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Estrogen + progestin

Estrogen + progestin has been studied in 29 papers since 2001: 2 trials and 13 observational studies in people, 14 reviews; 14 in the past year. It has not reached trials in people. The newest story, Nov 13, 2026: “Combined hormone therapy linked to worsening headaches”.

InterventionPreclinical

29 papers study it20 findingsUpdated

2 new papers in 30 daysSee all 29 papers on estrogen + progestin

At a glance

Independent labs found the same change in people. 14 independent labs in 6 countries.

“E+P MHT was significantly associated with worsening headache trajectory (aRR= 1.53, 95% CI: 1.14-2.03).”
Menopausal hormone therapy, migraine history, and headache severity: Results from the Women's Health Initiative Hormone Therapy clinical trialsHeadache2026doi:10.1111/head.70168

1 of its findings points the other way.

Humans: replicated by independent labs. Cells, worms or flies and mice: nothing yet.

C, W, M, H: cells, worms or flies, mice, humans. Dark: independent labs found the same change there. Light: one lab or one study. Outline: nothing yet.

Labs are independent when their papers share no last author and no institution.

Against: findings that point the other way from most findings on the same outcome.

Company ties: findings with an author at a company, or from a paper whose competing-interests statement declares ties to one.

  • 14 independent labs in 6 countries
  • 1 finding against
  • Funders: National Institute on Aging and others
  • 3 of 19 findings with company ties
  • Human trial2
  • Humans13

Studies in people

2 studies gave estrogen + progestin to people and measured what changed.

What changedDesignPeopleSource

down: Impairs headache severityaRR 1.53, 95% CI 1.14-2.03

Randomized trial1 year22,876 peopleWomenaverage age 64 yearsOlder adults; Postmenopausal women; in participants with a history of migraineHeadache, Jul 8, 2026

no change: Has no effect on plasma Alzheimer's biomarker

Randomized trialaverage 15-year follow-upWomenPostmenopausal women; postmenopausal womenMaturitas, Feb 11, 2026

What did studies of estrogen + progestin find?

7

Studies of estrogen + progestin measured 7 outcomes, among them headache severity, plasma Alzheimer's biomarker and meningioma.

Headache severity

downin humans1

1 study

  1. Estrogen + progestin impairs headache severity in participants with a history of migraine (aRR 1.53, 95% CI 1.14-2.03).

    “E+P MHT was significantly associated with worsening headache trajectory (aRR= 1.53, 95% CI: 1.14-2.03).”

    Human trialin participants with a history of migraineoral1 yearfemales

    Combined hormone therapy linked to worsening headaches

    Headache

Plasma Alzheimer's biomarker

no changein humans1

1 study

  1. Estrogen + progestin showed no clear effect on plasma Alzheimer's biomarker in humans (postmenopausal women; compared with placebo).

    “did not significantly differ for estrogen alone vs placebo or estrogen plus progestin vs placebo.”

    Human trialpostmenopausal women; compared with placeboplasmaaverage 15-year follow-upfemales

    Randomization to hormone therapy and changes in plasma biomarkers of Alzheimer's pathology: The women's health initiative memory study

    Maturitas

More on Plasma Alzheimer's biomarker

Meningioma

no changein humans1HR 1.13

1 study

  1. Estrogen + progestin was not clearly linked with meningioma in humans (Compared with never-use; no statistically significant association) (HR 1.13, 95% CI 0.94–1.34).

    “Use of continuous, but not cyclic estrogen-progestin was associated with increased meningioma risk.”

    HumansCompared with never-use; no statistically significant associationcyclic regimenfemales

    Menopausal hormone therapy and central nervous system tumors: Danish nested case-control study

    PLoS medicine

More on Meningioma

Glioma

no changein humans1HR 1

1 study

  1. Estrogen + progestin was not clearly linked with glioma in humans (Compared with never-use) (HR 1.00, 95% CI 0.86–1.16).

    “There was no evidence of increased glioma risk with estrogen-progestin use.”

    HumansCompared with never-usefemales

    Menopausal hormone therapy and central nervous system tumors: Danish nested case-control study

    PLoS medicine

More on Glioma

Net benefit for primary prevention of chronic conditions

no changein humans1

1 study

  1. Estrogen + progestin showed no clear effect on net benefit for primary prevention of chronic conditions in humans (postmenopausal persons with an intact uterus).

    “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.”

    Reviewpostmenopausal persons with an intact uterus

    Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: US Preventive Services Task Force Recommendation Statement

    JAMA

Lobular tumors

upin humans1OR 1.68

1 study

  1. Estrogen + progestin is linked with higher lobular tumors in humans (OR = 1.68 [95% CI 1.07-2.65]).

    “and an association with lobular tumors (OR = 1.68 [95% CI 1.07-2.65])”

    Humansfemales

    Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer

    Breast cancer research and treatment

Poorly differentiated tumors

downin humans1OR 0.57

1 study

  1. Estrogen + progestin is linked with lower poorly differentiated tumors in humans after adjustment for screening (OR = 0.57 [95% CI 0.38-0.85]).

    “EPT use was associated with tumor characteristics related to improved prognosis in older women after adjustment for screening, including an inverse association with poorly differentiated tumors (OR = 0.57 [95% CI 0.38-0.85])”

    Humansafter adjustment for screeningfemales

    Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer

    Breast cancer research and treatment

What is estrogen + progestin linked with?

11

Studies link estrogen + progestin with 11 measures, most often breast cancer (3 studies).

Breast cancer

upin humans3HR 1.27

3 studies

  1. Estrogen + progestin raises the risk of breast cancer in humans (long-duration use and early initiation after menopause (<3 years)) (RR/HR~1.5-2.5).

    “Combined EPT consistently increases breast cancer risk (RR/HR~1.5-2.5), with high-er risk for long-duration use and early initiation after menopause (<3 years).”

    Reviewlong-duration use and early initiation after menopause (<3 years)

    MENOPAUSAL HORMONE THERAPY AND BREAST CANCER RISK

    International Journal of Innovative Technologies in Social Science

  2. Estrogen + progestin raises the risk of breast cancer in humans (HR 1.27, 95% CI 1.18–1.37).

    “Combined estrogen–progestin therapy was associated with increased breast cancer risk (HR 1.27; 95% CI 1.18–1.37)”

    Reviewfemales

    Cardiovascular and Cancer Risks Associated with Different Hormone Replacement Therapy Regimens: A Systematic Review and Meta-Analysis (2020–2025 Evidence)

    Journal of medical & health sciences review.

  3. Estrogen + progestin raises the risk of breast cancer in menopause.

    “combined estrogen-progestogen therapy has been associated with a higher risk of developing breast cancer”

    Reviewin menopause

    Menopausal hormone therapy and breast cancer: Balancing risks and benefits

    Maturitas

More on Breast cancer

Venous thromboembolism

upin humans1RR 1.52

1 study

  1. Estrogen + progestin raises the risk of venous thromboembolism in humans (RR 1.52; 95% CI 1.12-2.06).

    “but increased stroke risk (RR 1.28; 95% CI 1.02-1.58) and venous thromboembolism (VTE) (RR 1.52; 95% CI 1.12-2.06).”

    Reviewfemales

    Cardiometabolic Effects of Menopause Hormone Therapy in Women with or at Risk for Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

    AHA Scientific Sessions 2026 abstract

More on Venous thromboembolism

Parkinson's disease

upin humans1RR 1.4

1 study

  1. Estrogen + progestin raises the risk of Parkinson's disease in humans (RR 1.40, 95% CI 1.07-1.82).

    “In subgroup analyses, combined therapy was associated with an increased PD risk (RR 1.40; 95% CI 1.07-1.82)”

    Reviewcombined estrogen-progestin

    Differential effects of hormone therapy formulations on Parkinson's disease risk: a systematic review and meta-analysis

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology

More on Parkinson's disease

Borderline ovarian tumor

upin humans1OR 1.426

1 study

  1. Estrogen + progestin raises the risk of borderline ovarian tumor in humans (OR 1.426, 95% CI 1.083-1.877).

    “Combined estrogen-progestin therapy showed a stronger, more consistent positive association (odds ratio 1.426, 95% confidence interval 1.083-1.877)”

    Review

    The use of menopause hormone therapy in borderline ovarian tumor survivors: a systematic review and meta-analysis

    Climacteric : the journal of the International Menopause Society

More on Borderline ovarian tumor

Meningioma

upin humans1HR 1.21

1 study

  1. Estrogen + progestin is associated with meningioma in humans (Compared with never-use) (HR 1.21, 95% CI 1.06–1.37).

    “Compared to never-use, exposure to estrogen-progestin or progestin-only were both associated with increased risk of meningioma”

    HumansCompared with never-usefemales

    Menopausal hormone therapy and central nervous system tumors: Danish nested case-control study

    PLoS medicine

More on Meningioma

Non-Alzheimer dementia

upin humans1HR 1.25

1 study

  1. Estrogen + progestin is linked with a higher risk of non-Alzheimer dementia in humans during menopause (HR 1.25, 95% CI 1.21–1.292).

    “The use of TIB, CEPM, and oral estrogen alone increased the risk of non-AD dementia”

    Humansduring menopausecombined by the manufacturerfemales

    Menopausal hormone therapy and risk of dementia: health insurance database in South Korea-based retrospective cohort study

    Frontiers in aging neuroscience

More on Non-Alzheimer dementia

Depression

upin humans1HR 2.01

1 study

  1. Estrogen + progestin is associated with depression in humans during menopause (HR 2.01, 95% CI 1.26–3.21).

    “The risk was especially elevated the year after initiation of both treatment with estrogen alone (HR, 2.03 [95% CI, 1.21-3.41]) and estrogen combined with progestin”

    Humansduring menopausesystemicthe year after initiationfemales

    Association of Hormone Therapy With Depression During Menopause in a Cohort of Danish Women

    JAMA network open

More on Depression

Colorectal cancer

downin humans1

1 study

  1. Estrogen + progestin lowers the risk of colorectal cancer in humans (postmenopausal persons; compared with placebo) (34 fewer cases per 10,000 persons (95% CI, 9–51 fewer)).

    “Participants using estrogen plus progestin compared with placebo experienced significantly lower risks, per 10 000 persons, for colorectal cancer over 5.6 years”

    Reviewpostmenopausal persons; compared with placebo5.6 years

    Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

    JAMA

More on Colorectal cancer

Invasive breast cancer

upin humans1

1 study

  1. Estrogen + progestin raises the risk of invasive breast cancer in humans (postmenopausal persons; compared with placebo) (51 more cases per 10,000 persons (95% CI, 6–106)).

    “Risks, per 10 000 persons, were significantly increased for invasive breast cancer (242 vs 191 cases; 51 more [95% CI, 6-106])”

    Reviewpostmenopausal persons; compared with placebo5.6 years

    Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

    JAMA

More on Invasive breast cancer

Breast cancer-related mortality

downin humans1HR 0.45

1 study

  1. Estrogen + progestin is linked with a lower risk of breast cancer-related mortality in humans after adjustment for age, study, mammography, stage, and treatment (HR = 0.45 [95% CI 0.26-0.80]).

    “Estrogen-progestin therapy (EPT) use was associated with a decreased risk of BCM (after adjustment for age, study, mammography, stage, and treatment), but only among older women (ever use: ≥ 65 years: HR = 0.45 [95% CI 0.26-0.80]”

    Humansafter adjustment for age, study, mammography, stage, and treatmentfemales

    Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer

    Breast cancer research and treatment

All 11

Latest

Dec 2025: 1Jan 2026: 0Feb 2026: 3Mar 2026: 0Apr 2026: 1May 2026: 1Jun 2026: 3Jul 2026: 2Aug 2026: 1Sep 2026: 0Oct 2026: 0Nov 2026: 214 papers in 12 months
Headache

Combined hormone therapy linked to worsening headaches

Among women with migraine histories, combined therapy was linked to 1.53 times the risk of worsening headaches over one year compared with placebo.Among women with migraine histories, combined therapy was linked to 1.53 times the risk of worsening headaches over one year compared with placebo.

Randomized trial · 22,876 peopleHeadache
Paper

See all 29 papers on estrogen + progestin

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