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Menopausal Hormone Therapy: What the Position Statements Report

Por Benn Bluestein-Veyra, M.Sc. en Química Orgánica · Actualizado el 8 de noviembre de 2026

The menopausal hormone therapy guidelines in current use agree on a central framing: the 2022 position statement of The North American Menopause Society (now The Menopause Society) states that "the risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used", and that for women "aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable" for bothersome vasomotor symptoms and prevention of bone loss.^[1] The Endocrine Society’s 2015 guideline reached the same conclusion and added that "current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia".^[2] Both rest on the two Women’s Health Initiative trials, 16,608 women with a uterus and 10,739 with prior hysterectomy, and their extended follow-up.^[3][4][5]

The federal label has moved since those statements were written. On 10 November 2025 FDA asked application holders to remove the cardiovascular disease, breast cancer and probable dementia language from the boxed warning, and on 12 February 2026 it approved the first six revised labels.^[6][7] As of 8 November 2026, FDA lists nine products with updated prescribing information, while the Premarin tablet label on DailyMed, effective 4 June 2026, still carries the full boxed warning.^[8][9]

The Menopause Society frames benefit and risk by age and years since menopause

The 2022 position statement was produced by an Advisory Panel recruited to review the 2017 statement, "evaluate new literature, assess the evidence, and reach consensus on recommendations", with the result approved by the Society’s Board of Trustees. It states that hormone therapy "remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause and has been shown to prevent bone loss and fracture".^[1]

The statement divides the population by timing. For women who "initiate hormone therapy more than 10 years from menopause onset or who are aged older than 60 years, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia". On duration, "longer durations of therapy should be for documented indications such as persistent VMS, with shared decision-making and periodic reevaluation", and treatment "should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing therapy".^[1] The body of the statement is behind the journal’s paywall, so this page attributes to it only what its indexed abstract states; its positions on routes, progestogens and compounded preparations are reported below through sources whose text was available.^[1]

The Endocrine Society guideline adds pre-treatment screening and a GRADE-rated evidence base

The Endocrine Society’s 2015 guideline was written by a task force of "six experts, a methodologist, and a medical writer" using the GRADE system, with three commissioned systematic reviews, and was co-sponsored by the Australasian, British, European and International menopause societies and the European Society of Endocrinology. Its conclusions parallel the Menopause Society’s: "benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause".^[2] The guideline adds a pre-treatment step. Health care professionals "should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations", should "individualize therapy based on clinical factors and patient preference", and should know that women with contraindications "should not use MHT".^[2]

The WHI trials reported the harms that produced the 2003 boxed warning

NHLBI describes the Women’s Health Initiative as "the largest women’s health prevention study ever conducted"; it began in 1991, original data collection ended in 2005, and its extension study runs through 2026.^[10] The hormone trials are registered as NCT00000611.^[11] The estrogen plus progestin trial enrolled 16,608 women aged 50 to 79 with an intact uterus at 40 US centers between 1993 and 1998, with coronary heart disease as the primary outcome and invasive breast cancer as "the primary adverse outcome". On 31 May 2002, after a mean of 5.2 years, the monitoring board recommended stopping it "because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits". Hazard ratios were 1.29 for coronary heart disease, 1.26 for breast cancer, 1.41 for stroke and 2.13 for pulmonary embolism, with fewer hip fractures and colorectal cancers, and "all-cause mortality was not affected during the trial".^[3] The estrogen-alone trial in 10,739 women with prior hysterectomy was stopped in February 2004 after 6.8 years with a stroke hazard ratio of 1.39, a hip fracture ratio of 0.61, no effect on coronary heart disease, and a breast cancer ratio of 0.77 that the authors said "requires further investigation".^[4]

FDA’s 2025 notice describes the consequence: "Based on the WHI findings, in 2003, FDA began approving class-wide labeling changes for estrogen plus progestogen and estrogen-alone products approved for VMS, VVA, and prevention of postmenopausal osteoporosis. These changes would eventually include a Boxed Warning for increased risk of serious adverse events, including cardiovascular disorders, invasive breast cancer, and probable dementia." The dementia item came from the WHI Memory Study trials in women aged 65 to 79.^[6]

Long-term WHI follow-up reported no mortality difference and a persistent breast cancer signal with estrogen plus progestin

The 2013 overview of both trials, at 13 years, reported that "most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up" for estrogen plus progestin, and that "neither regimen affected all-cause mortality".^[12] The 2017 mortality analysis of 27,347 women found all-cause mortality of 27.1 percent with hormone therapy and 27.6 percent with placebo (hazard ratio 0.99) and no difference in cardiovascular or cancer mortality over 18 years; the ratio of hazard ratios for women aged 50 to 59 against 70 to 79 was 0.61 during the intervention phase.^[5] The 2020 breast cancer follow-up reported lower incidence (0.78) and mortality (0.60) with estrogen alone, and higher incidence (1.28) with "no significant difference in breast cancer mortality" with estrogen plus progestin.^[13] The investigators’ 2024 review states that the trials "do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases", while it "is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy".^[14]

The timing hypothesis rests on a WHI secondary analysis and a Cochrane subgroup

The age-and-timing framing traces to a 2007 secondary analysis of the WHI trials: the coronary heart disease hazard ratio rose from 0.76 within 10 years of menopause to 1.28 at 20 or more years, but the authors reported that this "trend test did not meet our criterion for statistical significance" and that "the risk of stroke was elevated regardless of years since menopause".^[15] The 2015 Cochrane review of 19 trials and 40,410 women found "high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects" on mortality or coronary events, with increased stroke and venous thromboembolism; in the subgroup starting within 10 years of menopause, mortality (relative risk 0.70) and coronary heart disease (0.52) were lower on moderate-quality evidence while venous thromboembolism remained raised (1.74).^[16] The 2017 Cochrane review of 22 trials and 43,637 women concluded that "risk of fracture was the only outcome for which strong evidence showed clinical benefit" and noted that "only about 30% of women were 50 to 59 years old at baseline".^[17]

FDA revised the boxed warning in 2025 and 2026, and the change is product by product

On 10 November 2025 FDA "informed application holders of menopausal hormone therapies (MHT), also commonly referred to as Hormone Replacement Therapy (HRT), about requested labeling changes aimed to better clarify the benefit/risk considerations for these medications", following a literature assessment, a drug utilization review, an Expert Panel held on 17 July 2025 and a public comment period. The requested changes, quoted from the notice, are to "Remove the language related to cardiovascular diseases, breast cancer, and probable dementia" from the boxed warning on all products, "Remove language related to endometrial cancer except in the systemic estrogen-alone drugs", "Remove the recommendation to use the lowest effective dose for the shortest amount of time", and, for systemic products, "Add consideration of starting hormone therapy for moderate to severe VMS in women < 60 years old or < 10 years since menopause" and "Retain information about cardiovascular diseases and breast cancer warnings" in the body of the label.^[6] The press announcement issued that day confirmed that "the FDA is not seeking to remove the boxed warning for endometrial cancer for systemic estrogen-alone products".^[18]

On 12 February 2026 FDA approved labeling changes for six products, "the first batch", covering each of the four categories of therapy, and stated that "at the FDA’s request, 29 drug companies have submitted proposed labeling changes".^[7] As of 8 November 2026, FDA’s page of products with updated prescribing information, current as of 30 October 2026, names nine: Prometrium; Divigel, Cenestin, Enjuvia, Minivelle, Vivelle and Vivelle-Dot; Estring; and Bijuva.^[8]

The unrevised label remains the one most products carry. The Premarin tablet label states in its box that estrogen-alone therapy "should not be used for the prevention of cardiovascular disease or dementia", that the WHI estrogen plus progestin substudy "reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI)" and "increased risks of invasive breast cancer", and that the WHI Memory Study "reported an increased risk of probable dementia in postmenopausal women 65 years of age and older".^[9] The revised Vivelle-Dot label keeps the endometrial statement and the instruction to "perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in menopausal women with abnormal genital bleeding of unknown etiology".^[19] The revised Bijuva label adds that "the timing of BIJUVA initiation can affect the overall risk-benefit profile".^[20]

Progesterone and synthetic progestins are reported separately in the observational literature

The WHI combination arm used medroxyprogesterone acetate, a synthetic progestin, and the breast cancer signal above belongs to that combination.^[3][13] Whether micronized progesterone carries the same association has been examined only observationally. A 2016 meta-analysis of two cohort studies and one case-control study in 86,881 women found a relative risk for breast cancer of 0.67 for progesterone against synthetic progestins, each combined with estrogen, no data on cardiovascular events, and a moderate risk of bias.^[21] A 2018 systematic review by an international expert panel stated that estrogens combined with oral micronized progesterone "do not increase breast cancer risk for up to 5 years of treatment duration", that there is "limited evidence" of an increase beyond five years, and that counseling "should cover breast cancer risk - regardless of the progestogen chosen".^[22] No randomized trial of the size of WHI has compared the two progestogen classes.

The societies draw a line between approved products and compounded bioidentical preparations

The Endocrine Society’s 2016 Scientific Statement concludes that "there is no rationale for routine prescribing of unregulated, untested, and potentially harmful custom compounded bioidentical hormone therapies".^[23] The Menopause Society’s 2015 survey of 3,725 women found that compounded products accounted for 35 percent of current hormone therapy use, that "nonapproved indications for using HT were selected more often by C-HT users", and that four endometrial cancers were reported among 326 compounded users against none among 738 users of approved products, with significance "not determined because of small numbers"; the authors called for "standardized data collection on the extent of use of compounded hormones and their potential risks".^[24] FDA’s Office of Women’s Health page puts the consumer-facing position in two lines: "Ask about the risks and benefits of hormones, including ‘bioidenticals.’" and "Be aware that natural doesn’t always mean safe."^[25] The 2025 and 2026 labeling actions apply to approved products; a compounded preparation carries no FDA-approved label, revised or otherwise, which the sibling page on the NASEM 2020 review takes up.^[6][7]

What the sources say a practice would document

Read together, the statements, the guideline and the current labels describe a documentation pattern. Each item is something a cited source states.^[1][2][19]

• Age and years since menopause onset at initiation, the two variables both societies and the revised FDA labels frame benefit and risk on.
• Pre-treatment screening for cardiovascular and breast cancer risk, which the Endocrine Society guideline states should precede initiation.
• The indication, since the Menopause Society ties longer durations to "documented indications such as persistent VMS", and the periodic reevaluation its statement names twice.
• Evaluation of abnormal genital bleeding of unknown etiology, which revised and unrevised labels alike direct toward endometrial sampling when indicated.
• Which product and label the patient received, because as of 8 November 2026 the boxed warning differs between the nine revised products and the rest.

Compounded hormone preparations reach a practice through ExaVeyra’s licensed 503A pharmacy partner on a patient-specific prescription, and the partner dispenses testosterone and any other controlled substance under its own DEA registration. The diagnosis, the choice between an approved product and a compounded preparation, and the monitoring plan are decisions for the prescribing practitioner.^[6][23]

This article summarizes publicly available federal regulation and peer-reviewed literature for licensed practitioner education. It is not legal advice, medical advice, or regulatory guidance, and it does not establish that any particular product or practice is compliant. Confirm current federal and state obligations with qualified counsel.