The American College of Physicians is recommending hormone therapy as first-line pharmacologic treatment for menopausal vasomotor symptoms in perimenopausal and postmenopausal patients, placing estrogen ahead of antidepressants, gabapentin, and newer neurokinin receptor antagonists.
In a clinical guideline published in Annals of Internal Medicine, the American College of Physicians (ACP) issued a strong recommendation for estrogen combined with a progestogen in patients with a uterus and estrogen monotherapy in those without a uterus, both supported by high-certainty evidence. For patients with contraindications to or intolerance of first-line therapy, the ACP conditionally recommends the serotonin-norepinephrine reuptake inhibitors desvenlafaxine or venlafaxine as second-line treatment.
Third-line options include the selective serotonin reuptake inhibitors escitalopram or paroxetine, gabapentin, and the neurokinin receptor antagonists elinzanetant or fezolinetant. ACP placed the neurokinin receptor antagonists third despite moderate-certainty evidence that their benefits exceeded harms compared with placebo. Economic evidence classified fezolinetant as a low-value treatment, and elinzanetant had a higher wholesale acquisition cost than fezolinetant.
The guideline was informed by systematic reviews evaluating effectiveness, comparative effectiveness, harms, patient values and preferences, and economic evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. Estrogen alone and estrogen combined with a progestogen reduced vasomotor symptom severity and frequency compared with placebo and improved menopause-related quality of life. The ACP concluded that the benefits of both approaches exceeded the harms and that both represented high-value treatments.
Route of estrogen administration did not appear to alter efficacy. However, the ACP cautioned that available evidence could not establish whether transdermal preparations carry different risks of breast cancer, cardiovascular disease, stroke, or venous thromboembolism compared with other routes because few harms were reported in eligible trials. Network meta-analysis data also showed that high-dose estrogen was more effective than low-dose estrogen for reducing vasomotor symptom severity and frequency. Still, evidence was insufficient to determine the overall balance of benefits and harms across estrogen doses. The ACP advises clinicians to use the lowest effective dose.
The evidence base also limits how broadly the recommendations can be applied. Most participants were generally healthy postmenopausal patients with an average age of 49 to 57 years who experienced 3.8 to 15.1 vasomotor episodes daily on average. Evidence in perimenopausal patients was limited, and studies commonly excluded patients with a history of breast or endometrial cancer, cardiovascular disease, stroke, or venous thromboembolism.
The ACP also noted that most eligible trials were relatively small and short, with a median duration of 12 weeks, limiting assessment of uncommon or longer-term harms. Longer-term nonrandomized studies have associated estrogen-containing treatment with increased risks of stroke and venous thromboembolism and combined estrogen-progestogen therapy with an increased risk of breast cancer.
For clinical practice, the ACP advises physicians to ask patients directly about vasomotor symptoms because patients may not initiate the discussion. Treatment efficacy should generally be assessed after 8 to 12 weeks, with clinicians using the lowest effective dose and considering contraindications, comorbidities, patient preferences, cost, and access. A common clinical approach is to avoid initiating hormone therapy after age 60 years or more than 10 years after the final menstrual period and to limit treatment to 3 to 5 years, although the ACP noted that the optimal duration remains unknown.
All financial and intellectual interests were declared, with potential conflicts reviewed and managed under American College of Physicians policy. The supporting systematic review and network meta-analysis were conducted by the ACP Center for Evidence Reviews at Minnesota and funded by the ACP.
Source: Annals of Internal Medicine
