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Hormone Replacement Therapy

Is hormone therapy for menopause safe, and what can you try first?

Hormone therapy is the most effective treatment for hot flashes and probably suits healthy women under 60; risks depend on the type, dose and timing.

Hormone therapy is the most effective treatment for hot flashes, and for healthy women under 60 or within 10 years of menopause the benefit-risk balance is favorable1. The risks are real and depend on the regimen: estrogen plus progestin raised breast cancer, stroke and clot risk in the Women's Health Initiative2, and pills carry more clot risk than patches3. Non-hormonal options exist4, and hormone therapy should not be used to prevent chronic disease5.

What you can do

  • For mild symptoms or to avoid hormones, try cognitive behavioral therapy (group or guided self-help), which reduced the bother of hot flashes and night sweats in a randomized trial8.
  • If you are overweight and flushes bother you, a behavioral weight-loss program improved them in a 6-month trial11.
  • If hot flashes disrupt sleep or work, ask about hormone therapy: for women under 60 or within 10 years of menopause without contraindications, benefits outweigh risks1.

Be careful if

  • Hormone therapy is not for preventing heart disease, dementia or other chronic conditions: the US Preventive Services Task Force recommends against it for that purpose5.
  • Women with estrogen-dependent cancers or cardiovascular disease are usually not candidates, so tell your clinician your full history, including any breast cancer, blood clots or stroke4.
  • Oral hormone therapy was linked to about 58 percent higher odds of a blood clot in legs or lungs, but skin forms were not; ask which route suits you3.

Go deeper

How it works What it does in your body, in plain words 3 min

What it does best

The Menopause Society (formerly NAMS) calls hormone therapy the most effective treatment for hot flashes and night sweats (vasomotor symptoms) and for the genitourinary syndrome of menopause (dryness, discomfort and urinary symptoms), and says it prevents bone loss and fracture. Its risks differ by type, dose, duration, route, timing and whether a progestogen is used1.

Who it suits

For women under 60, or within 10 years of menopause, with no contraindications, the benefit-risk balance is favorable for bothersome hot flashes and for preventing bone loss. Starting more than 10 years after menopause, or after 60, looks less favorable because absolute risks of coronary disease, stroke, clots and dementia are higher1. In ELITE, estradiol slowed thickening of the carotid artery wall in women under 6 years past menopause but not in those 10 or more years past it6.

What the large studies show

In the Women's Health Initiative (WHI), women with a uterus took estrogen plus progestin and women without one took estrogen alone. Estrogen plus progestin raised breast cancer (hazard ratio 1.28 over 13 years), stroke, clots and, from age 65, dementia, while lowering hip fractures and diabetes. Estrogen alone did not raise breast cancer (0.79). Neither changed all-cause mortality2. Pooled worldwide data show every type except vaginal estrogen raised breast cancer risk, more with estrogen plus progestagen than estrogen alone and rising with years of use. Five years of use from age 50 would add about 1 breast cancer per 50 users by age 69 with estrogen plus daily progestagen, 1 per 70 with intermittent progestagen and 1 per 200 with estrogen alone, if the link is causal7. In a UK study, oral therapy raised clot odds 1.58-fold; skin (transdermal) forms did not3.

Non-hormonal options

The Menopause Society recommends cognitive-behavioral therapy, clinical hypnosis, SSRI or SNRI antidepressants, gabapentin and fezolinetant, and also oxybutynin and weight loss with weaker evidence; it does not recommend supplements or herbal remedies, soy, exercise or yoga for hot flashes4. Group or self-help CBT eased the problem rating of hot flashes and night sweats at 6 and 26 weeks8. Plant-based phytoestrogens trimmed daily hot flashes by about 1.3, but most trials were at high risk of bias9. In pooled MsFLASH trials, low-dose estradiol, venlafaxine and escitalopram beat placebo, while aerobic exercise, yoga and omega-3 did not10. An intensive weight-loss program helped flushing in women with overweight11.

Vaginal dryness alone

When systemic therapy is not needed, low-dose vaginal estrogen is recommended for bothersome symptoms not relieved by over-the-counter products1. In a large observational study, users had no higher risk of breast cancer, endometrial cancer, stroke, clots or cardiovascular disease12. See menopause natural support and perimenopause.

The evidence The studies, what they found, and how much to trust them 4 min · 12 sources

The Women's Health Initiative

The WHI randomized 27,347 women aged 50 to 79 at 40 US centers. Women with a uterus took conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg (n=8,506) or placebo (n=8,102) for a median 5.6 years; women without a uterus took estrogen alone (n=5,310) or placebo (n=5,429) for 7.2 years, with 13 years of cumulative follow-up. During the estrogen-plus-progestin phase, invasive breast cancer occurred in 206 versus 155 women (hazard ratio 1.24, 95% CI 1.01 to 1.53) and coronary heart disease in 196 versus 159 (1.18, 0.95 to 1.45); stroke, pulmonary embolism, dementia from age 65, gallbladder disease and incontinence rose, while hip fractures, diabetes and hot flashes fell. Breast cancer risk stayed elevated over cumulative follow-up (434 versus 323 cases; 1.28, 1.11 to 1.48). With estrogen alone, cumulative breast cancer was lower (168 versus 216 cases; 0.79, 0.65 to 0.97) and coronary disease unchanged (0.94, 0.78 to 1.14). Neither regimen affected all-cause mortality. The global index of adverse events ranged from 12 excess cases per 10,000 women a year at ages 50 to 59 to 38 at 70 to 79 for estrogen plus progestin, and from 19 fewer to 51 excess for estrogen alone. The authors concluded the findings do not support use for chronic disease prevention, though it is appropriate for symptom management in some women2.

Timing, type and route

ELITE randomized 643 healthy postmenopausal women to oral estradiol 1 mg daily (with sequential vaginal progesterone gel if they had a uterus) or placebo. Among women under 6 years past menopause, carotid wall thickness rose 0.0044 mm a year on estradiol versus 0.0078 on placebo (P=0.008); among women 10 or more years past menopause it was 0.0100 versus 0.0088 (P=0.29). Coronary calcium and plaque on CT did not differ, so the "timing hypothesis" rests on an imaging surrogate6. The Collaborative Group pooled prospective studies with 108,647 breast cancers. Compared with never-users, current users of estrogen plus progestagen had a relative risk of 1.60 (1.52 to 1.69) in years 1 to 4 and 2.08 (2.02 to 2.15) in years 5 to 14; for estrogen alone it was 1.17 (1.10 to 1.26) and 1.33 (1.28 to 1.37). Some excess risk persisted for more than 10 years after stopping long-term use. These are observational associations7. In nested case-control studies of 80,396 women with a clot and 391,494 controls, oral therapy raised odds 1.58 (1.52 to 1.64); conjugated equine estrogen with medroxyprogesterone acetate was highest (2.10), estradiol with dydrogesterone lowest (1.18), and transdermal therapy showed no association (0.93, 0.87 to 1.01)3.

Non-hormonal options

In MENOS 2, 140 women with at least 10 problematic hot flushes or night sweats a week were randomized to group CBT, guided self-help CBT or no treatment. At 6 weeks the problem rating (scale 1 to 10) fell 2.12 points more with group CBT and 2.08 more with self-help, and 1.33 and 1.19 more at 26 weeks8. Franco's meta-analysis of 62 trials (6,653 women) found phytoestrogens cut daily hot flashes by 1.31 (0.61 to 2.02) but not night sweats, and 74 percent of the trials had high risk of bias9. The pooled MsFLASH analysis of 899 women with at least 14 bothersome symptoms a week found 8-week reductions relative to placebo of 2.4 flashes a day for low-dose estradiol, 1.8 for venlafaxine and 1.4 for escitalopram, with no effect of aerobic exercise, yoga or omega-310. In a 6-month trial of 338 women with overweight and urinary incontinence, an intensive weight-loss program improved bothersome flushes among the 154 who had them (odds ratio 2.25, 1.20 to 4.21)11. In the WHI Observational Study (45,663 women not using systemic estrogen), vaginal estrogen users had no higher risk of invasive breast cancer, endometrial cancer, stroke or clots12.

Where the evidence conflicts

WHI enrolled women up to age 79 and its two trials pointed in different directions on breast cancer2. The Menopause Society does not recommend supplements, although a pooled analysis shows small effects from phytoestrogens4,9, and exercise and yoga did not reduce hot flashes in MsFLASH, though they have other benefits10. Risk by route and regimen comes from observational studies, which cannot rule out differences between women who choose each option3,7,12.

Bottom line

Confidence is fairly high (4 of 5). Hormone therapy is the most effective treatment for vasomotor symptoms1,4, with a favorable balance for healthy women under 60 or within 10 years of menopause1. Breast cancer (regimen- and duration-dependent), clots (route-dependent) and, later in life, stroke and dementia are real risks2,3,7. CBT and some non-hormonal medicines help, while most herbal options show little4,8,9,10.

Sources

  1. The 2022 hormone therapy position statement of The North American Menopause Society. The 2022 Hormone Therapy Position Statement of The North American Menopause Society Advisory Panel. Menopause, 2022. PubMed 35797481
  2. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. Manson JE, Chlebowski RT, Stefanick ML, et al.. JAMA, 2013. PubMed 24084921
  3. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. Vinogradova Y, Coupland C, Hippisley-Cox J. BMJ, 2019. PubMed 30626577
  4. The 2023 nonhormone therapy position statement of The North American Menopause Society. The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society Advisory Panel. Menopause, 2023. PubMed 37252752
  5. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: US Preventive Services Task Force Recommendation Statement. Mangione CM, Barry MJ, Nicholson WK, et al. (US Preventive Services Task Force). JAMA, 2022. PubMed 36318127
  6. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. Hodis HN, Mack WJ, Henderson VW, et al.. N Engl J Med, 2016. PubMed 27028912
  7. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet, 2019. PubMed 31474332
  8. Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial. Ayers B, Smith M, Hellier J, et al.. Menopause, 2012. PubMed 22336748
  9. Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis. Franco OH, Chowdhury R, Troup J, et al.. JAMA, 2016. PubMed 27327802
  10. Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms. Guthrie KA, LaCroix AZ, Ensrud KE, et al.. Obstet Gynecol, 2015. PubMed 26241433
  11. An intensive behavioral weight loss intervention and hot flushes in women. Huang AJ, Subak LL, Wing R, et al.. Arch Intern Med, 2010. PubMed 20625026
  12. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study. Crandall CJ, Hovey KM, Andrews CA, et al.. Menopause, 2018. PubMed 28816933

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