Estrogens

Endometrial cancer accounts for 95% of uterine cancers, which are the fourth most common cancer in women in the US.1 Approximately 1 in 32 women in the US will develop endometrial cancer in their lifetimes. Eighty percent of endometrial cancer cases in the US are diagnosed in postmenopausal women, and the average age at diagnosis is 60 years. However, rates of endometrial cancer are increasing in both older and younger women in the US and worldwide.

A leading risk factor for endometrial cancer is obesity. Other common risk factors are diabetes and a personal or family history of inherited conditions such as Lynch syndrome (a genetic disorder that increases the risk of multiple types of cancer). Additional risk factors include use of estrogen without progesterone, tamoxifen (a medication to treat or prevent hormone receptor–positive breast cancer), and having never been pregnant. In contrast, combined oral contraceptives and progesterone therapy, including progesterone-releasing intrauterine devices, are associated with a decreased risk of endometrial cancer.

Management of Premenstrual Disorders

Megan George — Mon, 09 Feb 2026 14:12:26 +0000

Date Added:

February 9, 2026

Journal/Publication:

JAMA

Publication Date:

February 4, 2026

URL:

Management of Premenstrual Disorders

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2025.26054

Keywords

Premenstrual Dysphoric Disorder

Luteal Phase

menstruation

Affective Symptoms

PMID (1):

41637081

MeSH

Premenstrual Dysphoric Disorder

A review of what we know and think about how to help women with premenstrual disorders. James W. Mold, MD, MPH

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Premenstrual disorders encompass a spectrum of cyclic affective and physical symptoms that interfere with daily functioning, occurring during the luteal phase and resolving with or immediately following menstruation. Premenstrual disorders may be caused by fluctuations of estrogen in the luteal phase, leading to dysregulation of serotonin, increased sensitivity to changes in the progesterone metabolite allopregnanolone, or both. Diagnosis can be made based on symptom assessment with daily ratings for at least 2 consecutive menstrual cycles, such as the Daily Record of Severity of Problems.1,2 Affective symptoms include lability (mood swings, sudden sadness or tearfulness, sensitivity to rejection), irritability or anger, depressed mood, and anxiety or tension. Physical symptoms include difficulty concentrating, lethargy or fatigue, appetite changes, sleep disturbances, breast tenderness, joint pain, and abdominal bloating.

Premenstrual syndrome (PMS) is characterized by the cyclic occurrence of any of these affective or physical findings during the premenstrual period and affects approximately one-quarter of menstruating individuals. Premenstrual dysphoric disorder (PMDD) is more severe than PMS and less common (affecting 2%-5% of females). Based on the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5), the diagnosis of PMDD requires at least 5 symptoms, including at least 1 affective symptom and 1 physical symptom, the week before menses. Symptoms of PMDD substantially decrease or resolve the week after menses.1,2 Treatment choices are based on the timing and severity of symptoms and patient goals such as desire for contraception.

Author/s:

Rebeca Ortiz Worthington, Lindsey M Eastman, Jason T Alexander

Nonhormonal Treatment of Menopausal Vasomotor Symptoms

Erin Blanchette — Wed, 07 May 2025 21:26:26 +0000

Date Added:

May 7, 2025

Journal/Publication:

JAMA Internal Medicine

Publisher:

American Medical Association

Publication Date:

May 5, 2025

URL:

Nonhormonal Treatment of Menopausal Vasomotor Symptoms

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jamainternmed.2025.0990

Keywords

Obstetrics and Gynecology

PMID (1):

40323611

MeSH

A concise evidence-based review of non-hormonal approaches to treatment of menopausal vasomotor symptoms. James W. Mold, MD, MPH

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Vasomotor symptoms are the most widely recognized menopause symptoms in Western nations, with at least 75% of women reporting hot flashes or night sweats during or after the menopause transition. Many women struggle to choose between treatments, given lack of data on direct comparisons of different treatments, concerns about short-term adverse effects and longer-term treatment risks, and confusion about complementary or alternative remedies with unclear evidence of benefit.

Author/s:

Alison J Huang, Stephanie Faubion, Deborah Grady

Genitourinary Syndrome of Menopause: A Systematic Review

Alex Haga — Tue, 20 Aug 2024 19:48:50 +0000

Date Added:

August 20, 2024

Journal/Publication:

Agency for Healthcare Research and Quality

Publication Date:

July 31, 2024

URL:

Genitourinary Syndrome of Menopause: A Systematic Review

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

Keywords

Genitourinary

Genitourinary Syndrome

MeSH

An evidence-based review of strategies for managing the GU symptoms of menopause. James W. Mold, MD, MPH

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Objectives. To conduct a systematic review of evidence regarding genitourinary syndrome of menopause (GSM) screening, treatment, and surveillance.

Data sources. Ovid/Medline®, Embase®, and EBSCOhost/CINAHL® from database inception through December 11, 2023.

Review methods. We employed methods consistent with the Agency for Healthcare Research and Quality Evidence-based Practice Center Program Methods Guidance to identify studies and synthesize findings for Key Questions related to screening for GSM, effectiveness and harms of U.S.-available interventions for GSM, appropriate followup intervals for patients using GSM treatments, and endometrial surveillance for patients using hormonal GSM treatments. For vaginal estrogen and vaginal or systemic non-estrogen hormonal interventions, energy-based interventions, and vaginal moisturizers, we first assessed study quality and then, for moderate or high-quality studies, reviewed outcomes related to GSM symptoms, treatment satisfaction, and adverse effects. For low-quality studies, we described limited study characteristics only. For studies of other non-hormonal interventions, we created an evidence map describing study characteristics without assessing study quality.

Results. After assessing 107 publications for risk of bias (RoB), we extracted and synthesized effectiveness and/or harms outcomes from 68 publications describing trials or prospective, controlled observational studies that were rated low, some concerns, or moderate RoB (24 estrogen publications, 35 non-estrogen, 11 energy-based, and 4 moisturizers). Of 39 high, serious, or critical RoB publications, we extracted long-term harms from only 15 uncontrolled studies of energy-based interventions (all serious or critical RoB due to confounding). An additional 66 publications evaluating 46 non-hormonal interventions, including natural products, mind/body practices, and educational interventions, were described in an evidence map. Across all 172 publications, studies differed in GSM definitions, diagnosis, enrollment criteria, and outcomes assessed. Few studies enrolled women with a history of breast or gynecologic cancers. Overall, we found that vaginal estrogen, vaginal dehydroepiandrosterone (DHEA), vaginal moisturizers, and oral ospemifene may all improve at least some GSM symptoms, while evidence does not demonstrate the efficacy of energy-based therapies, vaginal or systemic testosterone, vaginal oxytocin, or oral raloxifene or bazedoxifene for any GSM symptoms. Harms reporting was limited, in part, by studies not being sufficiently powered to evaluate infrequent but serious harms, though most studies did not report frequent serious harms. Common non-serious adverse effects varied by treatment and dose. No studies evaluated GSM screening or directly addressed appropriate followup intervals or the effectiveness and harms of endometrial surveillance among women with a uterus receiving hormonal therapy for GSM. The longest followup period for active endometrial surveillance in an included trial was 12 weeks (vaginal estrogen) or 1 year (non-estrogen hormonal interventions).

Conclusions. This systematic review provides comprehensive, up-to-date information to guide patients, clinicians, and policymakers regarding GSM. Despite the breadth of included studies, findings were limited by several factors, including heterogeneity in intervention-comparator-outcome combinations. Future studies would be strengthened by a standard definition and uniform diagnostic criteria for GSM, a common set of validated outcome measures and reporting standards, and attention to clinically relevant populations and intervention comparisons. Lack of long-term data assessing efficacy, tolerability, and safety of GSM treatments leaves postmenopausal women and clinicians without evidence to guide treatment longer than 1 year.

The Women’s Health Initiative Randomized Trials and Clinical Practice

Alex Haga — Mon, 13 May 2024 21:25:57 +0000

Date Added:

May 13, 2024

Journal/Publication:

JAMA

Publisher:

JAMA

Publication Date:

May 1, 2024

URL:

The Women’s Health Initiative Randomized Trials and Clinical Practice

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1001/jama.2024.6542

Keywords

PMID (1):

38691368

A summary review of the results of the Womens Health Initiative Study pertaining to HRT, Vit D/calcium supplementation, and low-fat diet in menopausal women. James W. Mold, MD, MPH

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Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.

Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.

Conclusions and relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Author/s:

Manson, J.E., Crandall, C.J., Rossouw, J.E.

Diagnosis and management of endometriosis

Rowan Hutchins — Sun, 19 Mar 2023 05:00:00 +0000

Date Added:

March 19, 2023

Journal/Publication:

CMAJ

Publisher:

Canadian Medical Association

Publication Date:

March 14, 2023

Issue:

Volume:

195

Pages:

E363-E371

URL:

Diagnosis and management of endometriosis

Type:

Meta-analyses, Reviews, and Guidelines

DOI (1):

10.1503/cmaj.220637

Keywords

PMID (1):

36918177

MeSH

A concise summary of what we know about endometriosis. James W. Mold, MD, MPH

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Endometriosis is a chronic condition defined by the presence of endometrial-like tissue outside of the uterus, which can lead to estrogen-driven inflammation. The extent of disease can be highly variable, ranging from minimal peritoneal deposits to deep disease that can invade into the bowel, bladder and ureter and, more rarely, spread to extrapelvic (e.g., cutaneous, thoracic) sites. Endometriosis is a complex disease that has considerable impact on the quality of life of those affected and that has no cure. It remains poorly understood. We review the epidemiology, pathophysiology, diagnosis and management of endometriosis, based on the best available evidence and clinical guidelines

Author/s:

Allaire, Catherine, Bedaiwy, Mohamed, Yong, Paul

Management of Menopausal Symptoms: A Review

Aubrey Delammermore — Wed, 08 Feb 2023 06:00:00 +0000

Date Added:

February 8, 2023

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

February 7, 2023

Issue:

Volume:

329

Pages:

405-420

URL:

Management of Menopausal Symptoms: A Review

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2022.24140

Keywords

sweat

Acetates

Cardiovascular Diseases

Progestins

menopause

PMID (1):

36749328

MeSH

A review of what we know and the current official recommendations regarding assistance with menopausal symptoms. James W. Mold, MD, MPH.

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Importance: Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]).

Observations: Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene.

Conclusions and relevance: During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.

Author/s:

Crandall, C. J., Mehta, J. M., Manson, J. E.

Hormone Therapy in Postmenopausal Persons: Primary Prevention of Chronic Conditions

Aubrey Delammermore — Sun, 06 Nov 2022 05:00:00 +0000

Date Added:

November 6, 2022

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

November 1, 2022

Issue:

Volume:

328

Pages:

1740-1746

URL:

Hormone Therapy in Postmenopausal Persons: Primary Prevention of Chronic Conditions

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2022.18625

Keywords

Retrospective Studies

postmenopause

Chronic Disease

hormone therapy

Recommendation Statement

PMID (1):

36318127

MeSH

The USPSTF recommends against using estrogen, progesterone, or combinations of the two in postmenopausal women in an attempt to prevent the development of chronic health problems. James W. Mold, MD, MPH

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Importance: Menopause is defined as the cessation of a person's menstrual cycle. It is defined retrospectively, 12 months after the final menstrual period. Perimenopause, or the menopausal transition, is the few-year time period preceding a person's final menstrual period and is characterized by increasing menstrual cycle length variability and periods of amenorrhea, and often symptoms such as vasomotor dysfunction. The prevalence and incidence of most chronic diseases (eg, cardiovascular disease, cancer, osteoporosis, and fracture) increase with age, and US persons who reach menopause are expected on average to live more than another 30 years.

Objective: To update its 2017 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of systemic (ie, oral or transdermal) hormone therapy for the prevention of chronic conditions in postmenopausal persons and whether outcomes vary by age or by timing of intervention after menopause.

Population: Asymptomatic postmenopausal persons who are considering hormone therapy for the primary prevention of chronic medical conditions.

Evidence assessment: The USPSTF concludes with moderate certainty that the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons with an intact uterus has no net benefit. The USPSTF concludes with moderate certainty that the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy has no net benefit.

Recommendation: The USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons. (D recommendation) The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy. (D recommendation).

Author/s:

US Preventative Services task Force, Mangione, C. M., Barry, M. J., Nicholson, W. K., Cabana, M., Caughey, A. B., Chelmow, D., Coker, T. R., Davis, E. M., Donahue, K. E., Jaén, C. R., Kubik, M., Li, L., Ogedegbe, G., Pbert, L., Ruiz, J. M., Stevermer, J., Wong, J. B.

Bisphosphonates for Postmenopausal Osteoporosis

John Bayhi — Sat, 19 Oct 2019 14:38:56 +0000

Date Added:

October 19, 2019

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

October 17, 2019

URL:

Bisphosphonates for Postmenopausal Osteoporosis

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2019.15781

Keywords

post-menopausal osteoporosis

bisphosphonates

antiresorptive agents

PMID (1):

31621799

MeSH

Bone Density Conservation Agents

Raloxifene Hydrochloride

Risedronate Sodium

Alendronate

Osteoporosis, Postmenopausal

Selective Estrogen Receptor Modulators

Gatroesophageal Reflux

Estrogens

vitamin D deficiency

Peptic Ulcer

risk reduction behavior

A short, sweet review of how, when, and for how long to treat postmenopausal osteoporosis. James W. Mold, MD, MPH

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Bisphosphonates are the first-line pharmacologic treatment for postmenopausal osteoporosis and the most commonly prescribed medication for this condition.1 Bisphosphonates, classified as antiresorptive agents, have a very high affinity for bone mineral and bind to hydroxyapatite crystals on bony surfaces, where they inhibit osteoclast-mediated bone resorption.

Author/s:

Ensrud, KE, Crandall, CJ

Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence

John Bayhi — Sat, 31 Aug 2019 15:40:18 +0000

Date Added:

August 31, 2019

Journal/Publication:

The Lancet

Publisher:

Elsevier Ltd.

Publication Date:

August 29, 2019

URL:

Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1016/S0140-6736(19)31709-X

Keywords

MeSH

The relevant information for advising individual patients is covered in the Summary Interpretation section and the last two paragraphs of the Discussion (end of paper).

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Summary

Background

Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.

Methods

Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.

Findings

During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.

Interpretation

If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

Funding

Cancer Research UK and the Medical Research Council.

Author/s:

Collaborative Group on Hormonal Factors in Breast Cancer