Condition: Perimenopause

The 2022 Hormone Therapy Position Statement of The North American Menopause Society, an evidence review by an expert panel, states that hormone therapy remains the most effective treatment for vasomotor symptoms and the genitourinary syndrome of menopause. It frames the decision around timing: for women who begin therapy before age 60 or within 10 years of menopause onset and have no contraindications, the favorable benefit-to-risk ratio supports treatment of bothersome symptoms and prevention of bone loss. Risks rise with older age, longer time since menopause, and the type and route of therapy.

SKYLIGHT 1 was a 12-week, phase 3, randomized, double-blind, placebo-controlled trial in 527 women aged 40 to 65 with an average of seven or more moderate-to-severe hot flushes per day, followed by a 40-week extension. Fezolinetant is a neurokinin 3 receptor antagonist that acts on the brain's temperature-control center. The 45 mg dose reduced hot-flush frequency by 2.55 more per day than placebo at week 12 (P<0.001) and severity by 0.20 (P=0.007), with benefit from week 1 and maintained to 52 weeks. Liver enzyme elevations were uncommon in the trial; liver monitoring is part of prescribing. The trial was funded by the manufacturer.

This multicenter, 8-week, double-blind trial randomized 205 healthy menopausal women (mean 9.8 hot flushes per day at baseline) to escitalopram 10 to 20 mg or placebo. Escitalopram reduced frequency by 1.41 more per day than placebo (95% CI 0.13 to 2.69, P<0.001), and 55% of women reached at least a 50% reduction against 36% on placebo (P=0.009). Bother and severity also improved. Effects were modest relative to hormone therapy but meaningful for a non-hormonal option, and symptoms returned somewhat after stopping.

This 8-week, three-arm randomized trial (MsFLASH network, 339 women) compared low-dose oral estradiol 0.5 mg, venlafaxine 75 mg, and placebo. Frequency fell to 3.9 per day on estradiol (52.9% reduction), 4.4 on venlafaxine (47.6%), and 5.5 on placebo (28.6%). Estradiol beat placebo by 2.3 per day (P<0.001) and venlafaxine by 1.8 (P=0.005); estradiol beat venlafaxine by only 0.6 per day (P=0.09), a difference the authors judged small and of uncertain clinical relevance. Both were well tolerated.

The MENOS 2 trial randomized 140 women with problematic hot flushes and night sweats to group CBT, self-help CBT, or usual care. Both CBT arms beat usual care on the problem-rating scale at 6 weeks (adjusted mean differences 2.12 and 2.08 on a 10-point scale); by 26 weeks the difference had narrowed to about 1.33 for group CBT and 1.19 for self-help, still statistically significant. What moved most was the distress and interference; hot-flush frequency changed much less, though night-sweat frequency did fall significantly. Participants could not be blinded, and the trial was run by the group that developed the intervention.

The Cochrane review Exercise for vasomotor menopausal symptoms searched for randomized trials of exercise against no active treatment, hormone therapy, or other interventions for hot flushes and night sweats. It found few eligible trials and insufficient evidence to show that exercise reduces vasomotor symptoms specifically. This sits alongside strong evidence that exercise benefits bone, cardiovascular health and mood through midlife, so the finding narrows the claim to the flushes, not dismissing exercise.

The Cochrane review Black cohosh (Cimicifuga spp.) for menopausal symptoms pooled 16 randomized trials in 2,027 perimenopausal and postmenopausal women. It found insufficient evidence to support black cohosh, with no statistically significant difference from placebo in the frequency of hot flushes or in a composite menopausal symptom score, though the authors noted trial quality and heterogeneity limited firm conclusions and called for better studies. Rare liver injury has been reported with black cohosh products, which is why regulators require a caution on the label.

The Cochrane review Phytoestrogens for menopausal vasomotor symptoms pooled numerous randomized trials of dietary soy, soy extracts, red clover and other phytoestrogens. Overall there was no conclusive evidence of a reduction in hot-flush frequency or severity, and heterogeneity was high. A subgroup signal suggested genistein-concentrated extracts might reduce flush frequency, but the reviewers cautioned that the placebo response was substantial (some placebo arms improved by up to 50%), which makes small active effects hard to read. Safety over the short term was reasonable, with long-term endometrial and breast safety of concentrated extracts not fully established.

The Stages of Reproductive Aging Workshop +10 (STRAW+10) is the international consensus staging of the menopausal transition, built by re-examining accumulated cohort data. It anchors early perimenopause (stage -2) to persistent variation of 7 days or more in consecutive cycle lengths, and late perimenopause (stage -1) to an interval of amenorrhea of 60 days or more. FSH is elevated but variable across both stages, which is why the criteria are based on the bleeding pattern, not on a hormone level. The system is descriptive: it names where a woman is, not what to do about it.

Reviews of menstruation across the transition describe a characteristic sequence: cycles typically shorten in early perimenopause as the follicular phase contracts, then become long and skipped in late perimenopause. Anovulatory cycles, in which no corpus luteum forms, leave the endometrium under unopposed estrogen, which can produce heavy or prolonged menstrual bleeding. The clinical point is that irregularity itself is expected, while flooding, clots, bleeding between periods, or bleeding after sex are not, and are the signs that need assessment.

The Penn Ovarian Aging Study followed women with no prior depression through the transition. High scores on the CES-D depression scale were 4.29 times more likely during the transition than premenopausally (95% CI 2.39 to 7.72), and a PRIME-MD diagnosis of a depressive disorder 2.50 times more likely (95% CI 1.25 to 5.02). Rising and more variable FSH, LH and estradiol around each woman's own mean were each associated with the higher scores, after adjustment for smoking, BMI, PMS, hot flushes, poor sleep, health status, employment and marital status.

The Guidelines for the Evaluation and Treatment of Perimenopausal Depression, produced jointly by the North American Menopause Society and the National Network of Depression Centers Women and Mood Disorders Task Group, reviewed the evidence and set out recommendations. Proven antidepressant therapies (SSRIs, SNRIs) and psychotherapy remain first-line. Estradiol has demonstrated antidepressant efficacy in perimenopausal women in randomized trials, an effect not shown in postmenopausal women, so the reproductive stage matters to the choice.

The Early versus Late Intervention Trial with Estradiol (ELITE) randomized 643 healthy postmenopausal women, stratified by time since menopause (under 6 years or 10 or more years), to oral 17-beta-estradiol or placebo and tracked carotid-artery intima-media thickness. Progression was slower on estradiol than placebo in the early group (0.0044 vs 0.0078 mm/year) but not the late group (0.0100 vs 0.0088 mm/year), interaction P=0.007. A CT measure of actual coronary plaque showed no significant difference in either group, so the finding is on an imaging marker of early atherosclerosis, not on heart attacks or deaths.

This MsFLASH trial randomized 106 perimenopausal and postmenopausal women (mean age 54 to 55) with insomnia and hot flushes to telephone-based CBT for insomnia or to menopause education. The Insomnia Severity Index fell 9.9 points on CBT-I against 4.7 on the control, a 5.2-point difference at 8 weeks; by 24 weeks 84% of the CBT-I group were in the no-insomnia range against 43% of controls. Hot-flush frequency itself barely changed; what improved was the sleep around the flushes.

The LIFTMOR randomized controlled trial assigned 101 postmenopausal women with low bone mass (mean age 65) to 8 months of twice-weekly, 30-minute supervised high-intensity resistance and impact training (5 sets of 5 reps above 85% of one-rep maximum, plus impact) or to a home-based low-intensity program. The training group gained 2.9% in lumbar-spine bone density against a 1.2% loss in controls (P<0.001) and gained at the femoral neck too, with improved functional performance and only one minor adverse event under supervision. The direct evidence is in older women with established low bone mass; the mechanism, that high-magnitude loading builds and preserves bone, is why it is relevant to the transition years when loss accelerates.

A consensus conference on contraception in women beyond 40 years of age reviewed the evidence and concluded that fertility is reduced but not absent and that contraception should be continued through the transition. Standard clinical guidance holds that spontaneous ovulation, and therefore pregnancy, can still occur until 12 months without a period confirm menopause, and that combined hormonal contraception in appropriately selected women (no smoking, no migraine with aura, no cardiovascular contraindication) provides effective contraception while also regulating cycle irregularity and easing vasomotor symptoms. Progestogen-only methods and the levonorgestrel intrauterine system are options where estrogen is contraindicated, and the IUS additionally treats heavy menstrual bleeding.

ECLIPSE was a pragmatic, multicenter randomized trial that assigned 571 women presenting to primary care with heavy menstrual bleeding to the levonorgestrel-releasing intrauterine system or to usual medical treatment (tranexamic acid, mefenamic acid, combined estrogen-progestogen, or progesterone alone). The primary outcome, the patient-reported Menorrhagia Multi-Attribute Scale, improved in both groups by 6 months and stayed improved over 2 years, with the levonorgestrel-IUS group gaining 13.4 points more (95% CI 9.9 to 16.9, P<0.001). Gains were larger across all MMAS domains and most quality-of-life domains. At 2 years, 64% of the IUS group were still using their assigned treatment against 38% of the usual-treatment group (P<0.001). There was no significant difference in rates of surgery or in serious adverse events. The trial was publicly funded by the UK National Institute for Health Research.