The effects of menopausal hormone therapy on cardiovascular disease,cancer,cognition and depression in younger women: A systematic review

Abstract

Objective

The Women's Health Initiative (WHI), a randomized controlled trial, found no overall health benefit of menopausal hormone therapy. Our objective was to evaluate the hypothesis that initiating hormonal therapy prior to age 60 or within a few years after the last menstrual period provides health benefits in menopausal women.

Design

A search was conducted in MEDLINE, Scopus, and ClinicalTrials.gov from inception until August 26, 2025. Randomized controlled trials in which at least one arm was a pharmaceutical oestrogen and one arm was a placebo were included. We required studies to present clinical health outcomes.

Setting

Systematic review

Participants

Menopausal women age 60 or younger or within a short time of the last menstrual period, as defined by individual study authors.

Main outcome measures

Studies were categorized based on primary endpoints, namely cardiovascular disease, cancer, depression, and cognition. Risk of bias was assessed using a standard tool. The reliability of conclusions was assessed using the core GRADE method.

Results

Thirty-one papers, reporting on seventeen randomized controlled trials, met eligibility criteria. Menopausal hormone therapy in young menopausal women was not shown to have beneficial effects on cardiovascular disease, cancer, depression, or cognition with the exception of some cardiovascular endpoints in women on oestrogen alone in the WHI, a finding not confirmed in other randomized controlled trials and not confirmed in women with vasomotor symptoms.

Conclusions

Menopausal hormone therapy in young menopausal women has not been shown in randomized controlled trials to have beneficial effects on cardiovascular disease, cancer, depression, or cognition.

Keywords

Menopause perimenopause hormone therapy timing hypothesis cardiovascular disease cognition depression cancer systematic review

Introduction

Proponents of hormone therapy argue that while the therapy may be harmful for women distant from menopause, hormones will have long-term health benefits in younger women closer to the time of menopause. This critical period or timing hypothesis^1,2 posits that beneficial health effects of menopausal hormone therapy require the initiation of therapy soon after the last menstrual period, for example, within 10 years.^3,4 Our objective was to identify published randomised controlled trials (RCTs) that evaluated disease outcomes associated with menopausal hormone therapy in younger women closer to their last menstrual period.

Methods

The search strategy is described in Supplementary Appendix S1. Study quality was evaluated using the Cochrane Collaboration Risk of Bias system,⁵ which assigns high, low or unknown risk of bias to six aspects of study design. Risk of Bias was assessed independently by two authors (PAB, ARS), and agreement was reached by consensus. No studies were excluded based on the Risk of Bias assessment, but a separate evaluation was conducted excluding papers with a high Risk of Bias. Papers were evaluated independently by two investigators.

After restricting papers to placebo-controlled RCTs on estrogen that included clinical endpoints in spontaneously menopausal women under the age of 60, we tabulated study interventions and results for four clinical endpoints: cardiovascular disease, cancer, depression and cognition. These endpoints were selected by the original study authors and were not selected by us as a basis for inclusion in the review. All studies excluded women with these disorders at baseline. Surrogate endpoints, including blood pressure and lipid concentrations, were not included. Synthesis of the results was based on consistency of findings among studies and comparisons to the Women's Health Initiative (WHI), the largest of the trials analysed. For all WHI analyses, we analysed the subgroups of women with a uterus randomised at age 50–59 and given daily conjugated equine estrogen (CEE) 0.625 + medroxyprogesterone acetate (MPA) 2.5 mg or placebo and hysterectomised women randomised at age 50–59 years to CEE only or placebo. A separate analysis included studies using 17β-estradiol. Data were presented as in the original papers without further manipulation or adjustment for missing data. The reliability of conclusions was assessed using the core GRADE method, which considers imprecision, inconsistency, risk of bias and indirectness.^6–12 Ethics review and consent were not required for this study.

Results

Article searches retrieved 5388 items. Based on titles, abstracts for 2013 citations were reviewed, which yielded 621 papers for full-text review. The article review resulted in 592 papers being excluded and 29 papers being retained. ClinicalTrials.gov yielded 241 items. After review, 11 items were retained, four of which were duplicates and seven of which were retrieved and read. Two papers were retained. The search and review process is summarised in Figure 1. Papers excluded after full-text review are listed in Table S1. Risk of Bias for included studies is shown in Figure 2.

Figure 1.

Results of the search and review of randomised controlled trials.

Figure 2.

Risk of bias evaluations.

Cardiovascular disease

Women's Health Initiative

Initiated in the early 1990s, the trial of CEE + MPA was halted in 2002 due to increased risks of breast cancer, heart disease, stroke and venous thrombosis (Table 1).^13,14 Two years later, the estrogen-alone trial was stopped early due to an unfavourable risk-benefit profile, primarily affected by stroke risk.¹⁴

Table 1.

Randomized clinical trials evaluating cardiovascular disease

Study	Age/time since menopause	Treatment (number at baseline)	Duration of treatment	Outcome measures	Result
Women’s Health Initiative (Manson et al., 2013¹⁵; Hsia et al., 2006¹⁶; Hendrix et al., 2006¹⁷; Wassertheil-Smoller et al., 2003¹⁸; Perez et al., 2012¹⁹; Liu et al., 2020²⁰; Manson et al., 2017²¹; Rossouw et al., 2025²²	50–59 years old	Oral CEE 0.625 mg/day + MPA 2.5 mg/day (2837) or placebo (2683)	Up to 5.6 years	Coronary heart disease, cardiovascular death, hospitalized angina, coronary interventions, myocardial infarction, stroke, atrial fibrillation, incident heart failure	No difference in coronary heart disease, atrial fibrillation, stroke, or incident heart failure at up to 13 years of follow-up. No difference in cardiovascular death.
	50–59 years old	Oral CEE 0.625 mg/day (1639) or placebo (1674)	Up to 7.1 years		No difference in coronary heart disease, hospitalized angina, acute coronary syndrome, or stroke. Protective effect of CEE on coronary heart disease (HR 0.65, 95% CI 0.44 to 0.96), coronary revascularization (HR 0.55, 95% CI 0.35 to 0.86), and composite of cardiovascular death + coronary revascularization (HR 0.66, 95% CI 0.45 to 0.96). The protective effect was not apparent when subjects with and without vasomotor symptoms were analyzed. No difference in atrial fibrillation or incident heart failure. No difference in the composite of MI or cardiovascular death.
	Within 10 years	Oral CEE 0.625 mg/day + MPA 2.5 mg/day (2780) or placebo (2711)	Up to 5.6 years		No difference in coronary heart disease. Increase in stroke in CEE-treated subjects within 5 but not 10 years of menopause.
Kronos Early Estrogen Prevention Study (Kantarci et al., 2024²³)	Within 3 years	Oral CEE 0.45 mg/day (230), transdermal estradiol 50 µg/day, or placebo patch and pill (275). Oral micronized progesterone 200 mg/day or placebo in subjects with a uterus.	Up to 4 years	Ten years after conclusion of treatment, 299 subjects were asked about health events.	No treatment-associated differences in heart attack, angina, heart failure, coronary artery disease, or stroke.
Estonian Postmenopausal Hormone Therapy Trial (Veerus et al., 2006²⁴)	50–59 years old; subgroup within 3 years of menopause	Oral CEE 0.625 + MPA 2.5 mg daily (284) or placebo (202)	Up to 5 years	Coronary heart disease	No association of treatment with coronary heart disease; however, results included a blinded and unblinded study and did not contribute meaningfully to this review.

CEE conjugated equine oestrogen, MPA medroxyprogesterone acetate

Reference numbers refer to the reference list in the main paper. Shading indicates high Risk of Bias

With up to 13 years of follow-up, there was no significant effect of MPA + CEE on coronary heart disease or cardiovascular death in either the general WHI study population or younger women. Coronary heart disease was diagnosed in 38 subjects who received CEE + MPA, and 27 who received placebo (hazard ratio [HR] 1.34, 95% confidence interval [CI] 0.82 to 2.19).¹⁵ In subjects randomised within 10 years of menopause, the HR was 0.90, 95% CI 0.56 to 1.45.¹⁵

CEE alone had a protective effect on some cardiovascular outcomes, but increased stroke. Among the 1639 women taking CEE alone, a diagnosis of coronary heart disease, hospitalised angina, or acute coronary syndrome occurred in similar proportions among those given hormones or a placebo.¹⁶ However, a protective effect was seen for CEE alone on coronary heart disease (HR 0.65, 95% CI 0.44 to 0.96), on coronary artery revascularisation (HR 0.55, 95% CI 0.35 to 0.86), and on the composite outcome of myocardial infarction, coronary heart disease, coronary revascularisation, and cardiovascular death (HR 0.66, 95% CI 0.45 to 0.96).

In subjects in the CEE-only arm, after an average follow-up of 7.1 years, there was no difference from placebo in stroke in women aged 50–59 at enrolment. However, stroke risk was increased in women randomised within 10 years of menopause, HR 2.62, 95% CI 1.01 to 6.81.¹⁷ With up to 13 years of follow-up, there was no significant effect of either CEE + MPA or CEE alone on stroke.¹⁵ There was no difference by hormone treatment in the occurrence of stroke among women enrolled at ages 50–59 and in women enrolled within five years of menopause.^17,18

Neither CEE + MPA nor CEE alone affected the incidence of atrial fibrillation,¹⁹ heart failure, or mortality from cardiovascular disease in women randomised at age 50–59.^20,21 An evaluation of women with or without vasomotor symptoms randomised at age 50–59 or within 10 years of menopause found no effect of CEE + MPA or CEE alone on atherosclerotic cardiovascular disease (a composite of nonfatal myocardial infarction, hospitalisation for angina, coronary revascularisation, ischaemic stroke, peripheral arterial disease, carotid artery disease, and cardiovascular death).²² There was no effect on total cardiovascular disease, all-cause death, coronary heart disease, stroke, or venous thromboembolism.

Other trials

The Kronos Early Estrogen Prevention Study (KEEPS) specifically enrolled younger women to test the effect of hormones on cardiovascular events, stroke and surrogate markers of atherosclerosis. KEEPS randomised menopausal women within three years of the last menses to oral CEE 0.45 mg/day (n = 230), transdermal estradiol 50 µg/day (n = 222), or placebo patch and pill (n = 275). Subjects with a uterus were given oral micronised progesterone 200 mg/day or placebo for 12 days/month. Treatment was continued for up to four years.

Ten years after the conclusion of the treatment period, 299 subjects, representing 41–43% of subjects assigned to each treatment arm, participated in a follow-up study in which they were asked about health events that had occurred after the original study ended.²³ This limited follow-up, representing less than half of the original cohort, identified no treatment-associated differences in heart attack or angina, congestive heart failure, coronary artery disease, or stroke. Although a sensitivity analysis of the 243 subjects who had not used menopausal hormone therapy after the end of the KEEPS study was described as showing no associations, the supplemental table showed only laboratory results and not diagnoses. At follow-up, subjects appear to have known their treatment assignment, giving rise to a high risk of bias.

The Estonian Postmenopausal Hormone Therapy trial recruited women between 50 and 64 years of age, although some results were given for women 65–70 years of age.²⁴ Among 251 subjects recruited within three years of menopause, there was no association between therapy with CEE + MPA and coronary heart disease. The analysis combined data from women recruited to a blinded and an unblinded study of these hormones. This trial had been entered in a clinical trials registry (https://www.isrctn.com/ISRCTN35338757), but raw data had not been entered by 20 February 2026. Although mentioned here for completeness, we excluded this study from our analysis because we cannot separate the data from the blinded and the unblinded portions of the trial.

In summary, the WHI findings suggest a protective effect of CEE alone, but not CEE + MPA, against coronary artery disease in young menopausal women who had undergone hysterectomy. Two smaller randomised clinical trials and an analysis of the WHI CEE arm did not confirm a protective effect of menopausal hormone therapy on cardiovascular disease outcomes.

Excluding studies with a high risk of bias left only the WHI. None of the studies used 17β-estradiol. Our GRADE conclusion is that CEE alone in young menopausal women who have had a hysterectomy may decrease heart disease and total death. Our confidence in this conclusion is low due to inconsistency in the evaluation of WHI data, lack of confirmation in other studies, and the possibility that the apparent decrease in the first WHI analysis was due to estrogen mitigation of adverse cardiovascular effects of oophorectomy.

Cancer

Women's Health Initiative

In the WHI, there was no difference in invasive breast cancer among women ages 50–59 at two years, but there was a significant increase at 20-year follow-up (Table 2). At two years, invasive breast cancer was diagnosed in 52 of 2837 women randomised to CEE + MPA and 40 of 2683 women randomised to placebo (HR 1.20, 95% CI 0.80 to 1.82). At 20 years, 203 women in the CEE + MPA group had invasive breast cancer diagnoses, significantly higher than the 143 women in the placebo group (HR 1.36, 95% CI 1.09 to 1.69).²⁵ Invasive breast cancers associated with CEE + MPA compared to placebo were more frequent, more likely to be lymph-node positive, and more likely to be advanced compared to cancers in women on placebo across all age groups. However, these results were not shown by age at randomisation.²⁶ There was no difference in breast cancer mortality by treatment group.

Table 2.

Randomized clinical trials evaluating cancer

Study	Age/time since menopause	Treatment (number at baseline)	Duration of treatment	Outcome measures	Result
Women’s Health Initiative (Chlebowski et al., 2020²⁵, 2003²⁶, 2015²⁸; Prentice et al., 2021²⁷)	50–59 years old	Oral CEE 0.625 mg/day + MPA 2.5 mg/day (2837) or placebo (2683)	Up to 5.6 years	Cancer of the breast, endometrium, colon	No difference in invasive cancer after 2 years, but invasive cancer was increased after 20 years of follow-up (HR 1.36, 95% Cl 1.09 to 1.69). No difference in endometrial or colon cancers.
	50–59 years old	Oral CEE 0.625 mg/day (1639) or placebo (1674)	Up to 7.1 years	Cancer of the breast, endometrium, colon	Decreased breast cancer after up to 18 years in unadjusted analysis, but fully adjusted analysis consistent with the null. No difference in endometrial or colon cancers.
Estonian Postmenopausal Hormone Therapy Trial (Veerus et al., 2006²⁴)	50–59 years old; subgroup within 3 years of menopause	Oral CEE 0.625 + MPA 2.5 mg daily (284) or placebo (202)	Up to 5 years	Cancer, not otherwise specified	No association of treatment with cancer; however, results included a blinded and unblinded study and did not contribute meaningfully to this review.

CEE conjugated equine estrogen, MPA medroxyprogesterone acetate

Reference numbers refer to the reference list in the main paper. Shading indicates high risk of bias.

Estrogen alone appeared to be protective against breast cancer in initial reports, but this effect disappeared in adjusted analyses. Women randomised at ages 50–59 to estrogen alone (n = 1629) had decreased invasive breast cancer diagnoses compared to placebo (n = 1674) in unadjusted analysis with up to 18 years of follow-up. However, the difference was no longer significant in the fully adjusted analysis.²⁷ The authors suggested that women with a longer time between oophorectomy and estrogen therapy had protection from invasive breast cancer.

Women with a uterus who are prescribed estrogen receive a progestogen to mitigate the risk of estrogen-induced endometrial cancer. There was no significant difference in endometrial cancer among women randomised to hormones or placebo at age 50–54 after a median cumulative follow-up of 13 years; seven women developed endometrial cancer in the CEE + MPA group compared to 11 women in the placebo group (HR 0.57, 95% CI 0.22 to 1.48).²⁸

After up to 18 years of follow-up, there was no difference in colorectal cancer risk among women taking CEE, CEE + MPA, or placebo at age 50–59 in the fully adjusted analysis.²⁷

Other trials

In the Estonian Postmenopausal Hormone Therapy Trial, risk of cancer, not otherwise specified, was similar among 251 women randomised to hormones or placebo within three years of menopause during the blinded portion of the trial (HR 3.26, 95% CI 0.35 to 9.95).²⁴ This study had a high Risk of Bias. There were no trials of 17β-estradiol.

In summary, CEE + MPA, but not CEE alone, increased breast cancer at 20-year follow-up. CEE-alone did not increase or decrease breast cancer risk. We had moderate certainty in the conclusion that CEE + MPA increases breast cancer at 20-year follow-up due to a lack of confirmation by another trial. In women under 60 years of age at randomisation, CEE with or without MPA had no effect on the risk of endometrial or colorectal cancer.

Depression and mood

The WHI RCTs on hormone therapy did not measure depression or mood (Table 3). Nine smaller RCTs with a combined total of 1280 women between the ages of 40–60 evaluated mood using oral CEE, oral 17β-estradiol, or transdermal 17β-estradiol, with different scales or inventories assessing depression and other mood states.^29–38 Some women met criteria for major depressive disorder at baseline, and some did not. Four of the nine trials had a high Risk of Bias.^31–33,35

Table 3.

Randomized clinical trials evaluating depression

Study	Age/time since menopause	Treatment (n)	Duration of treatment	Outcome measures	Result
Bech et al., 1998²⁹	6–24 months	Continuous E2 2 mg + NETA 1 mg (50) versus cyclic E2 2 mg + NETA 1 mg (50) versus placebo (51)	12 months	BDI-21 BDI-12 GHQ-10	Depression, and anxiety scores improved with either hormone regimen but not with placebo. Neurasthenia score worsened on placebo. Effects not separable from symptom improvement.
Gordon et al., 2018³¹	44–57 years old (mean ± 2 SD), early perimenopausal (menstrual cycle length ≥ 7 days longer than usual), late perimenopausal (at least 2 skipped cycles + amenorrhea ≥ 60 days but within 1 year of last menses), early postmenopausal (1–2 years of amenorrhea)	E2 0.1 mg/day patch (probably changed weekly) + oral micronized P 200 mg/day for 12 days every 2 or 3 months (86 randomized, 12 withdrawals) or placebo patch and placebo pill (86 randomized, 17 withdrawals)	12 months	CESD after 1, 2, 4, 6, 8, 10, and 12 months	Subjects were euthymic at baseline. CESD score of 16 occurred on at least one assessment more often in placebo than in hormone group, odds ratio 2.5, 95% CI 1.1 to 5.7. The number of follow-up visits with a CESD score of 16 or more was not shown. Analysis by reproductive stage showed the protective effect of hormone therapy in early perimenopausal but not late perimenopausal or early postmenopausal subjects. There was no interaction of the results with an assessment of bothersome hot flashes at baseline.
KEEPS ^aGleason et al., 2015³⁰Raz et al., 2016³⁴	47–58 years old (mean ± 2 SD), 0–2.8 months since last menses (mean ± 2 SD)	Oral CEE 0.45 mg/day + cyclic micronized P 200 mg/day (220) versus Transdermal E2 50 µg/day + cyclic micronized P 200 (211) mg/day versus placebo patch and pills (262)	48 months	POMS BDI-21	CEE vs. placebo: Depression and anxiety improved, anger, fatigue, vigor, confusion unchanged. Transdermal E2 vs. placebo: No difference in any POMS domain. No effect of hormone therapy on BDI.
Joffe et al., 2011³²	Subjects had depression, hot flashes, and sleep disturbance, 40–60 years old, some with irregular menses, some without menses	Transdermal E2 50 µg/day (27) versus zolpidem 10 mg/day (31) versus placebo patch and pill (14)	8 weeks	MADRS BDI	Similar response of depression scores in all treatment groups. In post-hoc analysis, serum estradiol concentration predicted better response to treatment in perimenopausal women. BDI scores after treatment were not given.
Morgan et al., 2005³³	41–52 (mean ± 2 SD), not menopausal but had perimenopausal symptoms.	Oral CEE 0.625 mg (11) Placebo (6)	6 weeks	HAMD	Woman with partial response of depression on one of six antidepressants were recruited for 14-week crossover trial. Trial stopped after six weeks due to disproportionate dropouts on placebo. Improvement in HAMD score greater in subjects on estrogen and more women on estrogen achieved remission.
Saletu et al., 1995³⁵	45–60 years old, 0.5–5 years after menses, diagnosed with MDD	Transdermal E2 50 µg twice/week (32) versus placebo (32)	3 months	HAMD	Depression rating improved in both groups without a difference between groups.
Schmidt et al., 2000³⁶	44–55 years old, perimenopausal, major or minor depression by structured clinical interview	Transdermal E2 50 µg/day (16) versus placebo (18)	3 weeks	CESD HAMD Self-rating	Depression scales and most items on the self-rating scale improved on estrogen and not on placebo; most depression symptoms did not show a difference according to whether hot flashes were present at baseline.
Soares et al., 2001³⁷	40–55 year old, perimenopausal, irregular menses, major or minor depression or dysthymic disorder	Transdermal E2 100 µg/day (25) versus placebo (25)	12 weeks	MADRS	Depression scores improved in both groups but to a greater extent on E2. Effect was not disentangled from improvement of hot flashes, although in a 4-week washout period, there was continued improvement of depression scores in both groups in spite of a return of hot flashes.
Thomson & Oswald, 1977³⁸	49–55 years old with insomnia, depression, anxiety, and hot flashes	Oral E2 1.5 mg twice daily (17) versus placebo (17)	8 weeks	self-rating HAMD HAMA	Improved mood in both groups, no difference between groups Hot flush counts decreased in both groups, no difference between groups

Abbreviations: BDI-21, Beck Depression Inventory (full sale); BDI-12, melancholia subscale; CESD, Center for Epidemiologic Studies Depression Scale; E1, estrone piperazine sulfate; E2, 17β-oestradiol; GHQ-10, General Health Questionnaire, neurasthenia subscale; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery-Åshberg Depression Rating Scale; MDD, major depressive disorder; NETA, norethindrone acetate; POMS, profile of mood states;

Kronos Early Estrogen Prevention Study–Cognitive and Affective Study (KEEPS-Cog)

Reference numbers refer to the reference list in the main paper.

Shading indicates high Risk of Bias.

Six RCTs showed an improvement in some aspect of mood on hormone therapy,^{29–31,33,36,37} while three studies showed no effect of hormones on any mood endpoint.^32,35,38

Among studies that specifically evaluated depression, hormone therapy improved depression scores compared to placebo in two studies,^29,30 and three studies found no difference in depression scores between hormone and placebo groups (both groups improved).^32,35,38

Mood may be affected by the presence of menopausal symptoms and by sleep, which may be disrupted by vasomotor symptoms. Some studies were able to disentangle improvements in mood from reduced hot flashes and improved sleep, while other studies were unable to do so. A study that randomised women with depression, hot flushes and sleep disturbances to estrogen therapy, zolpidem (a sedative-hypnotic), or placebo found similar responses of depression in all groups. Improvement in depressive symptoms was predicted by improved sleep quality in peri- and postmenopausal women.³² In an RCT that tested an estrogen patch against a placebo, estrogen improved sleep only in women with severe nocturnal hot flashes.³⁹

In two short-term studies (8–12 weeks) that tested transdermal hormone therapy in perimenopausal women (women who were menstruating and had blood hormone concentrations suggestive of approaching menopause), depressive symptoms improved to a greater extent on estrogen compared to placebo.^36,37 Another study of euthymic women concluded that estrogen plus progestogen prevented the onset of depression in early perimenopausal women but not in late perimenopausal women or early postmenopausal women.³¹ The depression outcome was determined by a score of 16 or more on the Center for Epidemiologic Studies Depression Scale in any of seven follow-up periods. In a six-week study in perimenopausal women, estrogen augmented the effect of antidepressant medications.³³

Transdermal estrogen had no clear advantage on mood. The KEEPS study found that depression and anxiety, in the Profile of Mood States Domain, improved among women taking oral CEE but not transdermal 17β-estradiol when compared to placebo.^30,34 Three of four studies investigating the effects of transdermal 17β-estradiol therapy found no difference between hormone and placebo groups.^30,32,35 The one study of transdermal estrogen that found an improvement in mood included data from participants on placebo who dropped out before completion of the trial.³⁶

In summary, inconsistent findings and measurements of hormone therapy effects on mood from RCTs do not support the hypothesis that hormones, independent of effects on hot flashes and sleep disturbance, are beneficial for depression. There was no clear advantage of 17β-estradiol over CEE. More detailed information on hormones used and outcome measures can be found in Table 3. Based on the GRADE evaluation, we have very low certainty that menopausal hormones decrease depression scores. Certainty was decreased by risk of bias, inconsistency and possible publication bias.

Cognition

Nine RCTs evaluated cognition in 2452 women. Two studies had a high Risk of Bias (Table 4).

Table 4.

Randomized clinical trials evaluating cognition

Study	Age/time since menopause	Treatment (number randomized)	Duration of treatment	Outcome measures	Result
Women’s Health Initiative Memory Study of Younger Women (WHIMSY) (Espeland et al., 2013⁴¹)	50–55 years old	Oral CEE 0.625 mg/day + MPA 2.5 mg/day or placebo (609 on one of the two CEE regimens, 559 on one of the two placebo regimens)	Up to 5.6 years, recontacted ∼7 years after WHI concluded	East Boston Memory Test, oral trail-making, verbal fluency–animals, digit-span subtest of the Wechsler Adult Intelligence Scale–Revised	No treatment-related differences
	50–55 years old	Oral CEE 0.625 mg/day or placebo (609 on one of the two CEE regimens, 559 on one of the two placebo regimens)	Up to 7.1 years, recontacted ∼7 years after WHI concluded		Decrease in verbal fluency with CEE, no other differences by treatment
Berent-Spillson et al., 2015⁴⁸	45–55 years old, 6–38 months from last menses	Cross-over design, daily oral E2 + cyclic P for 10 days (16)	12 weeks in each condition	Hopkins Verbal Learning Test–Revised, Brief Visuospatial Memory Test–revised	No difference in scores by treatment
Davison et al., 2013⁴³	49–55 years old; 1–5 years since menopause	Oral E2 1 mg + drospirenone 2 mg daily (12) Placebo (11)	26 weeks	CogState	No differences between groups except improved psychomotor function/processing speed in subjects taking placebo.
Gleason et al., 2015³⁰ Gleason et al., 2024⁴⁹ KEEPS ^a	3–36 months since menopause	Transdermal E2 50 µg/day (211) Oral CEE 0.45 mg/day (220) Placebo (262) ± cyclic micronized P (200 mg/day, 12 days/month)	4 years	Modified MMS, PMA, subscales^b	No difference in cognitive performance by treatment group
Gleason et al., 2015³⁰ Gleason et al., 2024⁴⁹ KEEPS ^a	3–36 months since menopause		10-year follow-up	Modified MMS, PMA, subscales^b	No difference in cognitive performance by treatment group after long-term follow up
Henderson et al., 2016⁴⁴	within 6 years of menopause	Oral E2 1 mg/day (137) Placebo (134) ± cyclic vaginal micronized P, 4% gel	up to 5 years (assessed at baseline, 2.5, and 5 years)	battery^c	No difference in cognitive performance by treatment group when adjusted for multiple testing
Joffe et al., 2006⁴⁵	40–60 years old	Transdermal E2 0.05 mg/day (26) Placebo (26)	12 weeks	CVLT WMS–R R–O	Estrogen reduced perseveration errors during verbal recall at P = 0.03 among 14 comparisons.
LeBlanc et al., 2007⁴⁶	3–36 months from menopause	Oral E2 2 mg/day (14) Placebo (18)	8 weeks, assessed at baseline, 4, and 8 weeks	Verbal memory, paragraph recall, paired associates, emotional memory, nonverbal memory, verbal fluency	No difference in cognitive performance by treatment group unrelated to relief of symptoms
Maki et al., 2007⁴⁷	Women with at least one cognitive complaint but with normal MMS; 45–55 years old, 12–36 months from menopause	Oral CEE 0.625 mg/day + MPA 2.5 mg/day (89) Placebo (91)	4 months	CVLT MFQ BTA BVRT CRT FAS WMS-R	No difference in cognitive performance by treatment group
Morgan et al., 2005³³	41–52 (mean ± 2 SD), not menopausal but had perimenopausal symptoms.	Oral CEE 0.625 mg (11) Placebo (6)	6 weeks	BSRT	Woman with partial response of depression on one of six antidepressants were recruited for 14-week crossover trial. Trial stopped after six weeks due to disproportionate dropouts on placebo. No significant improvement in the BSRT, a test of memory.

Abbreviations: BSRT Buschke Selective Reminding Test; BVRT Benton Visual Retention Test, BTA Brief test of Attention; CEE conjugated equine estrogens; CogState (includes visual attention/vigilance, psychomotor function/speed, visual learning and memory, verbal learning and memory, executive function/spatial problem solving); CRT Card Rotation Test; CVLT California Verbal Learning Test; E2 17β-oestradiol; FAS Letter Fluency Test; MFQ Memory Functioning Questionnaire; MMS Mini-Mental State exam; P progesterone; PMA primary mental abilities, R–O Rey–Osterreith Complex Figure test; WMS–R Wechsler Memory Scale–revised

Kronos Early Estrogen Prevention Study--Cognitive and Affective Study (KEEPS-Cog)

Subscales of California Verbal Learning Test, 2nd edition, New York University Paragraph Recall, Benton Visual Retention Test, Controlled Oral Word Association Test–Phonemic Fluency, Controlled Oral Word Association Test–Category Fluency, Trail Making Test A, Trail Making Test B, Stroop Color Word Interference Test, Wechsler Adult Intelligence Scale, 3rd edition (WAIS-3), Letter-Number Sequencing, Wechsler Memory Scale, 3rd edition (WMS-3) Digit Span, WAIS-3 Digit Symbol

The battery included the Symbol Digit Modalities test, Trail Making Test, part B, Shipley Abstractions scale, Letter-Numbering Sequencing, Block Design, Judgment of Line Orientation, Verbal Fluency (Animal), Boston Naming test, California Verbal Learning tests, East Boston Memory tests, Faces I and II, Verbal Episodic

Women's Health Initiative

The Women's Health Initiative Memory Study (WHIMS) reported that global and domain-specific cognitive function were impaired in women randomised to receive hormone therapy at age 65 or older.^40,41 The Women's Health Initiative Study of Younger Women (WHIMSY), a sub-study of the WHI, included women starting treatment at age 50–55. Telephone assessments of cognition in these subjects 7.2 years after the WHI ended included the East Boston Memory Test, the Oral Trail Making Test, Verbal Fluency–Animals, and the Digit Span subtest of the Wechsler Adult Intelligence Scale–Revised. Except for a decrease in verbal fluency among women who received CEE only, there were no differences among placebo, CEE-treated, or CEE + MPA-treated women in global or domain-specific cognitive function.⁴²

Other trials

Eight other RCTs are summarised in Table 4.^{30,33,43–49} With one exception, no trial showed an improvement in any cognitive measure in menopausal women randomised to hormone therapy. The exception, the paper by Joffe et al., reporting a 12-week trial supported by industry,⁴⁵ was one of two in the cognitive group with a high risk of bias. Among 14 comparisons in this study, not necessarily independent, only one comparison favoured 17β-estradiol therapy; perseveration errors on verbal recall in the California Verbal Learning Test decreased by a mean of 2.2, 95% CI −4.0 to −0.3. None of the other studies confirmed memory errors, and the association may have arisen by chance. The KEEPS study did not find a difference in cognitive performance during the four-year trial,³⁰ neither was there any difference between treatment group and placebo in the 10-year follow-up.⁴⁹

In summary, no benefit of hormones on cognition was shown in eight RCTs; the ninth showed a benefit in only one of 14 comparisons and is not reliable. There was no apparent advantage of 17β-estradiol, used in six of the studies, over CEE, used in three of the studies. Our conclusion, using GRADE criteria, is that available RCTs do not show a cognitive benefit of menopausal hormone therapy.

Discussion

Main findings

Although critics have stated that women in the WHI were too old to provide informative data about hormone therapy in women close to menopause, the WHI remains the largest RCT of menopausal hormone therapy in young menopausal women. In the CEE + MPA trial, the WHI randomised 5522 women who were 50–59 years old, 4092 of whom were fewer than 10 years from the onset of menopause.⁵⁰ The CEE-only trial included 3310 women 50–59 years old, 1237 of whom were within 10 years of menopause onset. Some results given for women 50–55 years of age or within five years of menopause did not show benefits. Whether these women might have benefited from starting menopausal hormones at a younger age or sooner after menopause is unknown.

In this systematic review, we examined randomised clinical trials of women aged 50–60 years or women who were within a short period of time after their last menses, as defined by the individual study authors. Despite casting a wide net (we did not restrict pharmaceutical estrogen, dose or route of exposure except vaginal administration), we found no preparation or route of administration that offered superior health benefits to those found in the WHI. Oral CEE was used in five trials, oral 17β-estradiol therapy was used in six trials, and transdermal 17β-estradiol therapy was used in six trials. Our findings are consistent with a Cochrane meta-analysis of randomised, placebo-controlled trials that lasted more than a year.⁵⁴ The analysis did not identify a beneficial effect of hormone therapy on the prevention of chronic disease.

Our results differ from three previous analyses. A systematic review and meta-analysis included open-label studies and surrogate endpoints, deficiencies that might account for its claim of a benefit of hormone therapy on cardiovascular mortality.⁵¹ Another meta-analysis of menopausal hormone therapy and coronary heart disease reported a reduction in disease in women enrolled before age 60, but the four-page report was too brief and lacked detail about its methods.⁵² A meta-analysis from the same group, reported in greater detail, noted a decrease in overall mortality in women starting hormone therapy before age 60, but found no advantage for hormones in cardiovascular or cancer mortality.⁵³ Some trials in that meta-analysis did not have a placebo arm or used calcium pills as a placebo. The authors of a Cochrane systematic review criticised the Salpeter et al. meta-analysis for including trials without a placebo arm and studies of less than one year duration, inappropriate for drawing conclusions about chronic diseases.⁵⁴

Among women in the WHI randomised to CEE at age 50–59, 1129 women had bilateral salpingo-oophorectomy, and 2008 women had hysterectomy with retention of at least part of one ovary.⁵¹ There was a decrease in all-cause mortality in oophorectomised women randomised to CEE (HR 0.68, 95% CI 0.48 to 0.96), but no effect of CEE treatment on coronary heart disease or invasive breast cancer. This possible protective effect on mortality was seen primarily in women randomised to estrogen within 10 years of surgery; it was not seen in women randomised 20 or more years after surgery. It is possible that oophorectomy increased the risk that was mitigated by estrogen treatment. No other randomised trial evaluated this possibility. Because the use of CEE alone in the WHI was a proxy for hysterectomy, which often included oophorectomy, we could not determine whether the protective effect in the CEE-alone group was due to attenuation of oophorectomy-associated risk or to hormone treatment independent of oophorectomy.

Mood and cognition may be influenced by vasomotor symptoms that interfere with sleep. Neither the WHI nor the other RCTs definitively addressed this possibility, with the exception of one study that showed similar benefits on depression of a sleep aid, hormone therapy, and placebo.

Strengths and limitations

This systematic review included all RCTs of menopausal hormone therapy in women under 60 or within a short period of time after the last menses. A strength is our acceptance of authors’ definitions of a short period of time after the last menses and our consideration of all pharmaceutical estrogens by any route except exclusively vaginal administration.

It could be considered a weakness that our review did not consider surrogate endpoints, including mechanistic endpoints, blood pressure, lipid concentrations, or other cardiovascular disease risk factors. Surrogate endpoints do not represent disease and may be misleading. For example, serum lipid concentrations in the WHI were favourably altered by menopausal hormone therapy, but cardiovascular disease was increased.⁵⁵ In the GRADE system, use of surrogate endpoints results in downgrading of certainty due to lack of direct evidence for the clinical outcome. To the extent that surrogate endpoints predict clinical disease, our review has not considered these endpoints.

Our findings offer little support for the timing hypothesis, although there is a reduction in some measures of cardiovascular disease and all-cause mortality in women treated with estrogen within 10 years after oophorectomy, particularly oophorectomy prior to age 45.⁵⁶ This protective effect was not confirmed in other studies or in a subsequent analysis of the WHI data. One study cited by proponents of the timing hypothesis is Schierbeck et al.,⁵⁷ which was not included in our analysis because of the lack of a placebo arm. In the Schierbeck et al. study, 1006 women aged 45–58 years and 3–24 months since their last episode of bleeding were randomised to menopausal hormone therapy (a cyclic estrogen- progestogen regimen in women with a uterus, estrogen-only in women who had a hysterectomy), or no therapy. After 10.1 years, when the findings of the WHI came out, subjects were advised to stop hormones, but continued to be followed up via national registries for an additional 5.7 years. At the end of the 10.1-year study period, a composite endpoint of death, myocardial infarction, and heart failure was reduced in the women taking hormones. At the end of the full 15.8 years of follow-up, the composite endpoint was described as reduced in women who were randomised to hormones. However, the result was not significant, because the 95% CI included the null value of 1.0. None of the secondary endpoints, including stroke, venous thromboembolism, pulmonary embolism, breast cancer, any cancer, or the individual components of the composite endpoint (death, myocardial infarction, heart failure) showed any difference between groups. This trial does not provide convincing evidence in favour of the timing hypothesis.

The Cochrane meta-analysis⁵⁴ found substantial heterogeneity among trials in hormone preparations and duration of treatment, and only meta-analysed subgroups of studies with the same active hormone treatment and similar lengths of treatment. As those authors found, the WHI was a prominent driver of findings due to its larger size compared to the other trials. We separately evaluated studies without a high Risk of Bias and studies of 17β-estradiol therapy and did not find evidence to support the timing hypothesis.

We did not consider the beneficial effects of hormones on vasomotor symptoms or bone health, which have been amply demonstrated. We do not suggest that it is inappropriate to prescribe menopausal hormones. However, in the risk-benefit calculus, the prevention of chronic disease should not be identified as a benefit unless and until randomised clinical trials demonstrate a benefit.

Conclusion

We did not identify consistent evidence to support the timing hypothesis for menopausal hormone therapy in the prevention of chronic disease. The WHI found no health benefits for early menopausal women using menopausal hormone therapy on cardiovascular disease, cancer or cognition, except a possible decrease in cardiovascular disease or all-cause mortality in women given estrogen within 10 years of oophorectomy, which may have been due to protection from oophorectomy-associated risks. The null findings of the WHI with respect to prevention of chronic disease have not been contradicted by other RCTs, including trials that tested different preparations and routes. We did not identify data supporting the concept that women starting hormone therapy in their 50s and stopping therapy after a given number of years have a rebalancing of risks and benefits. This systematic review supports the recommendations of professional groups not to use menopausal hormone therapy for the prevention of chronic disease.^58–61

Supplemental Material

sj-docx-1-shr-10.1177_20542704261455970 - Supplemental material for The effects of menopausal hormone therapy on cardiovascular disease, cancer, cognition and depression in younger women: A systematic review

Supplemental material, sj-docx-1-shr-10.1177_20542704261455970 for The effects of menopausal hormone therapy on cardiovascular disease, cancer, cognition and depression in younger women: A systematic review by Patricia A Bencivenga, Natalie Fort, Adriane Fugh-Berman and Anthony R Scialli in JRSM Open

Footnotes

Acknowledgements

The authors thank Caroline Renko for expert manuscript preparation.

Contributorship

Patricia A. Bencivenga: conceptualisation, data curation and validation, manuscript review and editing. Natalie Fort: data curation and validation, manuscript review and editing. Adriane Fugh-Berman: methodology, data validation, manuscript review and editing. Anthony R. Scialli: conceptualisation, supervision, investigation, original draft. All authors read and approved the final version.

Declaration of conflicting interests

Anthony R. Scialli has been a consultant for pharmaceutical companies, including AbbVie, Altimmune, Alvylam Pharmaceuticals, Amgen, Biohaven Pharmaceuticals, Bayer, Bristol Myers Squibb, Celgene, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, Merck, Mitsubishi Tanabe, Myovant Science, Moderna, Novartis, Roche, Sanofi, Satsuma Pharmaceuticals, Seqirus, and Vertex Pharmaceuticals. Adriane Fugh-Berman is a paid expert witness at the request of plaintiffs in litigation regarding pharmaceutical marketing practices. Patricia A. Bencivenga and Natalie Fort have no conflicts of interest.

Ethical approval

Ethical approval was not required because no patients were involved in this systemtic review.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Guarantor

Anthony R. Scialli, M.D.

Provenance

Not commissioned, peer reviewed by Julie Morris and Roxanna Pirhadi.

Supplemental material

Supplemental material for this article is available online.

ORCID iD

Anthony R. Scialli

References

Hodis

Mack

. Menopausal hormone replacement therapy and reduction of all-cause mortality and cardiovascular disease: it is about time and timing. Cancer J 2022;28(3):208–223.

Wharton

Gleason

Miller

Asthana

. Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective sub study (KEEPS Cog). Brain Res 2013;1514:12–17.

Khan

Kapoor

Faubion

Kling

. Vasomotor symptoms during menopause: a practical guide on current treatments and future perspectives. Int J Womens Health 2023;15:273–287.

Lobo

. Where are we 10 years after the Women’s Health Initiative? J Clin Endocrinol Metab 2013;98(5):1771–1780.

Higgins

JPT

Altman

Gøtzsche

, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Br Med J 2011;343:d5928.

Guyatt

Vandvik

Iorio

, et al. Core GRADE 7: principles for moving from evidence to recommendations and decisions. Br Med J 2025;389:e083867.

Guyatt

Yao

Murad

, et al. Core GRADE 6: presenting the evidence in summary of findings tables. Br Med J 2025;389:e083866.

Guyatt

Iorio

De Beer

, et al. Core GRADE 5: rating certainty of evidence-assessing indirectness. Br Med J 2025;389:e083865.

Guyatt

Wang

Eachempati

, et al. Core GRADE 4: rating certainty of evidence-risk of bias, publication bias, and reasons for rating up certainty. Br Med J 2025;389:e083864.. Erratum in: BMJ. 2025 Jul 29;390:r1468. doi: 10.1136/bmj.r1468.

10.

Guyatt

Schandelmaier

Brignardello-Petersen

, et al. Core GRADE 3: rating certainty of evidence-assessing inconsistency. Br Med J 2025;389:e081905.

11.

Guyatt

Zeng

Brignardello-Petersen

, et al. Core GRADE 2: choosing the target of certainty rating and assessing imprecision. Br Med J 2025;389:e081904.

12.

Guyatt

Agoritsas

Brignardello-Petersen

, et al. Core GRADE 1: overview of the Core GRADE approach. Br Med J 2025;389:e081903.

13.

Anderson

Limacher

Assaf

, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291(14):1701–1712.

14.

Office on Women’s Health. Largest women’s health prevention study ever – Women’s Health Initiative. Office on Women’s Health. Accessed May 2, 2024. https://web.archive.org/web/20240424164022/https://www.womenshealth.gov/30-achievements/25

15.

Manson

Chlebowski

Stefanick

, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310(13):1353–1368.

16.

Hsia

Langer

Manson

, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med 2006;166(3):357–365.

17.

Hendrix

Wassertheil-Smoller

Johnson

, et al. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation 2006;113(20):2425–2434.

18.

Wassertheil-Smoller

Hendrix

Limacher

, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003;289(20):2673–2684.

19.

Perez

Wang

Larson

, et al. Effects of postmenopausal hormone therapy on incident atrial fibrillation: the Women’s Health Initiative randomized controlled trials. Circ Arrhythm Electrophysiol 2012;5(6):1108–1116.

20.

Liu

Klein

Eaton

, et al. Menopausal hormone therapy and risks of first hospitalized heart failure and its subtypes during the intervention and extended postintervention follow-up of the Women’s Health Initiative randomized trials. J Card Fail 2020;26(1):2–12.

21.

Manson

Aragaki

Rossouw

, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials. JAMA 2017;318(10):927–938.

22.

Rossouw

Aragaki

Manson

, et al. Menopausal hormone therapy and cardiovascular diseases in women with vasomotor symptoms: a secondary analysis of the Women's Health Initiative randomized clinical trials. JAMA Intern Med 2025;185:1330–1339. doi: https://doi.org/10.1001/jamainternmed.2025.4510

23.

Kantarci

Tosakulwong

Lesnick

, et al. Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial. Menopause N Y N 2024;31(1):10–17.

24.

Veerus

Hovi

Fischer

, et al. Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757]. Maturitas 2006;55(2):162–173.

25.

Chlebowski

Anderson

Aragaki

, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA 2020;324(4):369–380.

26.

Chlebowski

Hendrix

Langer

, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA 2003;289(24):3243–3253.

27.

Prentice

Aragaki

Chlebowski

, et al. Randomized trial evaluation of the benefits and risks of menopausal hormone therapy among women 50-59 years of age. Am J Epidemiol 2021;190(3):365–375.

28.

Chlebowski

Anderson

Sarto

, et al. Continuous combined estrogen plus progestin and endometrial cancer: the Women’s Health Initiative randomized trial. JNCI J Natl Cancer Inst 2015;108(3):djv350.

29.

Bech

Munk-Jensen

Obel

Ulrich

Eiken

Nielsen

. Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-related outcome measures. Psychother Psychosom 1998;67(4-5):259–265.

30.

Gleason

Dowling

Wharton

, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-cognitive and affective study. PLoS Med 2015;12(6):e1001833; discussion e1001833.

31.

Gordon

Rubinow

Eisenlohr-Moul

Xia

Schmidt

Girdler

. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry 2018;75(2):149–157.

32.

Joffe

Petrillo

Koukopoulos

, et al. Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition. J Clin Endocrinol Metab 2011;96(7):E1044–E1054.

33.

Morgan

Cook

Rapkin

Leuchter

. Estrogen augmentation of antidepressants in perimenopausal depression: a pilot study. J Clin Psychiatry 2005;66(6):774–780.

34.

Raz

Hunter

Dowling

, et al. Differential effects of hormone therapy on serotonin, vascular function and mood in the KEEPS. Climacteric J Int Menopause Soc 2016;19(1):49–59.

35.

Saletu

Brandstätter

Metka

, et al. Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression. Psychopharmacology (Berl) 1995;122(4):321–329.

36.

Schmidt

Nieman

Danaceau

, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183(2):414–420.

37.

Soares

Almeida

Joffe

Cohen

. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58(6):529–534.

38.

Thomson

Oswald

. Effect of oestrogen on the sleep, mood, and anxiety of menopausal women. Br Med J 1977;2(6098):1317–1319.

39.

Tansupswatdikul

Chaikittisilpa

Jaimchariyatam

Panyakhamlerd

Jaisamrarn

Taechakraichana

. Effects of estrogen therapy on postmenopausal sleep quality regardless of vasomotor symptoms: a randomized trial. Climacteric J Int Menopause Soc 2015;18(2):198–204.

40.

Rapp

Espeland

Shumaker

, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289(20):2663–2672.

41.

Espeland

Rapp

Shumaker

, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291(24):2959–2968.

42.

Espeland

Shumaker

Leng

, et al. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med 2013;173(15):1429–1436.

43.

Davison

Bell

Robinson

, et al. Continuous-combined oral estradiol/drospirenone has no detrimental effect on cognitive performance and improves estrogen deficiency symptoms in early postmenopausal women: a randomized placebo-controlled trial. Menopause N Y N 2013;20(10):1020–1026.

44.

Henderson

St John

Hodis

, et al. Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis. Neurology 2016;87(7):699–708.

45.

Joffe

Hall

Gruber

, et al. Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women. Menopause N Y N 2006;13(3):411–422.

46.

LeBlanc

Neiss

Carello

Samuels

Janowsky

. Hot flashes and estrogen therapy do not influence cognition in early menopausal women. Menopause N Y N 2007;14(2):191–202.

47.

Maki

Gast

Vieweg

Burriss

Yaffe

. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology 2007;69(13):1322–1330.

48.

Berent-Spillson

Briceno

Pinsky

, et al. Distinct cognitive effects of estrogen and progesterone in menopausal women. Psychoneuroendocrinology 2015;59:25–36.

49.

Gleason

Dowling

Kara

, et al. Long-term cognitive effects of menopausal hormone therapy: findings from the KEEPS Continuation Study. PLoS Med 2024 Nov 21;21(11):e1004435. doi: 10.1371/journal.pmed.1004435

50.

Rossouw

Prentice

Manson

, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297(13):1465–1477. doi:10.1001/jama.297.13.1465

51.

Nudy

Chinchilli

Foy

. A systematic review and meta-regression analysis to examine the “timing hypothesis” of hormone replacement therapy on mortality, coronary heart disease, and stroke. Int J Cardiol Heart Vasc 2019;22:123–131. doi:10.1016/j.ijcha.2019.01.001

52.

Salpeter

Walsh

Greyber

Salpeter

. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med 2006;21:363–366.

53.

Salpeter

Walsh

Greyber

Ormiston

Salpeter

. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med 2004;19:791–804.

54.

Marjoribanks

Farquhar

Roberts

Lethaby

Lee

. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017;(1):Art. No.: CD004143. doi: 10.1002/14651858.CD004143.pub5

55.

Rossouw

Cushman

Greenland

, et al. Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women’s Health Initiative trials of hormone therapy. Arch Intern Med 2008;168(20):2245–2253. doi:10.1001/archinte.168.20.2245

56.

Manson

Aragaki

Bassuk

, et al. Menopausal estrogen-alone therapy and health outcomes in women with and without bilateral oophorectomy: a randomized trial. Ann Intern Med 2019;171(6):406–414. doi: 10.7326/M19-0274. Epub 2019 Sep 10.

57.

Schierbeck

Rejnmark

Tofteng

, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. Br Med J 2012;345:e6409. doi: 10.1136/bmj.e6409

58.

NAMS. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause N Y N 2022;29(7):767–794. doi:10.1097/GME.0000000000002028

59.

Stuenkel

Davis

Gompel

, et al. Treatment of symptoms of the menopause: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015;100(11):3975–4011. doi:10.1210/jc.2015-2236

60.

American College of Obstetricians and Gynecologists. ACOG Committee opinion No. 565: hormone therapy and heart disease. Obstet Gynecol 2013;121(6):1407–1410. doi:10.1097/01.AOG.0000431053.33593.2d

61.

Gartlehner

Patel

Feltner

, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: evidence report and systematic review for the US preventive services task force. JAMA 2017;318(22):2234–2249. doi:10.1001/jama.2017.16952

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.06 MB