INTRODUCTION — Genitourinary syndrome of menopause (GSM) is defined as a collection of symptoms and signs caused by hypoestrogenic changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder that occur in menopausal patients. The term GSM was introduced by the International Society for the Study of Women's Sexual Health and the North American Menopause Society in 2014 and replaced the term vaginal atrophy (other terms include vulvovaginal atrophy, urogenital atrophy, or atrophic vaginitis) [1]. The syndrome may include, but is not limited to, genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections. Patients may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. The spectrum of adverse consequences requires long-term treatment in many patients. Treatment options include both hormonal and nonhormonal interventions.
Although vaginal atrophy typically occurs in menopausal patients, it can occur in females of any age who experience a decrease in estrogenic stimulation of the urogenital tissues. In premenopausal patients, a hypoestrogenic state may occur during the postpartum period or lactation or due to hypothalamic amenorrhea or antiestrogenic drugs. Not all patients with atrophic changes on examination are symptomatic.
Clinical manifestations and diagnosis of GSM are reviewed here. Treatment of symptomatic vaginal atrophy, as well as use of estrogen and other pharmacologic therapies for other menopausal symptoms, is discussed in detail separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment" and "Treatment of menopausal symptoms with hormone therapy" and "Preparations for menopausal hormone therapy" and "Menopausal hormone therapy: Benefits and risks".)
PATHOPHYSIOLOGY — Female urogenital atrophy results predominantly from a decline in serum estrogen levels. This is most commonly due to natural or surgical menopause but may also occur with premature ovarian insufficiency or, temporarily, during the postpartum period or lactation, or due to hypothalamic amenorrhea or antiestrogenic drugs. Androgens also appear to play a role in the maintenance of genitourinary tissue structure and function but are less well studied and appreciated.
The locations of these steroid receptors appear to vary within the genitourinary system. For example, estrogen receptor density appears higher in the vagina compared with the external genitalia, while androgen receptor density is lower in the vagina compared with the external genitalia. Progesterone receptors are found both in the vagina and transitional vulvovaginal area [2,3].
Premenopausal physiology — In premenopausal patients, estradiol is the predominant form of circulating estrogen. Serum estradiol concentrations in premenopausal patients fluctuate during the menstrual cycle (figure 1), as follows:
●Early follicular phase – An average of 50 pg/mL
●Ovulation – A range of 200 to 350 pg/mL
●Early luteal phase – An average of 100 pg/mL
●Mid-luteal phase – An average of 200 pg/mL
●Onset of menses – A range of 30 to 50 pg/mL
Estrogen stimulation is responsible for maintaining a well-epithelialized vaginal vault during the reproductive years. Estrogen acts on its receptors in the vagina, vulva, urethra, and trigone of the bladder to [4]:
●Maintain the collagen content of epithelium, which affects its thickness and elasticity
●Maintain acid mucopolysaccharides and hyaluronic acid, which keep epithelial surfaces moist
●Maintain optimal genital blood flow
●Maintain a healthy vaginal microbiome [5]
As a result, the nonkeratinized stratified squamous epithelium of the vagina in response to estrogen is thick, rugated, and rich in glycogen. Glycogen from sloughed cells is the substrate for Döderlein lactobacilli, which convert glucose into lactic acid, thereby creating an acidic vaginal environment. The acidity of the vagina helps maintain the normal vaginal flora and protects the urogenital area from vaginal and urinary tract infections [6].
Effects of hypoestrogenism — Menopause leads to a dramatic reduction in estrogen production, with an approximate 95 percent decline in estradiol levels from the premenopausal to postmenopausal state [6]. After menopause, serum estradiol concentrations plateau at levels averaging 5 pg/mL [7]. It should be noted that most estradiol assays are not sufficiently sensitive to detect postmenopausal estradiol levels accurately, and therefore, measurement of estradiol levels should not be a routine aspect of clinical care [8].
The marked decrease in serum estrogen levels, exacerbated by the normal aging process, is responsible for many of the changes that comprise vaginal atrophy [9,10]. These changes usually develop gradually over a period of years. Hypoestrogenic vaginal changes may include:
●Thinning of the top layer of superficial epithelial cells; this layer may be completely absent in patients with severe atrophy
●Loss of rugae
●Loss of elasticity of the vaginal epithelium
●Shortening and narrowing of the vaginal canal, with loss of distensibility
●Increased subepithelial connective tissue
●Reduction in vaginal secretions from 3 to 4 g/4 hours to 1.7 g/4 hours
●Increase in vaginal pH to ≥5
Thinning of the vaginal epithelium increases susceptibility to trauma, resulting in bleeding, petechiae, and ulceration with pressure, including sexual activity or the performing of a Pap test (figure 2). Thinning also exposes the underlying connective tissue, which is more vulnerable to inflammation or infection.
The low glycogen content of the thinned epithelium leads to a reduction in lactic acid production by lactobacilli, resulting in an increase in vaginal pH [11,12]. These changes in the vaginal environment encourage the overgrowth of nonacidophilic coliforms and the reduction of lactobacillus species, thereby predisposing affected patients to infection by skin and rectal flora (eg, Gardnerella vaginalis, streptococci, staphylococci, coliforms, diphtheroids [6]), as well as trichomonas species. The shifting flora and resulting inflammatory changes were the source of the older term for this condition, atrophic vaginitis. However, although the vaginal microbiome in the menopausal patient appears to be related to vaginal health, there are no proven interventions to treat atrophic vaginitis through vaginal microbiome manipulation. Currently, no probiotic therapies have been validated to be an effective management intervention for GSM [13]. However, a combination of vaginal low-dose estriol and lactobacilli is an approved therapy in many countries other than the United States, but further study of this combination is needed [14].
Urinary tract structures are derived from the same embryologic origin as the genital tract and also contain estrogen receptors. Thus, the bladder, urethra, pelvic floor musculature, and endopelvic fascia are affected by a hypoestrogenic state. Possible consequences of atrophy of the urinary tract include urethral discomfort, urinary frequency, hematuria, dysuria, and an increased frequency of urinary tract infection.
Menopause increases the risk for both pelvic organ prolapse and stress urinary incontinence. While it might seem intuitive to use estrogen therapy for these issues, some data suggest that oral estrogen therapy results in the development or exacerbation of urinary incontinence. However, vaginal estrogen may improve continence [15], decrease urinary urgency or frequency symptoms, and decrease recurrent urinary tract infections. Systemic or vaginal estrogen does not appear to be effective as treatment of pelvic organ prolapse. (See "Female urinary incontinence: Treatment", section on 'Topical vaginal estrogen' and "Pelvic organ prolapse in females: Epidemiology, risk factors, clinical manifestations, and management", section on 'Estrogen therapy'.)
While the effects of estrogen loss on urogenital tissue have been well described, emerging data suggest that androgens also play a role in urogenital health, as androgen receptors have been reported in the mucosa, muscularis, and adventitial layers of the vagina [16]. Since there are both estrogen receptors and androgen receptors in the genitourinary tract of females, and androgens are precursors to the synthesis of estrogens, it can be conjectured that there is an indirect role of androgens on vulvovaginal health. The scant data available suggest androgens, such as testosterone, may have a direct effect on this tissue and not indirectly through the aromatization pathway [3,17-19].
EPIDEMIOLOGY
Prevalence — The prevalence of GSM is not well established. Most menopausal patients or patients in a hypoestrogenic state will develop urogenital atrophy. Representative studies include:
●Internet surveys suggest that vaginal dryness affects up to 85 percent of patients over 40 years of age, with an additional 29 to 59 percent reporting dyspareunia and another 26 to 77 percent reporting vaginal itching and irritation [20,21].
●The prevalence of vaginal dryness symptoms by age group was best illustrated in a longitudinal study in which the symptoms were reported by 3 percent of patients of reproductive age, 4 percent of patients in early menopausal transition, 21 percent of patients in the later years of the menopausal transition, and 47 percent of patients three years after menopause [22,23].
●An international survey of over 4000 menopausal patients reported that 39 percent had experienced menopause-related vaginal discomfort; 52 percent of those with vaginal discomfort reported that their quality of life had been affected by this symptom [24].
Etiology and modifying factors — GSM occurs primarily in patients who are peri- or postmenopausal. Conditions or medications that induce a transient or chronic hypoestrogenic state can also cause atrophic vaginal changes. The duration of hypoestrogenism is a major factor in the development and severity of GSM. Etiologies of hypoestrogenism include:
●Natural menopause.
●Bilateral oophorectomy.
●Primary ovarian insufficiency.
●Ovarian failure due to radiation therapy, chemotherapy, or an adverse consequence of uterine artery embolization; these may be temporary or permanent.
●Premenopausal use of medications with antiestrogenic effects, such as tamoxifen, aromatase inhibitors, danazol, medroxyprogesterone acetate, gonadotropin-releasing hormone agonists (eg, leuprolide, nafarelin, goserelin) or antagonists (eg, ganirelix).
●Postpartum reduction in estrogen production, particularly during lactation.
●Prolactin elevation due to hypothalamic-pituitary disorders with secondary reduction of estrogen secretion by the ovary.
●Hypothalamic amenorrhea or amenorrhea in the setting of severe systemic lupus erythematosus or rheumatoid arthritis (due to hypothalamic hypogonadism or primary ovarian insufficiency) combined with glucocorticoid therapy – The combined suppression of ovarian and adrenal activity (loss of adrenal androstenedione reduces estradiol synthesized through extraovarian aromatization) results in extremely low estradiol levels.
Factors other than low estrogen and possibly diminished androgen levels can modulate the degree of vulvovaginal atrophy or the severity of symptoms. For example, vaginal nulliparity or vaginal surgery may intensify vaginal atrophy symptoms [25,26]. Abstinence from sexual activity appears to exacerbate atrophic changes whereas sexual activity helps preserve the vaginal epithelium, presumably by increasing blood flow and tissue elasticity. Cigarette smoking causes relative estrogen deficiency and may reduce vaginal perfusion [4].
Patients with depression and urinary incontinence may be more likely to report distressing vulvovaginal atrophy symptoms that more negatively impact their quality of life, including their sexual functioning. With urinary incontinence, this may be due to chronic perineal pad use [27].
CLINICAL PRESENTATION — By definition, patients with GSM are symptomatic. However, not all patients with atrophic changes on pelvic examination are symptomatic.
Up to 70 percent of patients with symptoms of vaginal atrophy do not discuss their condition with a health care provider [24]; some believe their symptoms are an expected and necessary part of the aging process [25]. Cultural, religious, and societal beliefs, as well as embarrassment, may also play a role in making patients feel uncomfortable discussing concerns related to the genitourinary system. In addition, many patients are not aware of treatment options [28]. Rather than seeking treatment, patients commonly make lifestyle changes to deal with their symptoms. As an example, they may stop sexual activity due to dyspareunia caused by vaginal dryness, loss of vaginal elasticity, or development of levator spasm.
Symptoms of GSM include [1,25]:
●Vulvovaginal dryness
●Decreased vaginal lubrication during sexual activity
●Dyspareunia, including vulvar or vaginal pain (at the introitus or within the vagina)
●Vulvar or vaginal bleeding (eg, postcoital bleeding, labial fissures)
●Decreased arousal, orgasm, or sexual desire
●Vulvovaginal burning, irritation, or itching
●Vaginal discharge (leukorrhea or yellow and malodorous)
●Levator spasm
●Urinary tract symptoms (eg, urinary frequency, urinary urgency, dysuria, urethral discomfort, hematuria, recurrent urinary tract infections)
●Urethral prolapse/caruncle
Symptoms accompanying vaginal atrophy are usually progressive and worsen as with duration of hypoestrogenism. Early in the menopause transition, patients may notice a slight decrease in vaginal lubrication upon sexual arousal, which is often one of the first signs of estrogen insufficiency. As the hypoestrogenic state becomes chronic, additional symptoms may be reported by the patient, including a sensation of vaginal dryness during daily activities, not necessarily during sexual activity (the most common symptom), and other symptoms (refer above) may develop.
EVALUATION — The evaluation for GSM typically includes both a medical history and a pelvic examination. Laboratory testing is not typically required. A telehealth visit may be utilized in some patients. (See "Telemedicine for adults".)
History — Patients who are peri- or postmenopausal or who have other etiologies of hypoestrogenism should be asked about symptoms of urogenital atrophy during routine clinical visits. As noted above, many patients with these symptoms do not bring them to the attention of a clinician [24]. (See 'Clinical presentation' above.)
A medical history should include the obstetric and gynecologic history, including menstrual history, and other conditions or medications to assess menopausal status and evaluate for etiologies of low estrogen other than menopause. The clinician should ask about response to any previous interventions. A complete review of systems should be performed, as urogenital symptoms may be due to etiologies other than loss of estrogen. A pertinent sexual history, including a history of sexual trauma, should be taken to evaluate whether the symptoms adversely impact sexual activity and cause distress.
The clinician should ask about painful vulvar symptoms, symptoms that may be associated with infection or inflammatory conditions (as part of a differential diagnosis), as well as use of products that may be irritants or result in allergic reactions (eg, perfumes, powders, panty liners, soaps, deodorants, spermicides, lubricants, tight clothing) [29]. This should also include a history of pelvic radiation. (See 'Differential diagnosis' below.)
Quality of life issues should also be assessed; these include degree of discomfort, behavioral responses to symptoms, as well as the impact of symptoms on daily activities, sexual activity, and partner relationships [30]. The clinician should ask about the patient's therapeutic goals. Patients who are not having vaginal intercourse due to pain or discomfort should be asked if this is something they would like to be able to have in the future, recognizing that there are often multiple factors (eg, relationship status, aging, partner sexual dysfunction, lack of interest) that affect this decision.
Pelvic examination — Signs associated with GSM include [1]:
●Labia minora resorption or fusion
●Tissue fragility/fissures/petechiae
●Introital retraction
●Loss of hymenal remnants
●Prominence of urethral meatus
●Urethral eversion or prolapse
●Vulvovaginal pallor/erythema
●Loss of vaginal rugae
●Decreased vulvovaginal secretions/lubrication
●Decreased elasticity
●Abnormal discharge
●Spasm of levator muscles on palpation of the posterior vagina
The external genitalia are examined and may show scarce pubic hair, diminished elasticity, and turgor of the vulvar skin; introital narrowing or decreased moisture; and fusion or resorption of the labia minora [31,32]. Some practitioners have the patient hold a mirror during the pelvic examination so that areas of vulvovaginal irritation or pain can be mutually noted. In severe cases, the labia majora may be fused [25]. It is necessary to exclude lichen sclerosus when there are structural changes like fused labia minora and loss of the clitoral hood. Loss of the labial fat pad gives the labia majora a pendulous appearance and makes the labia minora less distinct and/or makes the clitoris appear more protuberant. A urethral caruncle may be present and appear as proliferative red tissue at the opening of the urethra. Urethral prolapse or polyps may also occur. (See "Vulvar lichen sclerosus" and "Urethral caruncle".)
In patients with severe atrophic changes, exercise caution when performing the speculum and bimanual examinations as even gentle contact can cause pain and bleeding. Assess for introital stenosis using a gloved finger before attempting insertion of the speculum. Levator spasm may make insertion of a gloved finger too uncomfortable; instead of a two-finger pelvic exam, a one-finger gloved examination is often better tolerated by the patient. A lubricated narrow speculum is also usually most comfortable. Thus, among metal speculums, a Pederson is usually chosen rather than a Graves speculum (picture 1). A narrow Pederson speculum or a pediatric speculum may be necessary for examining some patients. If the insertion of a gloved finger or speculum is too distressing for the patient, then it is best to stop the examination and ask the patient if she is too uncomfortable to continue. For some patients, treatment of the vaginal atrophy may be necessary before a complete pelvic examination can be performed. Rectal examination or transabdominal pelvic ultrasound may allow evaluation of uterus and organs when the vagina is too stenotic or the examination is too uncomfortable. When an office examination cannot be comfortably completed and is deemed essential before management can begin, and an adequate ultrasound that excludes pathology is not possible, an examination under anesthesia may be necessary.
Classic vaginal findings of atrophy include a pale, dry vaginal epithelium that is smooth and shiny with loss of most rugation. If inflammation is present, there may be patchy erythema, petechiae, blood vessels visible through the thinned epithelium, friability, bleeding, and discharge. The vagina may be shortened, narrowed, and poorly distensible. The cervix may become flush with the vault, and it may be difficult to identify the cervix or the cervical os. The vaginal fornices may become obliterated. The urethra is often prominent due to loss of collagen support and eversion of urethral mucosa may occur.
Laboratory evaluation — Laboratory tests are usually not necessary for the diagnosis and evaluation of GSM, other than for exclusion of other etiologies under consideration or to assess the efficacy of treatments in research studies.
●Vaginal pH – The pH of an estrogenized vagina is acidic, typically in the range of 4 to 4.5 [33,34], though broader ranges (3.5 to 5) have been reported [35]. Vaginal pH may reach levels of 5.5 to 6.8 or higher in postmenopausal patients, especially those who are not on estrogen therapy [36]. Thus, a pH of ≥5 in the absence of other causes (eg, infection, semen in setting of recent intercourse) can be an indicator of vaginal atrophy due to estrogen deficiency. The pH should be documented in the chart and also allows the patient to see the effects of lack of estrogen on the vaginal pH. This is discussed in more detail separately. (See "Vaginal discharge (vaginitis): Initial evaluation", section on 'Normal discharge'.)
●Maturation index – The maturation index is the proportion of parabasal, intermediate, and superficial cells in each 100 cells counted on a smear of the upper two-thirds of the vagina. It is used to quantify the proportions of cell types of the vaginal epithelium [37]. It is usually done in a laboratory experienced in running this test. In premenopausal patients with adequate estrogen levels, intermediate and superficial cells predominate. The maturation index for these patients is typically 40 to 70 intermediate cells, 30 to 60 superficial cells, and 0 parabasal cells. In patients with vaginal atrophy, an increase in parabasal cells and a decrease in superficial cells are observed. Patients in early menopause typically have a maturation index of 65 parabasal cells, 30 intermediate cells, and 5 superficial cells. As patients age, parabasal cells will continue to increase, and the maturation index may eventually consist entirely of parabasal cells.
If vaginitis is suspected, microscopy or other testing should be performed. Yeast or clue cells may indicate need for treatment. If urinary tract infection is suspected, this should be evaluated as appropriate. (See "Vaginal discharge (vaginitis): Initial evaluation", section on 'Initial diagnostic evaluation' and "Acute simple cystitis in females", section on 'Diagnostic approach'.)
DIAGNOSIS — GSM is a clinical diagnosis made in patients who are in a hypoestrogenic state and have characteristic symptoms and findings on pelvic examination. Patients may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis.
The presence of symptoms in a perimenopausal or postmenopausal patient is sufficient since physical findings may not be present after a short duration of low estrogen. Laboratory tests to confirm hypoestrogenic findings are available, but such testing is typically not necessary.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of symptomatic urogenital atrophy includes other causes of vulvovaginal discomfort, scarring, or discharge or urinary symptoms [29,30]. These include:
●Vaginitis and vaginosis (eg, candidiasis, bacterial vaginosis, trichomoniasis, desquamative inflammatory vaginitis). (See "Vaginal discharge (vaginitis): Initial evaluation".)
●Vulvar dermatitis in response to environmental agents (eg, perfumes, deodorants, soaps, panty liners, perineal pads, spermicides, lubricants, or tight-fitting/synthetic clothing) resulting in contact or irritant dermatitis. (See "Vulvar dermatitis".)
●Vulvar lichen sclerosus. (See "Vulvar lichen sclerosus".)
●Vulvovaginal lichen planus. (See "Vulvar lichen planus".)
●Genital tract ulcers or fissures may be due to herpes lesions or systemic disease (eg, Crohn disease). (See "Vulvar lesions: Differential diagnosis of red lesions", section on 'Crohn disease'.)
●Genital tract bleeding may be due to trauma, infection, or malignancy. Females with postcoital bleeding should be evaluated for cervical cancer. (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers", section on 'Trauma (physical and chemical)' and "Causes of female genital tract bleeding" and "Vulvar lesions: Differential diagnosis of white lesions", section on 'Squamous cell carcinoma'.)
●Vulvodynia. (See "Vulvar pain of unknown cause (vulvodynia): Clinical manifestations and diagnosis".)
●Other etiologies of frequent urinary tract infection or associated symptoms (eg, anatomic or hygiene issues, bladder pain syndrome). (See "Recurrent simple cystitis in women" and "Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Menopause".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Vaginal dryness (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Genitourinary syndrome of menopause (GSM) is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder. (See 'Introduction' above.)
●Female urogenital atrophy results primarily from a decline in the serum estrogen concentration. This is most commonly due to natural or surgical menopause but may also occur with premature ovarian insufficiency or, temporarily, during the postpartum period or lactation or due to hypothalamic amenorrhea or antiestrogenic drugs. The likelihood and severity of symptoms increases with duration of hypoestrogenism. Loss of serum androgen concentration also appears to play a role. (See 'Pathophysiology' above.)
●Symptoms may include vulvovaginal dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections. Approximately 50 percent of menopausal patients report bothersome vulvovaginal discomfort. Many patients have symptoms but do not seek medical care; thus, clinicians should ask menopausal patients if they have pain, itching, or sexual symptoms during routine well-women checkups. (See 'Clinical presentation' above.)
●The evaluation includes a medical history and pelvic examination; a telehealth visit may be utilized in some patients. Laboratory testing is not typically necessary. Pelvic examination findings may include tissue fragility/fissures/petechiae; labia minora resorption or fusion; introital retraction; loss of vaginal moisture, rugae, and elasticity; urethral meatus appears prominent; and urethral eversion or prolapse. A single-finger gloved examination may be more comfortable than a bidigital examination. Rectal examination may provide additional information if vaginal examination is limited. However, for some patients with severe atrophic changes, treatment of the vaginal atrophy may be necessary before a complete pelvic examination can be performed. (See 'Evaluation' above.)
●GSM is a clinical diagnosis made in patients who are in a hypoestrogenic state and have characteristic symptoms and findings on pelvic examination. Patients may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. (See 'Diagnosis' above.)
●The differential diagnosis of symptomatic urogenital atrophy includes other causes of vulvovaginal discomfort, scarring, or discharge or urinary symptoms, including vaginitis; vulvar lichen sclerosus; vulvovaginal lichen planus; vulvar contact or irritant dermatitis; genital ulcers or fissures due to herpes lesions or systemic disease; genital tract bleeding due to trauma, infection, or malignancy; other etiologies of urinary tract infection; or associated symptoms. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Santen, MD, who contributed to an earlier version of this topic review.
