The Women's Health Initiative tested one hormone combination, in one population — and the backlash treated every form of hormone therapy as if it were that one pill. It isn't. Modern options differ enormously in how they're delivered and how they behave in the body, and the evidence now lets us be specific about what helps, how much, and for whom.
This page describes categories of treatment, not products, and points to the clinical evidence behind each. Effect sizes and evidence quality are stated honestly, including their limits. None of this is a substitute for an individualized conversation with a qualified clinician.
Systemic estrogen
Best for: moderate-to-severe hot flashes and night sweats, several symptom domains at once, and bone protection — especially when started under 60 or within 10 years of menopause.
Evidence: well-establishedSystemic estrogen is the single most effective treatment for vasomotor symptoms, and it also prevents the bone loss of early menopause.1 The modern questions are not whether it works but which form and when.
The molecule
Estradiol (17β-estradiol) is identical to the body's own estrogen; conjugated equine estrogens — the form used in the WHI — are not. Either can relieve symptoms, but most menopause specialists now favor bioidentical estradiol when starting therapy.
The route matters
How estrogen is delivered changes its risk profile. Oral estrogen passes through the liver first and activates clotting factors; transdermal estrogen (patch, gel, spray) largely bypasses this.
In the ESTHER study, oral estrogen was associated with an increased risk of venous blood clots, while transdermal estrogen had little effect on clotting — a key reason transdermal is often preferred, particularly for women with clot risk factors.2
Longer-acting "depot" options place estradiol under the skin so levels last weeks to months. Two forms exist: a subcutaneous injection of an estradiol ester (estradiol valerate or cypionate in oil), and a subcutaneous pellet — a tiny crystalline implant inserted under the skin that releases estradiol over roughly three to six months. Both bypass the liver's first pass and can hold steady levels, which appeals to women who absorb transdermal estrogen poorly or struggle with a daily routine.14
In the United States there is no FDA-approved estradiol pellet — pellets are compounded, and both the Menopause Society and ACOG specifically advise against routine use of compounded pellets: they can produce supraphysiologic or fluctuating hormone levels, can't be removed once placed, and may need ever-earlier reinsertion as the body adjusts.1,15 Injectable estradiol for menopause is likewise mostly compounded and given off-label by the subcutaneous route. These can be reasonable choices in experienced hands, but they are a shared-decision option rather than a first-line one — and, like any systemic estrogen, they still require a progestogen if you have a uterus.
The timing matters
Benefit and safety depend heavily on age at initiation. Major guidance now holds that for women under 60 or within 10 years of menopause without contraindications, the benefit–risk balance is favorable; starting much later shifts it unfavorably.1 In a randomized trial, estradiol slowed early arterial changes when started within six years of menopause but not a decade out3 — the "timing hypothesis" detailed in The HRT Story.4
Progesterone & progestogens
Best for: protecting the uterine lining in anyone with a uterus who takes systemic estrogen. Not needed after hysterectomy, or for low-dose local vaginal estrogen.
Evidence: well-established (protection); observational (breast safety)Unopposed estrogen thickens the endometrium and raises uterine-cancer risk, so a progestogen is added to protect it. But the type of progestogen appears to matter for the breast.
In the large French E3N cohort, estrogen combined with a synthetic progestin carried a higher breast-cancer risk (relative risk ~1.4) than estrogen combined with micronized (bioidentical) progesterone, whose risk was not significantly raised (~0.9).5 This is observational evidence, not a randomized trial — but it is a major reason micronized progesterone is widely preferred today.
The route matters here too
Micronized progesterone can be delivered several ways, and they are not interchangeable for the job that matters most — protecting the uterine lining.
Oral (capsule). The best-studied route and the standard for endometrial protection. A systematic review by an international expert panel concluded that oral micronized progesterone protects the lining when taken sequentially at 200 mg/day for 12–14 days each month; a lower continuous daily dose is also widely used.16 Because it passes through the liver it produces calming metabolites — many women take it at bedtime and find it aids sleep, though some feel groggy. (It is usually suspended in peanut oil, which matters for those with a peanut allergy.)
Vaginal. The same review found vaginal micronized progesterone may protect the lining when used sequentially (for example, 100 mg every other day), and it delivers progesterone closer to the uterus with less daytime drowsiness — helpful for women who can't tolerate the oral route.16 The trade-offs: it is off-label for this purpose, its long-term endometrial evidence is thinner than oral's, and some find discharge or messiness bothersome.
Transdermal (cream). This is the one to get right. The same review found that transdermal progesterone cream does not provide endometrial protection — absorption into the bloodstream is too low and inconsistent, and blood or saliva levels don't reliably reflect what reaches the uterus.16
If you have a uterus and take systemic estrogen, do not rely on a progesterone cream to protect your lining. It is not a substitute for oral (or appropriately dosed vaginal) progesterone, and using it that way can leave the endometrium unprotected.16
Injectable and suppositories. Progesterone in oil by injection, and vaginal suppositories, are used mainly in fertility treatment rather than menopause: daily injections are impractical and uncomfortable long-term, and suppositories sit in the same off-label, less-validated category as other vaginal forms. Neither is a standard choice for menopausal endometrial protection.
One other delivery route is worth knowing: the levonorgestrel intrauterine device (IUD). It releases a synthetic progestin — not bioidentical progesterone — directly into the uterus, giving strong local protection. It's a recognized way to supply the progestogen part of therapy (approved for that use in some countries, used off-label for it in the U.S.) and can suit women who also want contraception during perimenopause.
Testosterone for women
Best for: hypoactive sexual desire disorder — low sexual desire that causes distress — in postmenopausal women.
Evidence: moderate (for desire); no FDA-approved product for women in the U.S.Women produce testosterone, and it contributes to sexual desire. A 52-week randomized trial found a testosterone patch produced a modest but clinically meaningful improvement in desire and satisfying sexual activity,6 and a systematic review and meta-analysis of randomized data confirmed a benefit for sexual function.7
A 2019 global consensus statement — endorsed by more than a dozen international societies — concluded that testosterone is effective for this specific indication when blood levels are kept within the normal premenopausal range, that desire-related distress is its only evidence-based use, and that there is no evidence to support it for other purposes such as energy or mood.8
Despite this evidence, no testosterone product is approved for women in the United States. In practice it is prescribed off-label using male formulations at much-reduced doses, or as compounded preparations — which are not FDA-approved and can vary in potency. Either way, the consensus is clear that levels should be monitored and kept in the female physiologic range, since excess testosterone can cause acne, unwanted hair growth, and, rarely, irreversible voice changes.8
Local / vaginal therapy
Best for: the genitourinary syndrome of menopause — vaginal dryness, painful sex, urinary symptoms. Can be used on its own or alongside systemic therapy.
Evidence: well-establishedLocal therapy treats the genital and urinary tissues directly, with minimal absorption into the bloodstream. Because absorption is low, it does not require an added progestogen even in women with a uterus, and it is often suitable for women who cannot use systemic hormones.1 The main options:
Low-dose vaginal estrogen (cream, tablet, or ring) restores the vaginal tissue and is highly effective for these symptoms.1 Notably, in November 2025 the FDA removed the boxed warning from low-dose vaginal estrogen, recognizing that its systemic absorption — and therefore its risk — is minimal.11
Vaginal DHEA (prasterone) is an FDA-approved insert for moderate-to-severe painful sex; it is converted locally to estrogen and androgen within the tissue while keeping blood hormone levels within the normal postmenopausal range.9
Ospemifene is an FDA-approved oral medication (a selective estrogen-receptor modulator) for painful sex due to vaginal atrophy — an option for women who prefer a pill to a vaginal product.1 Non-hormonal moisturizers and lubricants also help milder symptoms.
Non-hormonal medicines
Best for: women who can't use hormones — for example after a hormone-sensitive cancer — or who prefer not to.
Evidence: moderate; rapidly evolvingA new class of drugs targets the brain pathway that triggers hot flashes directly. Fezolinetant (a neurokinin-3 receptor antagonist) was FDA-approved in 2023 as the first such option and reduces the frequency and severity of hot flashes in placebo-controlled trials.10
In December 2024, after post-marketing reports of serious liver injury, the FDA added a boxed warning for rare but serious liver injury to fezolinetant, with a recommendation for liver-function monitoring. Anyone taking it should know the warning signs (jaundice, dark urine, persistent nausea, unusual fatigue) and seek care promptly.12
In 2025 a second drug in this family, elinzanetant (the first dual NK1/NK3 receptor antagonist), received FDA approval for moderate-to-severe vasomotor symptoms, supported by the OASIS trials — expanding the non-hormonal choices.13
Older non-hormonal options remain useful too: a low-dose form of the antidepressant paroxetine is FDA-approved for hot flashes, and several other SSRIs and SNRIs are used off-label with modest benefit.1
Lifestyle & behavioral approaches
Best for: everyone, as a foundation — and as the main approach for milder symptoms or when medication isn't wanted.
Evidence: moderate, varies by approachCognitive behavioral therapy can reduce how much hot flashes bother women, even if it changes their frequency less; regular physical activity, healthy weight, good sleep habits, and not smoking all support overall menopausal health.1 It's worth being honest about what's weaker: many marketed botanical supplements (such as black cohosh) have not shown consistent benefit over placebo in trials, so money and hope are often better spent elsewhere.
Matching treatment to you — and who shouldn't use hormones
There is no single "right" regimen. The choice depends on which symptoms dominate, your age and time since menopause, your personal and family history, and your own preferences. Vaginal symptoms alone are usually best treated locally; multiple disruptive symptoms often point toward systemic therapy; low desire may add a role for testosterone.
Hormone therapy is not appropriate for everyone. A history of certain hormone-sensitive cancers, blood clots, stroke, or active liver disease, and some other conditions, can make systemic hormones unsafe — which is exactly why these decisions belong with a clinician who can weigh your individual risks and arrange appropriate monitoring.1 The encouraging reality is that even when systemic hormones are off the table, local and non-hormonal options usually remain.
The point the WHI era missed: specifics decide everything.
Molecule, route, timing, dose, and whether a progestogen is needed — these are not footnotes. They are what separate a favorable balance from an unfavorable one. Good menopause care is the patient work of matching those specifics to you.
References
Every clinical claim links to its source. These also appear in the site-wide bibliography.
- "The 2022 Hormone Therapy Position Statement of The North American Menopause Society" Advisory Panel. Menopause. 2022;29(7):767–794. doi:10.1097/GME.0000000000002028
- Scarabin PY, Oger E, Plu-Bureau G; ESTHER Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362(9382):428–432. doi:10.1016/S0140-6736(03)14066-4
- Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221–1231. doi:10.1056/NEJMoa1505241
- Manson JE, Crandall CJ, Rossouw JE, et al. The Women's Health Initiative randomized trials and clinical practice: a review. JAMA. 2024;331(20):1748–1760. doi:10.1001/jama.2024.6542
- Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448–454. PMID 15551359
- Davis SR, Moreau M, Kroll R, et al; APHRODITE Study Team. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med. 2008;359(19):2005–2017. doi:10.1056/NEJMoa0707302
- Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019;7(10):754–766. doi:10.1016/S2213-8587(19)30189-5
- Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. J Sex Med. 2019;16(9):1331–1337. doi:10.1016/j.jsxm.2019.07.012
- Labrie F, Archer DF, Koltun W, et al. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause. 2016;23(3):243–256. PMID 26731686
- Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401:1091–1102.
- U.S. Food and Drug Administration. FDA requests labeling changes related to safety information to clarify the benefit/risk considerations for menopausal hormone therapies (boxed warning removed from low-dose vaginal estrogen). November 10, 2025. fda.gov
- U.S. Food and Drug Administration. FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. Drug Safety Communication, September 12, 2024; boxed warning added December 2024. fda.gov
- U.S. Food and Drug Administration. Approval of elinzanetant (Lynkuet), a dual NK1/NK3 receptor antagonist, for moderate-to-severe vasomotor symptoms due to menopause; supported by the OASIS 1 and 2 trials. 2025. fda.gov
- Subcutaneous estradiol pellets as hormone therapy in menopause: clinical pharmacology, patient selection and safety considerations (narrative review). 2025. PMC12786477
- American College of Obstetricians and Gynecologists (ACOG). Compounded Bioidentical Menopausal Hormone Therapy. Clinical Consensus. November 2023. acog.org
- Stute P, Neulen J, Wildt L. The impact of micronized progesterone on the endometrium: a systematic review. Climacteric. 2016;19(4):316–328. doi:10.1080/13697137.2016.1187123