertake a systematic review of the literature to identify all published clinical trials of intravaginal testosterone in women. We have focused on VVA, as opposed to the more recent clinical descriptor of genitourinary syndrome of the menopause (GSM), as no study of intravaginal testosterone has had GSM as an outcome. Our aim was to determine whether there are sufficient available data to support the efficacy and safety of this therapy as a treatment for VVA in women with and without breast cancer.

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