Genitourinary syndrome of menopause, a new term for a condition more renowned as atrophic vaginitis, is a hypoestrogenic condition with external genital, urological, and sexual implications that affects >50% of postmenopausal women. Due to sexual embarrassment and the sensitive nature of discussing symptoms, genitourinary syndrome of menopause is greatly underdiagnosed. The most up-to-date literature pertaining to clinical manifestations, pathophysiology, etiology, evaluation, and management of genitourinary syndrome of menopause is comprehensively reviewed. Early detection and individually tailored pharmacologic (eg, estrogen therapy, selective estrogen receptor modulator, synthetic steroid, oxytocin, and dehydroepiandrosterone) and/or nonpharmacologic (eg, laser therapies, moisturizers and lubricants, homeopathic remedies, and lifestyle modifications) treatment is paramount for not only improving quality of life but also for preventing exacerbation of symptoms in women with this condition.
Introduction
Genitourinary syndrome of menopause (GSM), previously known as vulvovaginal atrophy, atrophic vaginitis, or urogenital atrophy, is a chronic, progressive vulvovaginal, sexual, and lower urinary tract condition characterized by a host of symptoms secondary to a clinical state of hypoestrogenism after onset of menopause. In 2014, the International Society for the Study of Women’s Sexual Health and the North American Menopause Society agreed that “genitourinary syndrome of menopause” is a more inclusive and accurate term to describe the conglomeration of external genital, urological, and sexual sequelae caused by hypoestrogenism during menopause. They also agreed the new terminology would carry less social stigma thus making it easier for women to openly talk about it, especially to their care providers. GSM-like symptoms may also be mirrored in hypoestrogenic premenopausal women. The syndrome or its features manifest in some manner in approximately 15% of premenopausal women and 40-54% of postmenopausal women. Because women have a higher life expectancy than men, and approximately >17% of the population will be age >65 years by 2030, the consequences of declined endogenous estrogen levels in menopausal women should be of great interest to clinicians.
GSM is often underdiagnosed due to sexual embarrassment or general disregard due to associating it as a liability of natural aging. In a recent study, only 4% of women were able to attribute vulvovaginal symptoms to GSM. Only around 25% of women with GSM go to a practitioner for consultation. Another European study found that only 54% of women discuss their sexual health with practitioners when asked, and 33% of women do not discuss it at all. Identifying postmenopausal women’s profiles (eg, their tendency to be proactive or reserved) may help bypass the social taboo on discussing GSM, thus expediting evaluation and management. In cases of abrupt estrogen deprivation, eg, surgical menopause, patients can experience significant sexual dysfunction and even poorer quality-of-life outcomes. We presently explore the signs, symptoms, and genitourinary manifestations of GSM; the importance of its early detection; as well as the crucial role of proper patient education in avoiding the long-term risks and complications that may severely compromise quality of life. Management of GSM must ideally be tailored to individual patient medical history, potential risks and benefits of exogenously administered estrogen therapy (ET), as well as patient lifestyle.
Clinical manifestations
Clinicians play a major role in recognizing the signs of GSM because many women are reluctant to report their symptoms due to personal reasons. Additionally, 50% of postmenopausal women with mild or moderate GSM are asymptomatic, making diagnosis particularly challenging. Only a weak correlation has been found between symptom score and physical examination of GSM.
Manifestations of GSM are primarily divided into external genital and urological signs and symptoms ( Table 1 ), which can be observed through physical examination. Genitourinary complications experienced secondary to GSM are included in Table 1 to further guide clinicians and health care providers. There may be a linking of certain signs and complications, eg, vaginal vault prolapse and urinary incontinence. Introital stenosis to a width <2 fingers, decreased vaginal depth, and vaginal dryness must be diagnosed before insertion of the speculum, otherwise the pelvic examination will cause considerable pain. Vaginoscopy is an alternative if the practitioner is unable to perform a pelvic/vaginal examination.
| External genital | Urological | Sexual | ||
|---|---|---|---|---|
| Signs and symptoms | Complications | Signs and symptoms | Complications | Signs and symptoms |
| Vaginal/pelvic pain and pressure Dryness Irritation/burning Tenderness Pruritus vulvae Decreased turgor and elasticity Suprapubic pain Leukorrhea Ecchymosis Erythema Thinning/graying pubic hair Thinning/pallor of vaginal epithelium Pale vaginal mucous membrane Fusion of labia minora Labial shrinking Leukoplakic patches on vaginal mucosa Presence of petechiae Fewer vaginal rugae Increased vaginal friability | Labial atrophy Vulvar atrophy and lesions Atrophy of Bartholin glands Intravaginal retraction of urethra Alkaline pH (5–7) Reduced vaginal and cervical secretions Pelvic organ prolapse Vaginal vault prolapse Vaginal stenosis and shortening Introital stenosis | Frequency Urgency Postvoid dribbling Nocturia Stress/urgency incontinence Dysuria Hematuria Recurrent urinary tract infection | Ischemia of vesical trigone Meatal stenosis Cystocele and rectocele Urethral prolapse Urethral atrophy Retraction of urethral meatus inside vagina associated with vaginal voiding Uterine prolapse Urethral polyp or caruncle | Loss of libido Loss of arousal Lack of lubrication Dyspareunia Dysorgasmia Pelvic pain Bleeding or spotting during intercourse |
GSM is most commonly diagnosed when the patient presents with dyspareunia secondary to vaginal dryness. Common signs and symptoms in order of prevalence and degree of atrophy include vaginal dryness (in 75% postmenopausal women), dyspareunia (38%) and vaginal itching, discharge, and pain (15%). When the vulvovaginal epithelium is inadequately lubricated, ulceration and fissures can develop during intercourse, causing dyspareunia. Vaginismus, or painful spasm of vaginal muscles, can also occur as a physiological response when there is anxiety toward expected sexual pain. Sexual manifestations are an extension of those of the external genitalia ( Table 1 ).
Clinical manifestations
Clinicians play a major role in recognizing the signs of GSM because many women are reluctant to report their symptoms due to personal reasons. Additionally, 50% of postmenopausal women with mild or moderate GSM are asymptomatic, making diagnosis particularly challenging. Only a weak correlation has been found between symptom score and physical examination of GSM.
Manifestations of GSM are primarily divided into external genital and urological signs and symptoms ( Table 1 ), which can be observed through physical examination. Genitourinary complications experienced secondary to GSM are included in Table 1 to further guide clinicians and health care providers. There may be a linking of certain signs and complications, eg, vaginal vault prolapse and urinary incontinence. Introital stenosis to a width <2 fingers, decreased vaginal depth, and vaginal dryness must be diagnosed before insertion of the speculum, otherwise the pelvic examination will cause considerable pain. Vaginoscopy is an alternative if the practitioner is unable to perform a pelvic/vaginal examination.
| External genital | Urological | Sexual | ||
|---|---|---|---|---|
| Signs and symptoms | Complications | Signs and symptoms | Complications | Signs and symptoms |
| Vaginal/pelvic pain and pressure Dryness Irritation/burning Tenderness Pruritus vulvae Decreased turgor and elasticity Suprapubic pain Leukorrhea Ecchymosis Erythema Thinning/graying pubic hair Thinning/pallor of vaginal epithelium Pale vaginal mucous membrane Fusion of labia minora Labial shrinking Leukoplakic patches on vaginal mucosa Presence of petechiae Fewer vaginal rugae Increased vaginal friability | Labial atrophy Vulvar atrophy and lesions Atrophy of Bartholin glands Intravaginal retraction of urethra Alkaline pH (5–7) Reduced vaginal and cervical secretions Pelvic organ prolapse Vaginal vault prolapse Vaginal stenosis and shortening Introital stenosis | Frequency Urgency Postvoid dribbling Nocturia Stress/urgency incontinence Dysuria Hematuria Recurrent urinary tract infection | Ischemia of vesical trigone Meatal stenosis Cystocele and rectocele Urethral prolapse Urethral atrophy Retraction of urethral meatus inside vagina associated with vaginal voiding Uterine prolapse Urethral polyp or caruncle | Loss of libido Loss of arousal Lack of lubrication Dyspareunia Dysorgasmia Pelvic pain Bleeding or spotting during intercourse |
GSM is most commonly diagnosed when the patient presents with dyspareunia secondary to vaginal dryness. Common signs and symptoms in order of prevalence and degree of atrophy include vaginal dryness (in 75% postmenopausal women), dyspareunia (38%) and vaginal itching, discharge, and pain (15%). When the vulvovaginal epithelium is inadequately lubricated, ulceration and fissures can develop during intercourse, causing dyspareunia. Vaginismus, or painful spasm of vaginal muscles, can also occur as a physiological response when there is anxiety toward expected sexual pain. Sexual manifestations are an extension of those of the external genitalia ( Table 1 ).
Pathophysiology
During female embryologic development, the urogenital sinus, müllerian ducts, and sinovaginal node (ie, Müller tubercle) form the vaginal vestibule and lower fifth of vagina, urinary bladder, trigone, and the entire urethra. Fused müllerian ducts form the uterus and upper four-fifths of the vagina. The genitalia and lower urinary tract share common estrogen receptor function. Due to the common embryological origin, hypoestrogenism has both vulvovaginal and urologic effects; urogenital tissue receptors are dependent on endogenous estrogen levels to maintain normal physiology. During postmenopause, the number of estrogen receptors continue to decrease but never fully disappear. However, in the presence of exogenous administration of estrogen, one can replenish lost estrogen receptors.
In the vulvovaginal tissue, estrogen receptor-α is predominantly present in premenopausal and postmenopausal women, whereas estrogen-β appears to only be expressed in premenopausal women. Estrogen is a vasoactive hormone that increases blood flow. Vaginal lubrication is caused by fluid transudation from blood vessels, and from endocervical and Bartholin glands. Activated estrogen receptors also encourage epithelial proliferation with redundant smooth muscle tissue layer. The formation of rugae aids in expandability, distensibility, and lubrication of the vagina during sexual stimulation. Vaginal secretions, lubrication, and improved blood flow of vaginal walls all help to increase vaginal mechanical compliance. In the advent of hypoestrogenism, these prolubricative and proelastic functions are lost due to diminished collagen, elastin, and hyaluronic acid content; thinned epithelium; impaired smooth muscle proliferation; denser connective tissue arrangement; and loss of vascularity, thus predisposing the woman to irritation and sexual trauma.
The vaginal and urethral epithelium is comprised of nonkeratinized stratified squamous epithelium with superficial, intermediate, and basal cell layers that store glycogen in the presence of physiologic estrogen levels. The epithelium of the vaginal wall is constantly exfoliating and producing glycogen, which is hydrolyzed to glucose. A healthy vaginal flora is composed of a variety of aerobic and anaerobic, gram-positive and gram-negative bacteria. Predominant Lactobacillus metabolizes glucose into lactic acid and acetic acid, lowering the vaginal pH to a range of 3.5-4.5. The acidity of the vagina provides natural protection against urinary tract infections (UTI) and vaginitis, discouraging the growth of pathogenic bacteria and infection. Estrogen is vital for modulating innate defenses of the urinary tract. Thus, knowledge of the association between GSM and recurrent UTI can help avoid unnecessary use of antibiotics and prevent antimicrobial resistance.
Atrophy of urogenital tissue is identified with declined endogenous estrogen levels with vaginal epithelium appearing thin, pale, and less rugated. The loss of estrogen is responsible for the reduction of Lactobacillus , changing the vaginal fluid to an alkaline pH of ≥5.0. The higher pH impairs the viability of healthy vaginal flora and promotes overgrowth of gram-negative rod fecal flora including group B streptococci, staphylococci, coliforms, and diphtheroids, inducing vaginal infection and UTI and inflammation. In decreased levels of circulating estrogen, substantial vascularization is lost in the urogenital tract, making the tissue atrophic. Estrogen deficiency causes loss in dermal collagen in dense connective tissue of the vagina, bladder, and urethra, and then causes the vaginal wall to become thinner and less elastic. In consequence, the vagina becomes shortened and narrowed, which may lead to dyspareunia. The bladder and urethra also become atrophic, causing urinary incontinence and frequency. One study reported that 20% of postmenopausal women experienced urge incontinence while roughly 50% experienced stress urinary incontinence. It is thought that estrogen receptors in the bladder trigone and urethra aid in increasing the sensory threshold when the bladder becomes distended. Lack of estrogen decreases the threshold and impairs urethral closure pressure and Valsalva leak-point pressure, contributing to urinary urgency. Research studies have also suggested that in postmenopausal women, the lack of estrogen impairs connective tissue and causes urethral sphincter dysfunction of stress urinary incontinence. In comparison, premenopausal women experience stress incontinence mainly due to anatomical changes. GSM-related incontinence is a key cause of recurrent UTI in postmenopausal women, signifying the importance of GSM evaluation and management to avoid the repercussions of inessential antibiotic therapy.
Etiology
The etiology of GSM is secondary to decreased levels of endogenous estrogen levels. In the female body, the 3 forms of estrogen produced mainly in the ovaries are estradiol, estrone, and estriol with estradiol being the most abundant in premenopausal women. During the transition between perimenopausal and postmenopausal years, estrone becomes the most prominent and is a less potent form of estrogen.
Table 2 outlines nonmenopause-related causes of estrogen deficiency that may mimic GSM sequelae, such as the hormonal therapies and chemotherapy from treating women with breast cancer. Table 3 lists risk factors for developing GSM such as cigarette smoking, which contributes to decreased circulation and impaired receptor function. Table 4 distinguishes between development of superficial and deep dyspareunia.
| Type | Cause |
|---|---|
| Systemic | Hyperprolactinemia (during breast-feeding) Postpartum estrogen deficiency Hypoestrogenism (eg, due to autoimmune disorders affecting ovaries, pituitary tumors) |
| Pharmacological | Gonadotropin-releasing hormone agonist analogs Leuprolide Nafarelin Selective estrogen receptor modulators Tamoxifen Aromatase inhibitors Danazol Medroxyprogesterone |
| Iatrogenic | Bilateral oophorectomy (ie, surgical menopause) Ovarian failure secondary to pelvic radiation Chemotherapy Radiation therapy |
| Menopause Nonmenopause hypoestrogenism Bilateral oophorectomy Cigarette smoking Alcohol abuse Decreased frequency and sexual abstinence Ovarian failure Lack of exercise Absence of vaginal childbirth |
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