This summary is an update on the treatment of menopause symptoms, to include vasomotor symptoms, genitourinary symptoms, and hair loss. Treatment options discussed for vasomotor symptoms include menopausal hormone therapy, nonhormonal medication options, and nonmedication treatments. Treatments for isolated genitourinary symptoms include topical estrogen, bazedoxifene, and dehydroepiandrosterone.
Key points
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Menopausal hormone therapy remains the most effective treatment for patients with vasomotor symptoms of menopause (VSM) without contraindications to hormonal therapy.
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Topical estrogen is first-line treatment for isolated genitourinary syndrome of menopause.
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Fezolinetant is the first in a new class of nonhormonal medications for treatment of VSM.
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Selectoive serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, and nonmedication treatments may also be effective for the treatment of VSM.
| CBT | cognitive behavioral therapy |
| DHEA | dehydroepiandrosterone |
| FPHL | female pattern hair loss |
| GSM | genitourinary syndrome of menopause |
| KNB | kisspeptin-neurokinin B |
| MHT | menopausal hormone therapy |
| NK3Ra | neurokinin receptor antagonists |
| UTI | urinary tract infection |
| VSM | vasomotor symptoms of menopause |
| WHI | Women’s Health Initiative |
Introduction
Up to 75% of women experience vasomotor symptoms, mood changes, sleep disturbances, genitourinary symptoms, and hair loss associated with menopause leading to decreased quality of life, lost production at work, and increased health care visits. The natural onset of menopause typically occurs between the ages of 48 and 52 in developed countries, and women often live 30 years or more postmenopause. Vasomotor symptoms tend to peak in the first year after the last menstrual period, and last 7 years on average. Elevated body mass index (BMI) and tobacco use are factors associated with menopausal symptoms. Barriers to treatment may include insufficient knowledge of treatment options, patient embarrassment, or lingering anxiety about menopausal hormone therapy (MHT) due to risks found in the Women’s Health Initiative (WHI). Further analysis has shown that the initially reported risks of MHT were not necessarily accurate and treatment indications have changed over time. , Nonhormonal pharmacologic treatments and complementary therapies are also options to treat symptoms related to menopause, and topical options are available for isolated genitourinary syndrome of menopause (GSM).
Menopausal hormone therapy
Hormone therapy continues to be the most effective treatment for vasomotor symptoms of menopause (VSM) including hot flashes, night sweats, and palpitations. Estrogen alone and combination estrogen-progestogen regimens effectively reduce the severity and intensity of vasomotor symptoms. Estrogen-only regimens are appropriate for patients without a uterus, but estrogen combined with a progestogen or bazedoxifene must be used in those with a uterus to prevent endometrial hyperplasia or cancer. Bazedoxifene is a selective estrogen receptor modulator that prevents endometrial hyperplasia, maintains the benefits of estrogen, and decreases the potential side effects of breast pain and vaginal bleeding from progestogens. Multiple formulations of systemic estrogen with similar efficacy are available ( Table 1 ). , The transdermal patch is the least likely to be discontinued. Table 2 shows common effects of MHT. Progestogen only regimens can be effective for treating VSM but are not Food and Drug Administration (FDA) approved, and no long-term studies have been conducted on safety. , , , Compounded bioidenticals are not recommended due to lack of safety and efficacy data.
| Hormone Therapy | Dosing | Use Recommendations |
|---|---|---|
| Conjugated equine estrogen oral | 0.3–1.25 mg/d | Avoid in hypertriglyceridemia, active gallbladder disease, known thrombophilia and history of VTE , , |
| Esterified estrogens oral | 0.3–1.25 mg/d | |
| Ethinyl estradiol oral | 0.5–2 mg/d | |
| Ethinyl estradiol topical gel | 0.25–1.25 g/d | Preferred in migraine headache with aura and may mitigate VTE risk , |
| Ethinyl estradiol topical spray | 1–3 sprays/d | |
| Ethinyl estradiol transdermal patch | 0.025–0.1 mg/d once weekly | |
| Ethinyl estradiol vaginal ring | 0.05–0.1 mg/d intravaginally q3 months | |
| Ethinyl estradiol cypionate intramuscularly | 1–5 mg q 3–4 wk | Not generally used |
| Ethinyl estradiol valerate IM | 10–20 mg q4 weeks | |
| Progesterone oral | 200 mg daily 12 d each mo | |
| Conjugated estrogen/bazedoxifene oral | 0.45 mg/20 mg daily |
| Increasing age and duration of use increase risk for adverse effects , | |
| Common side effects | Breast tenderness, nausea, bloating, headaches, abnormal uterine bleeding |
| Gallbladder disease | Increased incidence |
| Venous thromboembolism (VTE) | Increased risk, highest with estrogen-progesterone , , , Mitigated with transdermal estrogen , |
| Breast cancer | Inconsistent findings with possible decreased or slightly increased incidence with estrogen only , , Slight increase with combined therapy , , |
| Endometrial cancer | Increased risk with estrogen only Decreased incidence with combined therapy |
| Coronary heart disease | Increased risk with combined therapy |
| Stroke | Increased risk with oral MHT, MHT use > 5 y Decreased risk with nonoral MHT |
Guidelines recommend making individualized decisions for MHT to achieve maximum benefit with minimal risk. , , Patients younger than 60 and within 10 years of menopause have the most favorable benefit-risk ratio, and MHT should be considered in these patients if they do not have contraindications like history of myocardial infarction, stroke, venous thromboembolism (VTE), or estrogen-dependent cancers (ie, breast). , , Patients over 60 years old and more than 10 years past the onset of menopause have a less favorable benefit-risk ratio, but it is still reasonable to consider MHT if benefits outweigh risks. , To minimize adverse events, all patients should receive the lowest effective dose of MHT for the shortest amount of time needed with annual evaluation. There are no specific guidelines on when to discontinue MHT, so decisions must be individualized. Tapering the dose has no proven benefit in mitigating symptom return.
MHT is not FDA approved for treatment of depressive symptoms but data are mixed. Studies have also shown improvement in insomnia. , ,
Nonhormonal pharmacologic treatments for VSM
SSRIs Paroxetine, escitalopram, citalopram, and SNRIs venlafaxine, and desvenlafaxine have all been shown to reduce VSM with a range in the reduction for VSM frequency of 25% to 69%. Paroxetine was the first nonhormonal treatment of VSM to be FDA approved. Paroxetine and venlafaxine both reduce VSM frequency by about 50%, and the latter is more often used. Duloxetine has been shown effective in smaller studies. , Research has indicated that 10 to 20 mg escitalopram and 75 mg venlafaxine are equivalent to 0.5 mg oral 17β – estradiol.
Gabapentin 900 mg daily improves VSM, and higher doses are more effective. Side effects of drowsiness, dizziness, headache, and disorientation are more common at higher doses. A meta-analysis showed gabapentin was associated with significant reductions versus placebo for VSM frequency, duration, and composite score. One study found that pregabalin at doses of 75 or 150 mg twice daily reduced VSM by about 60% compared with 35% for placebo.
Fezolinetant represents a new class of drugs called neurokinin receptor antagonists (NK3Ra). The mechanism of action is via a group of neurons in the hypothalamus, kisspeptin-neurokinin B (KNB) neurons. Menopausal decrease in estrogen levels leads to hyperstimulation of KNB neuron production of kisspeptin, which in turn stimulates the thermoregulatory center to increase sensitivity to external cues and triggers more frequent heat dissipation responses, such as VSM. Antagonist blockade of NK3 receptors alleviates thermoregulatory disturbances related to the female low estrogen state.
Fezolinetant is the second nonhormonal medication approved by the FDA to treat menopausal vasomotor symptoms. Although significantly more effective than other nonhormonal medications, the cost of approximately $540/mo may limit use. Approval trials had durations of up to 1 year, so postmarketing surveillance is required to evaluate longer-term use.
A meta-analysis comparing fezolinetant to placebo among postmenopausal participants with moderate to severe VSM showed a pooled odds ratio for reduction of symptoms by at least 50% versus placebo of 2.78 (95% confidence interval: 1.81–4.27) with 70% decreased odds of sleep problems. There was about a 1% incidence above placebo of elevated alanine transaminase.
Another meta-analysis compared the results of venlafaxine or desvenlafaxine placebo-controlled trials to NK3Ra placebo-controlled trials for VSM frequency and severity, and night-time awakenings/night sweats. NK3Ra treatment resulted in reduction in frequency from baseline to week 12 by 62% to 93% (placebo 28%–55%) compared with 48% to 67% for SNRIs (placebo 25%–51%) and were better tolerated regarding nausea, dry mouth, insomnia, dizziness, and constipation.
Other nonhormonal pharmacologic treatments for VSM include clonidine and oxybutynin. Clonidine is more effective than placebo, but less effective than other options and limited by anticholinergic effects. Oxybutynin is somewhat effective but associated with cognitive decline in older persons. See Table 3 for a summary of nonhormonal pharmacologic treatments.
| Medication | Dosing | Notes |
|---|---|---|
| Paroxetine | 7.5 mg IR capsule nightly | FDA approved. SSRI/SNRIs may increase rate of fragility fractures |
| Escitalopram | 10–20 mg daily | Start at 10 mg daily and increase after 4 wk if symptoms are not adequately controlled, SSRI/SNRIs may increase rate of fragility fractures |
| Citalopram | 10–20 mg daily | Off-label use, SSRI/SNRIs may increase rate of fragility fractures |
| Venlafaxine | 37.5–75 mg daily | Off-label use, SSRI/SNRIs may increase rate of fragility fractures |
| Desvenlafaxine | 50–100 mg daily | Off-label use, SSRI/SNRIs may increase rate of fragility fractures |
| Gabapentin | 900 mg | Off-label use, start 100–300 mg nightly and increase gradually over 3–12 d based on response and tolerability , |
| Pregabalin | 75–150 mg twice daily | Off-label use, start 50 mg nightly and increase weekly based on response and tolerability, may cause weight gain |
| Fezolinetant | 45 mg daily | FDA approved Cost may be prohibitive. Associated with abdominal pain, diarrhea, and increased risk of hepatic transaminase elevation. Liver function tests should be obtained prior to initiation and at 3, 6, and 9 mo |
| Clonidine | 0.05 mg twice daily | Anticholinergic effects, may titrate up based on response and tolerability to a dosage range of 0.1–1 mg/d in divided doses , |
Nonpharmacological treatments for menopausal symptoms
The 2023 North American Menopause Society position statement recommended the use of cognitive behavioral therapy (CBT), clinical hypnosis, weight loss, and stellate ganglion blocks as scientifically supported modalities for management.
As elevated (BMI) and tobacco use are risk factors for VSM, weight reduction, and smoking cessation are encouraged. Dietary guidelines include a whole food, plant-based diet with an emphasis on protein intake of at least 0.8 g/kg of body weight/day. , Strength training is encouraged to mitigate metabolic changes associated with menopause, help prevent osteoporosis, and decrease VSM.
CBT utilizes psychotherapeutic behavior modifications to change negative patterns associated with VSM of menopause. , Sessions focus on developing deep awareness of one’s mind and body with meditation, breathing techniques, and yoga. CBT decreases the frequency and severity of VSM, anxiety, and sleep problems. CBT provided in individual sessions, group sessions, virtual sessions, and self-guided online modules is efficacious and cost-effective. ,
Clinical hypnosis has shown similar efficacy to CBT for short-term reduction of VSM and associated sleep disturbances. Sleep quality significantly improved in groups that had either phone or in-person delivery of hypnosis.
Stellate ganglion blocks can be effective for VSM. These blocks are performed at the anterolateral aspect of the right C6 vertebra under fluoroscopy and may alleviate symptoms for up to 12 weeks but is reserved for patients with severe or refractory VSM due to limited availability and higher risk.
While not recommended by North American Menopause Society (NAMS), phytoestrogen (“plant” estrogen) use is a popular form of alternative therapy for VSM. All classes of phytoestrogens have varying efficacy. Supplementation is effective in some patients; however, the lack of regulation of supplements introduces challenges to therapy. Genistein, the most prevalent isoflavone in soy, can stimulate breast cancer growth and may interfere with the antitumor activity of tamoxifen and should not be utilized in this population. ,
Genitourinary syndrome of menopause
GSM is a prevalent condition affecting up to 90% of postmenopausal women. Symptoms include vaginal burning, itching, dryness, and pain (including dyspareunia), and recurrent urinary tract infections (UTIs). These symptoms can significantly impair quality of life and sexual function.
The pathophysiology of GSM involves thinning, dryness, and inflammation of vaginal tissue due to decreased estrogen stimulation resulting in a reduced number of epithelial cells, degeneration of collagen and elastin fibers in connective tissue, and an overall increase in mucosal fragility which impacts sexual and urinary function.
Diagnosis of GSM is based on patient history, physical examination, and vaginal pH measurement. Visual inspection for signs of keratinization and loss of rugae can be helpful.
Treatment options for GSM include lifestyle modifications, vaginal moisturizers/lubricants, estrogen, dehydroepiandrosterone (DHEA), and ospemifene. Lifestyle modifications that can mitigate symptoms include smoking cessation, regular sexual activity, which helps to maintain vaginal elasticity and lubricative response to sexual arousal, and pelvic floor exercises. Vaginal moisturizers and lubricants offer relief from coital discomfort without reversing atrophic changes.
Estrogen therapy in the form of topical creams, suppositories, or rings, effectively decreases GSM symptoms, reducing the incidence of incontinence and recurrent UTIs in postmenopausal women. Systemic estrogen can be considered for more severe symptoms. In one study, vaginal estrogen improved incontinence symptoms (relative risk [RR]: 0.74; CI: 0.64–0.86) while systemic estrogen alone worsened incontinence (RR: 1.32). In a small study, vaginal estrogen reduced the frequency of recurrent UTIs in postmenopausal women, while the serum estrogen levels remained within postmenopausal range in another study of women treated with low-dose vaginal estrogen therapy. Vaginal estrogen therapy should be used at the lowest effective dose and frequency and avoided in cases of undiagnosed vaginal or uterine bleeding.
DHEA, an intermediate in androgen and estrogen biosynthesis, is a newer treatment option. A low-dose DHEA vaginal insert is approved in the United States for treatment of moderate to severe dyspareunia in menopausal women. It has been shown to have no significant impact on endometrial cytology. The most common side effect of this treatment is vaginal discharge.
Ospemifene is an estrogen agonist/antagonist indicated for treatment of vaginal dryness and moderate to severe dyspareunia. A 52-week study showed sustained improvement without any cases of venous thromboembolism, endometrial hyperplasia, or cancer. The most common side effect was vasomotor symptoms. Ospemifene reduced recurrent UTIs in a 6-month retrospective observational study. It should not be recommended for patients with known or suspected breast cancer. Treatment options are summarized in Table 4 .
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