1.1. Background

The term genitourinary syndrome of menopause (GSM) describes the spectrum of symptoms and physical changes resulting from declining estrogen and androgen concentrations in the female genitourinary tract during and after menopause.^{1, 2} Menopause is defined as 12 months without a menstrual period, and is a natural function of physiologic changes in ovarian function around age 51 (or after surgical or medical interventions).³ For some women, menopause is associated with vasomotor symptoms (i.e., hot flashes/flushes and/or night sweats) and/or genitourinary symptoms, with wide variability in prevalence, duration, and severity.⁴

Since the introduction of the term GSM in 2014,^{1, 2} no consensus has been reached about the number or type of symptoms (vulvovaginal, urinary, or sexual) needed to diagnose GSM, nor a requirement for identifying concurrent physical signs.^{5, 6} Vulvovaginal symptoms associated with menopause include dryness, burning, and irritation.⁷ Urinary symptoms include urgency, frequency, dysuria, and recurrent urinary infections.⁸ The vulvovaginal and urinary effects of menopause are often considered the cause of sexual symptoms of GSM, including dyspareunia and bleeding during intercourse, as well as broader impacts on sexual function, such as reduced libido, arousal, and orgasm.^8–10 Physical changes associated with GSM include labial atrophy, reduced moisture, introital stenosis, and clitoral atrophy.^{1, 2} The vaginal surface may be friable and hypopigmented, with petechiae, ulcerations, and tears; urethral findings may include caruncles, prolapse, or polyps.¹¹ However, presence and severity of physical exam findings do not directly correlate with self-reported GSM symptoms.^11–13

Clinicians generally diagnose GSM based on symptoms in a postmenopausal woman, with or without related physical findings, and after ruling out other etiologies or co-occurring pathologies (e.g., infectious vaginitis, vulvar lichen sclerosis, dermatitis, lichen planus, or an active urinary infection).^{8, 14, 15} Objective measures of postmenopausal vaginal changes include the Vaginal Maturation Index (VMI)¹⁶ and vaginal pH.¹⁷ The VMI demonstrates a shift from superficial cells to parabasal cells as the vaginal epithelium thins, and vaginal pH then rises as fewer superficial epithelial cells exfoliate and break down to release glycogen and glucose, which would typically be broken down into lactic acid by lactobacilli in an estrogenized vagina.⁷ Trials sometimes limit inclusion to women with at least moderate to severe GSM symptoms, 5% or fewer superficial cells on VMI, and vaginal pH greater than 5, but these measures are neither required nor commonly used for clinical diagnosis and treatment of GSM.¹⁸

GSM prevalence estimates in postmenopausal women vary widely from 13 to 87 percent.¹⁹ This inconsistency stems from many factors including variation in the symptoms and/or signs assessed and evaluated, the symptom assessment tools used, and the demographics and settings of study populations.¹⁹ Unlike vasomotor symptoms of menopause (i.e., hot flashes and/or night sweats), the prevalence and intensity of some genitourinary symptoms, such as vulvovaginal dryness, increase with advancing age.^{20, 21} GSM may be associated with reduced quality of life and sexual functioning, and a higher likelihood of urinary complaints, all of which may interfere with interpersonal relationships.^22–27 Despite the potentially disruptive nature of GSM, only about half of women with GSM symptoms report discussing their symptoms with their clinicians, and of those who did, most said the clinician did not initiate the conversation.^{28, 29}

Several organizations recommend identifying GSM through a case-finding approach, by screening women for symptoms with routine questions.^30–32 However, few tools have been validated for GSM assessment and existing tools are limited to vulvovaginal symptoms.^{33, 34} The urinary symptoms associated with GSM are also associated with other common urinary conditions in older women, such as reduced bladder capacity, idiopathic overactive bladder, and detrusor muscle overactivity, making identification, evaluation, and treatment of these and other symptoms complex.¹¹ A causal relationship between reduced hormone levels and urinary symptoms remains controversial.^35–37 Some have even questioned whether GSM meets the definition of a disease syndrome.³⁸ These questions create uncertainty around the optimal approach to screening, identification, evaluation, and management of GSM.

Nonetheless, the range of GSM treatments has increased substantially in recent years.^{39, 40} Traditional therapies include vaginal estrogen, moisturizers, and lubricants. Estrogen binds to receptors in the vagina, vulva, urethra, bladder, and pelvic floor, shifts the vaginal cytology toward superficial cells, away from parabasal cells, and reduces the vaginal pH. Vaginal moisturizers increase the fluid content in the endothelium and reduce the vaginal pH. Personal lubricants can be water, silicone, or oil-based and are primarily used to provide short-term lubrication during sexual activity; lubricants are often used as a placebo or control treatment in clinical trials. Newer hormonal approaches include vaginal or systemic dehydroepiandrosterone (DHEA), vaginal oxytocin, selective estrogen receptor modulators (SERMs), and testosterone. DHEA is a precursor to both androgens and estrogens that is transformed into estradiol and testosterone, for example, within vaginal mucosal cells. Oxytocin is a pituitary hormone primarily implicated in uterine labor contractions and lactation, but vaginal oxytocin gel has also been shown to reduce vaginal pH and increase the proportion of superficial cells in small studies. SERMs have varied estrogen agonist/antagonist effects throughout the body; among SERMs, ospemifene has unique estrogen receptor agonist activity in vaginal tissue. Testosterone may improve libido and is aromatized to estradiol.⁴¹ Complementary therapies, including oral and vaginal natural products (herbal supplements, phytoestrogens, vitamins, probiotics), mind-body practices, and educational interventions, offer various mechanisms of action while appealing to women who wish to avoid hormonal treatments. Finally, energy-based treatments such as laser and radiofrequency devices claim to stimulate collagen formation, angiogenesis, and epithelial thickening by causing microtrauma or heating superficial tissue layers.

Some of these treatments aim to improve a broad range of GSM symptoms, while others target a specific bothersome symptom. Randomized trials are typically short term, and lack long-term intervention efficacy, adherence, or harms data. Consequently, guidance for longer-term followup and surveillance as well as treatment in special populations, such as women with a history of breast cancer, has relied on expert consensus in the absence of robust evidence.^{30, 31, 42}

1.2. Purpose of Review

The Agency for Healthcare Research and Quality conducted a systematic evidence review on the topic of GSM that was funded by the Patient Centered Outcome Research Institute (PCORI^®) and will serve as the basis for development of American Urological Association (AUA) clinical practice guidelines. The intended audience includes guideline developers, health system administrators, clinicians, patients, and others interested in making informed decisions about GSM screening, evaluation, and treatment.