This is an updated version of the article that appeared in print.
Note: In May 2023, while this article was in production, the U.S. Food and Drug Administration approved fezolinetant (Veozah), a neurokinin 3 receptor antagonist, for treatment of moderate to severe vasomotor symptoms due to menopause. This article has been revised to incorporate information about this nonhormonal medication.
Am Fam Physician. 2023;108(1):28-39
Author disclosure: No relevant financial relationships.
Menopausal symptoms are widespread and significantly impact quality of life. Common symptoms of menopause are vasomotor (i.e., hot flashes and night sweats) and genitourinary (e.g., vulvovaginal irritation and dryness, dyspareunia, urinary problems), although women may also experience changes in sexual function, mood, and sleep. Estrogen-containing hormone therapy is effective treatment for vasomotor symptoms. Nonhormonal medications for vasomotor symptoms include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, gabapentin, and fezolinetant, which is a neurokinin 3 receptor antagonist [updated]. Selective serotonin reuptake inhibitors should not be administered to women taking tamoxifen. Cognitive behavior therapy and clinical hypnosis are effective for short-term reduction of vasomotor symptoms and associated sleep disturbances, but data are lacking to support the effectiveness of other nonpharmacologic treatments such as herbal or botanical supplements, exercise, and acupuncture. Hormone-free vaginal moisturizers are noninferior to estrogen-based therapies for treating genitourinary syndrome of menopause. Other treatment options for vaginal dryness and dyspareunia associated with menopause include ospemifene and intravaginal dehydroepiandrosterone. Management of menopausal symptoms should involve shared decision-making that is informed by the best available evidence and individual risks and preferences.
The menopausal transition (perimenopause) is characterized by a persistent decline in ovarian function and hormonal fluctuations that may cause bothersome vasomotor (i.e., hot flashes and night sweats) and genitourinary symptoms (e.g., vulvovaginal irritation and dryness, dyspareunia, urinary problems), and affect mood, sleep, sexual function, bone health, and overall quality of life.1 Perimenopause usually begins during the fifth decade of life and lasts several years before completion of natural menopause, a clinical diagnosis made only after cessation of menses for 12 consecutive months. Vasomotor symptoms may affect as many as 80% of women worldwide and last, on average, a total of seven to eight years, including four to five years after the final menstrual period.2–4 Vasomotor symptoms account for 1.5 million excess outpatient visits per year and an additional $330 million in annual U.S. health care costs when left untreated.5 Genitourinary syndrome of menopause affects up to 50% of women worldwide; unlike vasomotor symptoms, it is progressive without treatment.6 Figure 1 suggests an approach for applying the best available evidence and an individualized risk-benefit assessment to guide shared decision-making about natural menopause symptoms.7–11,54 [updated] This article does not discuss surgical menopause or premature menopause (also known as primary ovarian insufficiency). The use of the term women is intended to include cisgender women and other people with ovaries.
| Long-term (18 years) follow-up of the Women's Health Initiative concluded that there was no significant increase in the risk of death from all causes or cardiovascular causes among women receiving hormone therapy with conjugated estrogen alone or conjugated estrogen and medroxyprogesterone during five to seven years of treatment. |
| Duavee, the combination drug containing conjugated estrogen plus bazedoxifene, a selective estrogen receptor modulator, is effective for vasomotor symptoms and osteoporosis prevention, precludes the need for endometrial protection with progesterone, and is well tolerated. |
| Although bioidentical synthetic estradiol is effective compared with placebo, there is no evidence to suggest greater effectiveness over other standard estrogens. |
| A 2018 meta-analysis of women in natural or treatment-induced menopause found that behavioral interventions significantly decreased short-term (i.e., less than 20 weeks) and medium-term (i.e., 20 weeks or longer) perceived severity, but not the frequency, of vasomotor symptoms. |
| Fezolinetant (Veozah), a neurokinin 3 receptor antagonist, received U.S. Food and Drug Adminstration approval in May 2023 for treatment of moderate to severe vasomotor symptoms due to menopause. Fezolinetant significantly reduces hot flashes when compared with placebo and may be considered in women who have contraindications to or prefer nonhormonal medications for vasomotor symptoms. [updated] |
What Are the Known Benefits and Harms of Hormone Therapy in the Treatment of Menopausal Vasomotor Symptoms?
Menopausal hormone therapy containing estrogen is effective for treating vasomotor symptoms of menopause.7,8,12 Unopposed estrogen is known to increase the risk of endometrial cancer and should not be administered without progesterone in women with a uterus. Estrogen-only hormone therapy may reduce breast cancer risk in those with a hysterectomy, whereas estrogen-progesterone hormone therapy may increase the risk in those with a uterus.13 Consensus guidelines support offering hormone therapy to women who are younger than 60 years and within 10 years of symptom onset, do not have contraindications to hormone therapy, and desire it for the treatment of moderate to severe vasomotor symptoms.7,8 Hormone therapy may be initiated cautiously in patients older than 60 years with risk-benefit analysis.7,10
EVIDENCE SUMMARY
The decision to initiate hormone therapy remains challenging. Several large systematic reviews, which included data from the Women's Health Initiative (WHI) and other randomized controlled trials (RCTs), have shown potential benefits and harms, although most participants were older than 60 years and postmenopausal.8,13–15 Table 1 presents cumulative data on the potential benefits and harms of hormone therapy for the prevention of chronic conditions; it is based on a large systematic review from 2022 that includes 20 RCTs and three large cohort studies.13
| Condition/outcome | Estrogen only | Estrogen plus progesterone |
|---|---|---|
| Absolute risk reduction (events per 10,000 people over 7.1 years)* | Absolute risk reduction (events per 10,000 people over 5.6 years)* | |
| Breast cancer (invasive) | ↓ 52 95% CI, −97 to 4; n = 10,739; one trial | ↑ 51 95% CI, 6 to 106; n = 16,608; one trial |
| Colorectal cancer | ↑ 16 95% CI, −21 to 67; n = 10,739; one trial | ↓ 34 95% CI, −51 to −9; n = 16,608; one trial |
| Coronary heart disease | ↓ 19 95% CI, −80 to 54; n = 11,310; three trials | ↑ 31 95% CI, −15 to 84; n = 18,155; three trials; 2 to 5.6 years of follow-up |
| Dementia | ↑ 63 95% CI, −21 to 213; n = 2,947; one trial | ↑ 88 95% CI, 15 to 212; n = 4,532; one trial |
| Diabetes mellitus | ↓ 134 95% CI, −237 to −18; n = 9,917; one trial | ↓ 78 95% CI, −133 to −15; n = 15,874; one trial |
| Fracture (osteoporotic) | ↓ 388 95% CI, −489 to −277; n = 10,739; one trial | ↓ 230 95% CI, −372 to −66; n = 20,499; five trials; 2 to 5.6 years of follow-up |
| Gallbladder disease | ↑ 377 95% CI, 234 to 540; n = 8,376; one trial | ↑ 260 95% CI, 169 to 364; n = 14,203; one trial |
| Stroke | ↑ 79 95% CI, 15 to 159; n = 10,379; one trial | ↑ 52 95% CI, 12 to 104; n = 16,608; one trial |
| Urinary incontinence | ↑ 885 95% CI, 659 to 1,135; n = 6,767; one trial; 1 year of follow-up | ↑ 562 95% CI, 412 to 726; n = 11,578; one trial; 1 year of follow-up |
| Venous thromboembolism | ↑ 77 95% CI, 19 to 153; n = 10,379; one trial | ↑ 120 95% CI, 68 to 185; n = 16,608; one trial |
| All-cause mortality | ↓ 21 95% CI, −57 to 109; n = 11,587; three trials; 2 to 7 years of follow-up | ↑ 4 95% CI, −46 to 61; n = 19,580; three trials |
In long-term (18 years) follow-up of the WHI, the use of conjugated estrogen alone significantly decreased the overall risk of breast cancer in women with a hysterectomy; however, in women with a uterus, the use of combination conjugated estrogen/medroxyprogesterone was associated with an increased risk of breast cancer but not breast cancer mortality.16 It also concluded that there were no significant increases in the risk of death from all causes or cardiovascular death among women receiving conjugated estrogen alone or conjugated estrogen/medroxyprogesterone during five to seven years of treatment.17
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