Genitourinary Syndrome of Menopause

Etiology

Estrogen plays a crucial role in maintaining the normal anatomy and physiology of the urogenital system. Estrogen receptors are present in the vagina, vulva, urethra, and bladder trigone, where they respond to estrogen stimulation by maintaining normal blood flow, tissue thickness, rugosity, elasticity, and moisture of epithelial surfaces. During the reproductive years, the vagina is rich in glycogen, which is converted by the normal flora, lactobacilli, into lactic acid. This process creates an acidic environment in the vagina, with a pH ranging from 3.5 to 5.0, allowing lactobacilli to continue to thrive and protect the vaginal and urinary tracts from infections. After menopause, the quantity of lactobacilli decreases, leading to an increase in the vaginal pH and the development of GSM.[2] 

Additionally, sexual activity promotes epithelial turnover and enhances vaginal lubrication. A decline in estrogen levels during menopause causes urogenital atrophy. As estrogen production decreases, secretions diminish, and the genitourinary tissues become atrophic, leading to the symptoms associated with GSM. Other causes of GSM include lactation, hypothalamic amenorrhea, and antiestrogen medications used in the treatment of uterine fibroids, endometriosis, and breast cancer.[3][4]

Epidemiology

GSM is a prevalent concern among the postmenopausal population. Study results indicate that while roughly 15% of women experience symptoms of vaginal atrophy before menopause, approximately 40% to 54% of postmenopausal individuals report bothersome symptoms. Menopause causes a dramatic 95% reduction in estrogen production, resulting in 75% of wo experiencing vaginal dryness, 40% reporting pain during intercourse, and 30% to 40% experiencing urinary urgency and frequency. Despite these symptoms, more than 50% of affected patients are not using any treatments to alleviate their discomfort.[5]

Approximately 70% of patients with signs and symptoms of GSM do not discuss their concerns with healthcare professionals.[6] Many patients feel reluctant or embarrassed to discuss or seek treatment, believing these symptoms are a normal part of aging. Cultural, religious, and societal beliefs also influence their willingness to discuss these quality-of-life issues. Additionally, many patients are unaware of available treatment options. As a result, less than 25% of affected women receive appropriate care. Clinicians often do not screen for symptoms of GSM. This omission leads to underdiagnosis and undertreatment of this condition.[2]

GSM most commonly arises from conditions that lead to a diminished estrogen state, such as natural menopause, where the ovaries cease estradiol production, resulting in a 95% decline in estradiol levels from premenopausal levels. However, GSM can also occur in individuals with other conditions associated with low estrogen, including those who have undergone surgical menopause following bilateral oophorectomy, primary ovarian insufficiency, chemotherapy, hypothalamic amenorrhea, or are breastfeeding. Additional risk factors include ovarian failure due to radiation or arterial embolization, hypothalamic-pituitary disorders, and the use of antiestrogen medications such as leuprolide or gonadotropin-releasing hormone antagonists, often prescribed for endometriosis. Breast cancer survivors, particularly, are at increased risk due to treatments such as chemotherapy or aromatase inhibitors, which can contribute to the early onset of GSM symptoms.[3][7][8]

Pathophysiology

Estrogen plays a critical role in maintaining healthy blood flow and a balanced microbiome in the vagina while maintaining the elasticity, thickness, and moisture of the vaginal epithelium by sustaining collagen levels. Estrogen also promotes the exfoliation of vaginal epithelial cells, leading to increased glycogen levels, which lactobacilli in the normal vaginal flora convert into lactic acid. This process allows for the renewal of the vaginal epithelium and maintains the vagina's typical acidic pH. When estrogen levels decline, this process is disrupted, resulting in an atrophic vaginal epithelium with reduced secretions and a less acidic environment characterized by a pH greater than 5.[8][9] These physiologic changes increase the risk of vaginal and urinary tract infections.

Traditionally, estrogen has been recognized as the primary hormone responsible for the health and function of the vagina. However, increasing evidence suggests that androgens also play a crucial role in maintaining urogenital tissue health. The vagina contains androgen receptors that, when stimulated, help reduce inflammation and maintain vaginal contractility. After menopause, dehydroepiandrosterone (DHEA), a weak androgen primarily secreted by the adrenal glands, becomes the prominent sex steroid in the body. Within the vagina, DHEA is converted into both estrogens and androgens. This understanding has led to a newer approach to GSM treatment, including local androgen therapy with DHEA.[10][11]

History and Physical

Diagnosing GSM requires a comprehensive patient history and a thorough physical examination. Laboratory testing is not required. Common symptoms include genital dryness, burning, and irritation. Patients may also experience pain and dryness during intercourse, as well as dysuria, urgency, and recurrent urinary tract infections. Many symptoms of GSM can be mistaken for other genitourinary conditions, such as vaginal or urinary tract infections, making it crucial for clinicians to obtain a detailed history, including a sexual history.[2] Inquiring about sexual habits and activities is important to rule out other causes, particularly infections. As GSM symptoms develop, many patients find sexual activity challenging due to changes in the vaginal mucosa, which can lead them to avoid vaginal intercourse, further exacerbating the atrophy.[8][9][12] 

Clinicians should ask about obstetric and gynecologic histories, menstrual history, current and past medications, and the use of any potential irritants in the area. Specific questions related to GSM symptoms should be addressed, as patients may not always volunteer this information without prompting. Symptoms of GSM may include dyspareunia, postcoital bleeding, and dysuria. A decrease in vaginal lubrication during sexual activities is often the first symptom, followed by discomfort during daily activities. Additionally, as the vaginal pH changes, the vaginal flora may also change, increasing the risk of recurrent urinary tract infections. Unlike vasomotor symptoms, which tend to improve over time, GSM is progressive without treatment.[2]

The anatomical changes associated with GSM can include fusion of the labia major or minora, introital stenosis, labial and clitoral atrophy, phimosis of the prepuce, and urethral caruncles, polyps, eversion, or prolapse. The urethral meatus may become susceptible to physical irritation.[1] Vaginal changes may include tissue fragility and friability, loss of rugae, the presence of petechiae, fissures, ulcerations, decreased elasticity, reduced lubrication or secretions, and a shortened, narrowed, and poorly distensible vaginal vault. Thinning and regression of the labia minora, retraction of the introitus, and involution of the hymenal carunculae can lead to dyspareunia. Other anatomical changes associated with GSM include reduced collagen content and hyalinization, thinning of the epithelium, and decreased elastin production. Pelvic and speculum exams may cause pain and bleeding.[2] Classic physical examination findings of atrophy may also include pale, dry, smooth, and shiny epithelium or inflammatory changes such as patchy erythema, petechiae, or increased visibility of blood vessels. There may also be friability, bleeding, and a thin, white, odorless discharge.[13]

Evaluation

Laboratory tests such as urinalysis and culture, sexually transmitted infection testing, and vaginal pathogen swabs may be employed to rule out genitourinary infections; they are typically not necessary for diagnosing GSM. Measuring estrogen levels via serum estradiol is also unreliable for diagnosing GSM, as current assays lack the sensitivity required for accurate detection.[14] Vaginal pH is typically greater than 5.0 in the absence of any infections or abnormal discharge, and atrophic changes in the vaginal epithelium include a shift from superficial cells to more basal cells.

One of the physical changes associated with GSM is having less than 5% superficial cells on the vaginal maturation index (VMI).[5] The VMI is derived from the microscopic evaluation of the vaginal epithelium, assessing the proportion of different vaginal epithelial cell types as follows:

• Parabasal cells are the least mature and are more prevalent when estrogen levels are low.
• Intermediate cells are moderately mature.
• Superficial cells are the most mature and predominate when estrogen levels are high.[15]

In early menopause, the VMI usually shows 30% intermediate cells, 5% superficial cells, and 65% parabasal cells. As atrophy progresses, the VMI may eventually display only parabasal cells. However, in clinical practice, neither the VMI nor vaginal pH measurement is necessary to diagnose GSM.[2] Moreover, the severity of GSM symptoms does not correlate well with vaginal pH or VMI. 

In 2020, the Menopause Society clarified that these laboratory tests are not essential for diagnosing GSM.[1] However, the use of a questionnaire like the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire, a brief yet comprehensive screening tool, may enhance the identification and treatment of GSM when used during annual wellness visits or when postmenopausal women present with vulvovaginal or genitourinary complaints.[16] Another tool frequently used to evaluate GSM symptoms is the Vaginal Health Index (VHI), which assesses vaginal secretions, pH, elasticity, hydration, and the epithelial mucous membrane condition. The VHI score ranges from 5 to 25, with lower scores indicating greater atrophy.[17]

Treatment / Management

GSM can be managed with various treatment modalities aimed at alleviating symptoms. These treatments are generally classified into nonhormonal and hormonal options. Below is an overview of the available treatments, including vaginal moisturizers, lubricants, vaginal estrogens, dehydroepiandrosterone (DHEA), systemic hormone replacement therapy, and ospemifene, an oral selective estrogen receptor modulator with both estrogen agonist and antagonist properties.[2] Patients with breast cancer deserve special mention as treatment of GSM presents a challenge due to the need to balance effective symptom management with the avoidance of estrogen-based therapies that could potentially exacerbate cancer risk.(B3)

Nonhormonal Treatments

Nonhormonal treatments such as vaginal and topical moisturizers and lubricants are considered the first-line therapy for GSM. Lubricants provide short-term relief, particularly for vaginal dryness during intercourse, while moisturizers offer longer-lasting effects and can be used daily or several times per week. Patients are also encouraged to engage in regular, safe sexual activity, as this helps maintain the health and integrity of the vaginal epithelium and flora. The use of moisturizers, lubricants, and regular sexual activity promotes vaginal health by supporting epithelial integrity and maintaining a balanced vaginal flora. The World Health Organization (WHO) recommends that personal moisturizers and lubricants have an osmolarity of less than 1200 mOsm/kg, as hyperosmolar products can be toxic to epithelial cells, potentially causing irritation and further compromising vaginal health.[2](B3)

Local Estrogen Therapy 

This therapeutic option comes in many forms. These forms include vaginal creams, intravaginal tablets or capsules for more accurate dosing of estrogen, and a vaginal ring that releases small amounts of estrogen daily. All preparations are similarly effective in alleviating vaginal atrophy symptoms. Low-dose local estrogen therapy has not been shown to increase total systemic estrogen levels. Thus, vaginal estrogen allows for an excellent safety profile demonstrating a minimal to no increased risk of endometrial hyperplasia in healthy people.[8][18]

Patients usually have an improvement in symptoms after 2 to 4 weeks of local estrogen treatment.[19] However, some individuals may take 1 to 3 months to experience reduced symptoms. When urinary symptoms are present, vaginal estrogen is recommended. Progestin use and routine endometrial surveillance are not necessary for women using local estrogen therapy. However, any vaginal bleeding after menopause does require an investigation.[2](B3)

As with all medication regimens, the risks and benefits should be discussed with patients before initiating any hormonal therapy. Local estrogen therapy has not been shown to increase circulating estrogen concentrations; it may be used in most patients to treat GSM. One contraindication for vaginal estrogen therapy is undiagnosed vaginal or uterine bleeding.[2](B3)

Vaginal Dehydroepiandrosterone

DHEA comes in a low-dose vaginal insert that can be used daily for the treatment of dyspareunia from GSM. The vaginal mucosa transforms DHEA into estradiol and androgens. Daily use showed few adverse effects and improvement of GSM symptoms in menopausal women.[2](B3)

Systemic Hormonal Therapy 

Systemic hormonal therapy becomes necessary for patients experiencing more widespread menopausal symptoms, such as night sweats and hot flashes, in addition to vaginal atrophy. For patients with these systemic symptoms, hormone replacement therapy (HRT)—including estrogen-progestin combinations or estrogen alone in patients who have had a hysterectomy—offers significant symptomatic improvement. Systemic HRT can promote the growth and revascularization of the vaginal epithelium, normalize vaginal pH, and increase lubrication. HRT can be administered systemically through oral or transdermal replacement. With an intact uterus, progesterone must be added to protect the endometrium. Study results indicate that systemic HRT alleviates symptoms of GSM in approximately 75% of cases, while local therapy is effective in 80% to 90% of cases. Although both therapies have comparable adverse events, local therapy is generally considered safer. In cases where moderate to severe vasomotor symptoms are also present, systemic hormonal therapy may be a particularly effective option.[2](B3)

Ospemifene

Ospemifene is a selective estrogen receptor modulator (SERM) and an oral product approved for the treatment of GSM. This treatment is beneficial for patients with a history of hormone-sensitive cancer. SERMs can have a positive effect on the vaginal epithelium while having minimal to no impact on estrogen-dependent organs. Vasomotor symptoms are the most common adverse effect. Using ospemifene reduced recurrent urinary tract infections and improved symptoms and examination findings with GSM. Ospemifene is an estrogen agonist/antagonist, and its use at 60 mg daily has not been shown to increase endometrial cancer, venous thromboembolism, breast cancer, or breast cancer recurrence.[2] (B3)

Additional Treatment Modalities 

Many other modalities are available to manage GSM, offering new options for symptom relief and improved patient outcomes. Pelvic floor physical therapy may also be used in combination with local estrogen therapy.[2] If there are anatomical vulvovaginal changes, vaginal dilators may be of use. This option is reserved for women who cannot take estrogen therapy and failed moisturizers and lubricants. Dilators have been shown to improve vaginal function.[20] (B3)

More recent treatment modalities for GSM include laser and radiofrequency therapy. Laser therapy induces collagen formation by causing microtrauma to the tissue and can promote revascularization to restore vaginal moisture and elasticity. However, the safety and efficacy are uncertain.[17][21][22][23][24] Studies are underway to evaluate energy-based devices, including lasers like fractional carbon dioxide and Erbium-YAG and radio-frequency devices, but none are currently approved for specifically treating GSM.(A1)

Herbal products and hyaluronic acid products are ineffective for GSM treatment.[2] Longer and larger studies are needed looking at vaginal testosterone as it currently does not have sufficient data to recommend its use for GSM. Other proposed treatments for GSM include the active ingredient of the medicinal plant Ammi visnaga, or toothpick weed, a member of the carrot family, which causes vasodilation.[25] Bovine colostrum cream, prenylflavonoids, phytoestrogens, and aloe vera extract have all been considered alternative treatments, but more research is necessary before recommending any of these options.[17](B3)

Treating Symptoms in Breast Cancer Patients

Patients with a personal history of breast cancer present several challenges related to GSM management. In patients who have had breast cancer, vaginal estrogen therapy for GSM is contraindicated per the Federal Drug Administration. However, the American College of Obstetricians and Gynecologists has endorsed its use and suggests safety when non hormonal therapy does not give satisfactory results. In a cohort study by McVicker, results indicate no evidence of an increase in mortality in breast cancer patients who used vaginal estrogen. These findings support vaginal estrogen therapy use for GSM in patients with breast cancer.[26] Vaginal DHEA has a cautionary label for use in patients with breast cancer because estrogen is a metabolite of DHEA, although it is not considered contraindicated. While ospemifene has shown a decreased risk of breast cancer and reduced recurrence rate, ospemifene is not recommended for GSM treatment in women with breast cancer because it has not been adequately studied. 

Differential Diagnosis

The differential diagnosis of GSM is essential for distinguishing it from other conditions with overlapping symptoms. Accurate diagnosis involves a thorough patient history, physical examination, and appropriate diagnostic tests to differentiate GSM from other conditions. Associated symptoms and signs of GSM overlap with many other gynecologic, urologic, and systemic conditions, making it more difficult for a clinician to contribute the symptoms solely to atrophy. Although these differential diagnoses must be ruled out, their presence does not exclude the additional diagnosis of GSM. Recurring symptoms or infections may be secondary to ongoing atrophy. Understanding these distinctions is crucial for implementing effective, targeted treatments and improving patient outcomes.

The differential diagnoses of GSM include the following:

• Allergic conditions
  • Contact dermatitis
  • Desquamative inflammatory vaginitis
• Inflammatory conditions
  • Lichen sclerosis
  • Erosive lichen planus
  • Cicatricial pemphigoid
• Infections                                             
  • Vulvovaginal candidiasis
  • Bacterial vaginosis
  • Trichomoniasis 
  • Herpes simplex virus
  • Chlamydia
  • Gonorrhea
  • Urinary tract infection
• Trauma
• Foreign bodies
• Malignancy
• Vulvodynia
• Vestibulodynia
• Chronic pelvic pain
• Provoked pelvic floor hypertonia (previously called vaginismus)
• Other medical conditions
  • Diabetes
  • Lupus erythematosus
  • Crohn disease
• Psychological disorders [2][4]                                                         

Prognosis

Patients who experience GSM can get significant symptomatic relief with treatment if the condition is diagnosed and discussed. Patients who do not undergo treatment will, unfortunately, continue to experience ongoing and progressive symptoms, which can increase frustration and lead to poor sexual lifestyles, recurrent infections, and a decreased quality of life. Clinicians can alleviate many distressing genitourinary symptoms and enhance the sexual health and quality of life of postmenopausal patients by educating them about, diagnosing, and effectively managing GSM. The choice of therapy should be based on the severity of symptoms, the efficacy and safety of available treatments for the individual patient, and the patient's preferences.[2]

Nonprescription, nonhormonal therapies often provide adequate relief for many patients with mild symptoms. For those with moderate to severe GSM, effective treatment options include low-dose vaginal estrogens, vaginal DHEA, systemic estrogen therapy, and ospemifene. When using low-dose vaginal estrogen, DHEA, or ospemifene, the addition of progesterone is not necessary; however, long-term endometrial safety beyond 1 year has not been established in clinical trials for some of these treatment modalities.[2]

Complications

GSM can lead to several complications if left untreated or undertreated. These complications include chronic vaginal dryness, recurrent urinary tract infections, and painful sexual intercourse, which can significantly impact an individual's quality of life. Additionally, GSM may cause urinary incontinence, increased susceptibility to vaginal infections, and overall discomfort in daily activities. The physical symptoms may also lead to emotional and psychological distress, including reduced self-esteem and intimacy issues. Early recognition and appropriate treatment are crucial to prevent these complications and improve overall well-being.