Perimenopause Treatment Algorithm by Line of Therapy

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Step 1: Confirm the stage before picking a treatment

A woman has reached menopause after 12 months in a row with no period, including no spotting. The time leading up to it is the menopausal transition, or perimenopause, which usually begins in the 40s, lasts about 4 years on average and can run up to 10 years [9][4]. Pregnancy is still possible during perimenopause [4].

STRAW+10 is the standard staging system, and it applies regardless of age, ethnicity or body size [10][3]. Stage -2, the early transition, is a difference of 7 days or more between consecutive cycle lengths, recurring within 10 cycles. Stage -1, the late transition, is 60 days or more without a period, and the final menstrual period is confirmed only after 12 further months without bleeding [3]. Perimenopause in these terms runs from stage -2 through the first year after the final period [3].

Of the hormone markers, only FSH has a quantitative criterion, and only for stage -1, where a random FSH above 25 IU/L suggests late transition. AMH, antral follicle count and inhibin B are supportive only because the assays are not standardized [3]. Women without a uterus, or after endometrial ablation, cannot be staged by bleeding, and FSH should be tested no sooner than 3 months after surgery [3].

Vasomotor symptoms are likely in stage -1 and most likely in the first two years after the final period, while vaginal dryness becomes more common later [3]. They also last: in SWAN, a study of 3,302 women at 7 US sites, the median total duration of frequent hot flashes or night sweats was 7.4 years, with a median 4.5 years of persistence after the final period [11]. The FDA cites a prevalence of moderate to severe vasomotor symptoms of about 34% among women aged 45 to 65 [12].

Step 2: Hormone therapy is the most effective treatment

Estrogen products replace the estrogen the ovaries stop making. When a woman has a uterus, a progestogen is added to reduce the risk of endometrial hyperplasia and cancer; a woman without a uterus does not need one, although some hysterectomized women with a history of endometriosis may [13].

Approved choices include oral conjugated estrogens, oral estradiol, and estradiol patches, gels and sprays; estrogen plus progestogen combinations such as Prempro, Activella, Angeliq, Climara Pro and Combipatch; progesterone capsules (Prometrium) for endometrial protection in women with a uterus taking conjugated estrogens; conjugated estrogens with bazedoxifene (Duavee) for women with a uterus; and low-dose vaginal estrogen creams, tablets and rings [13][14][15][16]. Duavee pairs estrogen with an estrogen agonist/antagonist instead of a progestin and is approved for moderate to severe vasomotor symptoms and prevention of postmenopausal osteoporosis [14].

For vasomotor symptoms the Premarin label starts at 0.3 mg daily and calls for the lowest effective dose with periodic reassessment [13]. The Divigel label, effective February 27, 2026, adds that initiation may be considered in women younger than 60 or less than 10 years since menopause onset [17].

The Menopause Society 2022 position statement says hormone therapy remains the most effective treatment for vasomotor symptoms and genitourinary syndrome of menopause and has been shown to prevent bone loss and fracture [1]. For women younger than 60 or within 10 years of menopause onset without contraindications, the benefit-risk ratio is favorable for bothersome symptoms and for prevention of bone loss; starting more than 10 years from onset or after age 60 appears less favorable because of greater absolute risks of coronary heart disease, stroke, venous thromboembolism and dementia [1]. Risks differ by type, dose, duration, route, timing of initiation and whether a progestogen is used, and longer durations should be for documented indications such as persistent symptoms, with shared decision-making and periodic reevaluation [1].

Route matters for clot risk. In a UK nested case-control study (observational) of 80,396 women with venous thromboembolism and 391,494 controls, oral hormone therapy was associated with increased risk (adjusted odds ratio 1.58, 95% CI 1.52 to 1.64), while transdermal preparations were not associated with venous thromboembolism risk [18].

Premarin's label lists these contraindications: undiagnosed abnormal genital bleeding; breast cancer or a history of it, except selected palliative use; estrogen-dependent neoplasia; active or past DVT or PE; active or past arterial thromboembolic disease such as stroke or MI; hepatic impairment or disease; protein C, protein S or antithrombin deficiency or another thrombophilia; and known anaphylaxis or angioedema with the product [13]. The label also advises monitoring thyroid function in women on thyroid replacement therapy [13].

Step 3: Non-hormonal options, ranked by evidence

The 2023 nonhormone position statement, written before elinzanetant was approved, recommends cognitive-behavioral therapy, clinical hypnosis, SSRIs/SNRIs, gabapentin and fezolinetant at Level I, oxybutynin at Levels I-II, and weight loss and stellate ganglion block at Levels II-III. It does not recommend paced respiration (Level I) or supplements and herbal remedies (Levels I-II) for vasomotor symptoms [2].

Paroxetine (Brisdelle). Brisdelle is paroxetine mesylate 7.5 mg once daily at bedtime, approved in 2013 for moderate to severe vasomotor symptoms. It is an SSRI at a dose lower than the doses used for depression, and it is not approved for any psychiatric condition [5]. Paroxetine is a strong CYP2D6 inhibitor and lowers plasma levels of tamoxifen's active metabolite, and the label says to consider avoiding the combination [5]. The label also carries the SSRI suicidality boxed warning, and the drug is contraindicated with MAOIs and within 14 days of stopping one, with thioridazine and pimozide, and in pregnancy [5].

Fezolinetant (Veozah). Fezolinetant is a neurokinin 3 receptor antagonist, not a hormone, taken as 45 mg once daily; it was approved in May 2023 [6]. In the two 12-week phase 3 trials, the label reports a week-12 reduction in daily moderate to severe hot flash frequency compared with placebo of 2.6 flashes (95% CI -3.4 to -1.7) in trial 1, which had 174 women on fezolinetant and 175 on placebo, and 2.5 (-3.6 to -1.5) in trial 2, with 167 in each group [6].

The liver warning matters here. Veozah carries a boxed warning for hepatotoxicity, added in December 2024 [8]. The label requires baseline liver tests, says not to start if ALT or AST is 2 times the upper limit of normal or more or total bilirubin is 2 times ULN or more, then monthly tests for the first 3 months and at 6 and 9 months, and says to stop if ALT or AST exceed 5 times ULN, or exceed 3 times ULN with bilirubin above 2 times ULN [6]. In pooled trials, transaminases above 3 times ULN occurred in 2.3% of women on fezolinetant 45 mg (25 of 1,100) versus 0.9% on placebo (8 of 952) [6]. Veozah is contraindicated in cirrhosis, severe renal impairment or end-stage renal disease, and with CYP1A2 inhibitors [6].

Elinzanetant (Lynkuet). Elinzanetant is a dual NK1 and NK3 receptor antagonist, not a hormone, taken as 120 mg (two 60 mg capsules) once daily at bedtime; it was approved in October 2025 [7]. At week 12, elinzanetant reduced moderate to severe vasomotor symptoms by 3.22 more episodes per day than placebo in OASIS 1 (199 women on drug, 197 on placebo) and 3.24 more in OASIS 2 (200 in each group) [20]. Lynkuet has no boxed warning, but the label calls for baseline liver tests and a follow-up at 3 months [7]. Nervous-system effects such as somnolence, fatigue, dizziness and presyncope occurred in 11.9% on elinzanetant versus 3.5% on placebo across the three OASIS trials [7]. It is contraindicated in pregnancy, with contraception advised during treatment and for 2 weeks after stopping, and the label says to avoid strong CYP3A4 inhibitors and grapefruit [7].

Gabapentin. Gabapentin is recommended at Level I by the 2023 statement but is not FDA-labeled for vasomotor symptoms [2]. The FDA-approved non-hormonal drugs for vasomotor symptoms are Brisdelle, Veozah and Lynkuet [5][6][7].

Step 4: Vaginal symptoms have their own line

For bothersome genitourinary syndrome of menopause that over-the-counter products do not relieve, the Menopause Society recommends low-dose vaginal estrogen, vaginal DHEA (prasterone) or oral ospemifene [1]. The Premarin label says that when a product is prescribed solely for vaginal symptoms, topical vaginal products should be considered [13]. Estring, a vaginal estradiol ring, shows no boxed warning in its current label data [16], while Osphena carries a box for endometrial cancer and cardiovascular disorders [21].

Step 5: Undiagnosed or postmenopausal bleeding

Undiagnosed abnormal genital bleeding is a contraindication to Premarin [13]. The label says adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [13]. Bleeding after menopause is not normal [4].

What the 2025-2026 boxed warning changes did and did not do

On November 10, 2025 the FDA asked manufacturers of menopausal hormone therapy to remove the cardiovascular disease, breast cancer and probable dementia statements from the boxed warning, remove the boxed recommendation to use the lowest effective dose for the shortest time, and add consideration of starting therapy for moderate to severe symptoms in women under 60 or within 10 years of menopause onset [12][22]. The endometrial cancer boxed warning was to be retained for systemic estrogen-alone products [22]. On February 12, 2026 the FDA approved labeling changes for a first batch of six products, spanning topical vaginal estrogen, systemic estrogen-alone, systemic estrogen plus progestogen and systemic progestogen-alone [23].

This is not a warning-free class. Systemic products keep the cardiovascular disease and breast cancer warnings in Warnings and Precautions [12], and the Premarin label effective June 4, 2026 and the Prempro label effective April 28, 2026 both still carry the older box [13][24]. Product labels continue to change, so the specific label is the reference point, not a general statement about hormone therapy.

Compounded bioidentical hormones

Compounded bioidentical hormones are not FDA-approved; the FDA says it has no evidence that they are safe and effective and recommends FDA-approved hormone therapy, and ACOG's 2023 clinical consensus says they should not be prescribed routinely when FDA-approved formulations exist [25][26]. No estriol drug is FDA-approved [25]. Weight loss is not a labeled use for Premarin [13].