New Guideline Recommends Hormone Therapy First for Menopausal Symptoms

Hormone therapy should be the first-line treatment for women with menopausal vasomotor symptoms, according to new guidance from the American College of Physicians (ACP).

Women with a uterus should receive estrogen in combination with progestogen, while those without a uterus can receive estrogen monotherapy as first-line therapy, according to ACP’s new clinical guideline on pharmacologic treatments for vasomotor symptoms.

Both are listed as strong recommendations based on high-certainty evidence, Amir Qaseem, MD, PhD, MHA, and guideline authors wrote in the Annals of Internal Medicine.

The serotonin-norepinephrine reuptake inhibitors (SNRIs) desvenlafaxine (Pristiq) or venlafaxine (Effexor) can be used as second-line treatment for those who have contraindications to or don’t tolerate first-line treatment, a recommendation based on moderate-certainty evidence, they reported.

Finally, third-line treatments include the selective serotonin reuptake inhibitors (SSRIs) escitalopram (Lexapro) or paroxetine (Paxil), or gabapentin — both based on low-certainty evidence — or the neurokinin (NK) receptor antagonists fezolinetant (Veozah) and elinzanetant (Lynkuet), based on moderate-certainty evidence.

The recommendations were based on a systematic review and meta-analysis by Susan Diem, MD, MPH, of the VA Health Care System in Minneapolis, and colleagues, also published in the Annals of Internal Medicine.

Vasomotor symptoms — hot flashes and night sweats — affect most women during the menopause transition and can greatly disrupt a patient’s life. Menopausal hormone therapy has long been known to be effective at treating vasomotor symptoms. However, findings about increased risks of cardiovascular disease and breast cancer from the Women’s Health Initiative (WHI) study led to boxed warnings and a decline in use of the therapy over the past two decades.

Recently, however, the FDA removed warnings about cardiovascular disease and breast cancer, and re-analyses of the WHI data have been completed, suggesting better outcomes with hormone therapy for women closer to menopause. In 2022, the Menopause Society released a position statement on hormone therapy, concluding that for women under 60 who are within 10 years of menopause onset and have no contraindications, the risk-benefit ratio is favorable for treatment of vasomotor symptoms.

In an accompanying editorial also published in Annals of Internal Medicine, Stephanie Faubion, MD, MBA, and Regina Castaneda, MD, both of the Mayo Clinic, in Jacksonville, Florida, wrote the decline in menopause hormone therapy use “reflects patient and clinician concerns and misconceptions about the risks” as well as barriers to accessing care and undertreatment of vasomotor symptoms.

“It is therefore noteworthy that the guideline encourages clinicians to proactively initiate conversations about menopause and provide education,” they wrote. “Explicitly incorporating these actions into the guideline reinforces their importance as part of comprehensive menopause care.”

To evaluate the overall benefits and harms of treatments, as well as the role of economics and patients’ values and preferences, Diem and colleagues searched Embase, Cochrane, and Medline from inception to March 3, 2026, ultimately including 90 trials in 102 publications. These randomized controlled trials had a treatment duration of at least 8 weeks (median of 12 weeks), and enrolled peri- or postmenopausal women 18 and older.

Patients in these trials tended to be healthy, postmenopausal white women ages 49 to 57 who experienced several episodes of vasomotor symptoms a day. Trials took place from 1980 to 2024, mostly in North America and Europe. Older trials were more likely to evaluate high-dose estrogen and newer ones were more likely to evaluate nonhormonal treatments. There were only 8 studies on perimenopausal women. Compounded estrogens were not evaluated.

Common exclusion criteria included history of breast cancer, endometrial hyperplasia or cancer, cardiovascular disease, stroke, or venous thromboembolism. Editorialists said future research should assess “populations excluded from the current evidence base who require evidence specific to their clinical circumstances rather than extrapolation from healthier populations.”

The review showed that the efficacy of menopausal hormone therapy didn’t vary by route of administration. However, the effects of estrogens alone or with progestogens was more pronounced with higher doses.

Reduction in the frequency of vasomotor symptoms was greatest with estrogens with or without progestogens, oxybutynin, and NK-receptor antagonists. Menopause-related quality of life, measured by the Hot Flash Related Daily Interference Scale, was modestly improved by estrogens with or without progestogen, NK-receptor antagonists, SNRIs, and SSRIs.

“Our results are consistent with previous systematic reviews reporting that estrogens, with and without progestogens, are highly effective for VMS [vasomotor symptoms],” Diem and colleagues wrote.

While oxybutynin reduced the frequency and severity of vasomotor symptoms and improved sleep quality, the evidence was low- to moderate-certainty from a small trial. ACP noted that more research is needed on this topic to ascertain benefits and harms. There was also insufficient evidence to determine how results vary by age, race, ethnicity, and menopausal status, which authors suggest as another avenue for future research.

They also noted some limitations, including that most of the studies were short-term and not designed to evaluate severe adverse events. Observational studies that could have provided insight on long-term harms were not included, they noted.

Menopausal vasomotor symptoms last a median of 7 years, meaning that “patients seeking treatment are likely to continue using these agents longer than the brief duration of existing trials.” There also was a “paucity of head-to-head comparisons of drug classes” and eligibility criteria varied between trials, the researchers wrote.

Editorialists noted that the pooling of fezolinetant and elinzanetant may obscure differences between the two NK-receptor agonists, and that the review identified several gaps in the evidence that still require robust trials.

They also commended ACP for considering patient-centered outcomes like “menopause-related quality of life, adverse events, endometrial safety, patients’ values and preferences, and cost-effectiveness” in addition to reductions in frequency and severity of vasomotor symptoms.