Progesterone

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Research Overview

Current progesterone research is most developed in reproductive biology and gynecologic disease, with substantial emphasis on progesterone receptor (PR) signaling (notably PR-A and PR-B isoforms) in uterine tissues, and on clinical use of progestins and selective progesterone receptor modulators (SPRMs). Major studied areas include implantation and pregnancy maintenance, menstrual regulation, and uterine pathologies such as endometriosis, uterine fibroids (leiomyomas), and endometrial cancer biology. A parallel, increasingly prominent literature examines progesterone/progestogen contributions to breast cancer risk in the context of hormonal contraception and menopausal hormone therapy, including the hypothesis that estrogen-associated risk may be mediated indirectly through induction of PR and amplification of progesterone signaling. Additional, but comparatively less mature, work addresses progesterone in broader physiology (e.g., exercise nutrition considerations across the menstrual cycle) and in cervical cancer and recurrent pregnancy loss.

The strongest evidence supports progesterone as a central regulator of uterine function via PR-mediated transcriptional programs, with clinically relevant consequences: progesterone signaling is required for endometrial receptivity, myometrial quiescence, and cervical closure during pregnancy, and withdrawal of PR-mediated signaling is implicated in menstruation and parturition. In disease contexts, evidence is strong that progesterone signaling promotes uterine fibroid growth and that pharmacologic modulation of PR (particularly with SPRMs such as mifepristone and ulipristal acetate) can reduce fibroid-related heavy menstrual bleeding and improve fibroid outcomes, albeit with recognized class effects on the endometrium (PAECs) and safety considerations for some agents. For endometriosis, progestins are widely supported as effective first-line therapy, while a substantial body of mechanistic work supports “progesterone resistance” (impaired progesterone responsiveness) as a key contributor to treatment failure in a subset of patients. In breast cancer epidemiology, converging clinical and experimental observations summarized in these abstracts support the view that progestogens (endogenous progesterone and/or synthetic progestins) may be major drivers of the breast cancer risk signal seen with combined estrogen–progestin exposures, whereas estrogen-alone menopausal therapy appears to have little adverse effect on risk in studied populations and may be beneficial in long-term follow-up in some settings.

Key research gaps include: (i) clearer causal attribution and mechanistic resolution of progesterone versus specific synthetic progestins in breast carcinogenesis, including dose, formulation, route, timing, and tissue-specific PR signaling; (ii) deeper definition of PR-A/PR-B isoform balance, coregulators, and post-translational modifications that determine normal versus pathological uterine responses, with translation into more selective therapeutics; (iii) clinically actionable biomarkers and interventions to diagnose and reverse progesterone resistance in endometriosis; and (iv) long-term safety and comparative effectiveness data for SPRMs and other PR-modulating strategies, including effects on endometrium, liver and other off-target tissues, fertility goals, and recurrence after treatment cessation. Additional areas needing stronger evidence include progesterone’s role in cervical cancer, the immunologic mechanisms potentially linking PR function to recurrent pregnancy loss, and rigorous, sex-specific performance and nutrition studies that explicitly model progesterone fluctuations across the menstrual cycle and lifespan.

1. What conditions has Progesterone been studied for?

  • Breast cancer risk in the context of exogenous hormones: assessed indirectly via studies of hormonal contraceptives and menopausal hormone therapy (estrogen-plus-progestin vs estrogen-alone), and via mechanistic work on progesterone signaling and antiestrogen effects.

  • Endometriosis: progestins as a common therapy; also studied in the context of progesterone resistance (reduced responsiveness of endometrial tissue to progesterone signaling).

  • Uterine physiology and pregnancy-related outcomes: implantation, maintenance of pregnancy, myometrial relaxation, cervical closure; also discussed in recurrent pregnancy loss (RPL) with uncertainty about therapeutic benefit.

  • Assisted reproductive technology (ART): luteal phase support (LPS), commonly using vaginal progesterone; questions remain about optimal regimen and when it is needed.

  • Uterine fibroids (leiomyoma): progesterone signaling implicated in development and growth; therapies that modulate progesterone receptor signaling (e.g., SPRMs) studied for symptom control (including heavy menstrual bleeding).

  • Heavy menstrual bleeding (HMB): particularly HMB associated with uterine fibroids, via progesterone receptor modulators (SPRMs).

  • Endometrial cancer: progesterone receptor signaling described as tumor-suppressive in endometrial cancer cells; SPRMs have been tested but without therapeutic success per the abstract.

  • Cervical cancer: role of progesterone receptors described as unclear.

  • Mood/brain health conditions linked to hormonal fluctuations: premenstrual dysphoric disorder (PMDD), postnatal depression (PND), and menopausal depression (reviewed as hormone-influenced conditions).

  • Animal fertility (non-human evidence): intravaginal progesterone inserts studied to improve pregnancy rates in lactating dairy cows undergoing timed artificial insemination programs (meta-analysis).

  • Sports nutrition / female athlete considerations: progesterone fluctuations across the menstrual cycle considered relevant to performance and nutrition guidance (review-level discussion).

2. Does it work in treating those conditions? Summarize the evidence.

  • ART luteal phase support (LPS): The abstracts state that progesterone LPS is the standard of care in assisted reproductive technology and that vaginal progesterone is the most widely used. However, the review notes ongoing uncertainties (need for LPS in fresh vs frozen transfer, route, duration, dose, and combination therapy), indicating that while it is established practice, optimization and subgroup benefit remain active questions.

  • Endometriosis symptom treatment (progestins): Progestins are described as the most commonly used treatment with “excellent therapeutic effects” and limited side effects, but some symptomatic patients do not respond, attributed to progesterone resistance. This supports effectiveness for many patients but highlights a meaningful non-responder subgroup.

  • Uterine fibroids / heavy menstrual bleeding (via SPRMs): In uterine fibroids, multiple SPRMs (mifepristone, ulipristal acetate, vilaprisan, asoprisnil) are reported to effectively treat heavy menstrual bleeding and show consistent efficacy for fibroids (notably mifepristone and ulipristal acetate; vilaprisan under investigation). Safety concerns halted some agents (asoprisnil, telapristone) in studies, indicating efficacy signals but incomplete safety acceptability for some compounds.

  • Endometrial cancer (SPRMs): The SPRM review states that none have shown therapeutic success in treating endometrial cancer, despite mechanistic discussion elsewhere that ligand-activated progesterone receptors can act as tumor suppressors in endometrial cancer cells. This suggests a gap between mechanistic rationale and clinical success for SPRMs in this indication (based on the abstracts provided).

  • Recurrent pregnancy loss (RPL): The progesterone receptor review notes progesterone/PRs likely regulate implantation and immunogenic factors relevant to RPL, but the exact role and the use of progesterone for therapeutic benefit remains uncertain—i.e., evidence is not definitive in the abstract.

  • Mood disorders linked to hormonal fluctuations (PMDD, PND, menopausal depression): The neurobiology review states there is increasing evidence that hormonal fluctuations contribute to onset/progression and discusses therapeutic approaches, but the abstract does not provide specific trial outcomes for progesterone treatment itself. Evidence in the provided text is therefore conceptual/associative rather than demonstrating efficacy of progesterone supplementation.

  • Animal fertility (dairy cows): A meta-analysis of 25 randomized controlled studies found progesterone supplementation via a single intravaginal insert increased pregnancy per AI (day 32 RR 1.08, 95% CI 1.02–1.14; day 60 RR 1.10, 95% CI 1.03–1.17), with larger benefit in cows lacking a corpus luteum at protocol initiation (day 60 RR 1.18, 95% CI 1.07–1.30). It also tended to reduce pregnancy loss (RR 0.84, 95% CI 0.67–1.00). This is strong evidence in a non-human context and may not directly translate to humans.

  • Breast cancer risk in hormone therapy contexts: The breast cancer abstract argues that progestogens (progesterone/progestins) appear to be the primary driver of the increased breast cancer risk seen with some “estrogen-associated” exposures. It cites that estrogen-plus-progestin HRT consistently increases breast cancer risk, while estrogen-alone HRT has little impact and WHI long-term follow-up suggests a benefit for estrogen alone. This does not evaluate progesterone as a treatment, but it supports clinically relevant risk differences by regimen.

3. What health benefits does it have?

  • Essential reproductive functions: Progesterone is described as a key regulator that prepares the uterus for implantation and supports establishment and maintenance of pregnancy, mediated through progesterone receptor isoforms PR-A and PR-B.

  • Pregnancy maintenance physiology: During pregnancy, progesterone via progesterone receptors promotes myometrial relaxation and cervical closure; withdrawal of PR-mediated signaling triggers menstruation and parturition.

  • Counterbalancing estrogen-driven proliferation in endometrium: PR-mediated progesterone signaling is described as anti-mitogenic in endometrial epithelial cells, mitigating estrogen’s trophic effects on normal endometrium and ectopic implants in endometriosis.

  • Clinical utility in fertility care: Progesterone luteal phase support is described as standard of care in ART, with vaginal administration widely used.

  • Therapeutic benefit via progesterone pathway modulation (SPRMs): SPRMs have demonstrated efficacy for uterine fibroids and fibroid-associated heavy menstrual bleeding (per the SPRM abstract), reflecting a benefit of targeting progesterone signaling in selected gynecologic conditions.

4. Does it have any downsides or side effects?

  • Potential increased breast cancer risk with progestogens in certain regimens: The breast cancer abstract states that the increased breast cancer risk seen with hormonal contraceptives is “mainly attributable to progestins,” and that estrogen-plus-progestin HRT consistently increases breast cancer risk in postmenopausal women, whereas estrogen-alone HRT has little impact. This frames a key potential downside of progestogen exposure depending on formulation, population, and context.

  • Progesterone resistance (loss of response): In endometriosis, some patients fail progestin therapy due to progesterone resistance, linked in the abstract to abnormal progesterone receptor signaling, chronic inflammation, aberrant gene expression, epigenetic alterations, and environmental toxins. This is a limitation/downsides in effectiveness rather than a classic adverse effect.

  • Fibroid growth promotion: Progesterone via PR activation is described as appearing to increase leiomyoma (fibroid) growth, and another review states progesterone signaling plays a crucial role in fibroid development and growth by activating multiple pathways. This suggests progesterone signaling can be detrimental in fibroid biology (even though PR modulators can be therapeutic depending on agonist/antagonist balance).

  • SPRM class effects and safety concerns: SPRMs are associated with benign PR modulator-associated endometrial changes (PAECs). Additionally, studies of some SPRMs (asoprisnil and telapristone) were halted for safety concerns (the abstract does not specify the exact adverse events). This indicates that manipulating progesterone signaling can carry clinically important risks depending on the agent.

  • Uncertainty in some indications: For recurrent pregnancy loss and cervical cancer, the abstracts emphasize uncertainty about progesterone’s role/benefit, which is a practical downside (insufficient evidence to guide clear benefit-risk decisions from these abstracts alone).

5. Is it beneficial or harmful for any genetic variations (pharmacogenomics)?

The provided abstracts do not report specific pharmacogenomic findings (e.g., progesterone receptor gene variants, metabolizing enzyme polymorphisms, or genotype-stratified outcomes) that demonstrate clear benefit or harm of progesterone/progestins by genetic variation.

  • Mechanistic relevance but no variant-specific outcomes: The uterine PR review emphasizes that progesterone effects depend on PR-A vs PR-B levels, transcriptional coregulators, and post-translational modifications, and that aberrant PR expression/function contributes to pathology. However, it does not link these differences to inherited genetic variants or provide genotype-guided treatment evidence.

  • Clinical implication: Based on these abstracts alone, there is insufficient evidence to recommend progesterone/progestin or SPRM selection or dosing based on genetic testing.

References

  1. Estrogens and breast cancer.
    J Kim, P N Munster (2025) - Annals of oncology : official journal of the European Society for Medical Oncology
  2. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms.
    Ping Zhang, Guoyun Wang (2023) - International journal of molecular sciences
  3. Role of nuclear progesterone receptor isoforms in uterine pathophysiology.
    Bansari Patel, Sonia Elguero, Suruchi Thakore, Wissam Dahoud, Mohamed Bedaiwy, Sam Mesiano (2015) - Human reproduction update
  4. Sex differences and considerations for female specific nutritional strategies: a narrative review.
    Kealey J Wohlgemuth, Luke R Arieta, Gabrielle J Brewer, Andrew L Hoselton, Lacey M Gould, Abbie E Smith-Ryan (2021) - Journal of the International Society of Sports Nutrition
  5. Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics.
    Mohamed Ali, Michał Ciebiera, Somayeh Vafaei, Samar Alkhrait, Hsin-Yuan Chen, Yi-Fen Chiang, Ko-Chieh Huang, Stepan Feduniw, Shih-Min Hsia, Ayman Al-Hendy (2023) - Cells
  6. Selective Progesterone Receptor Modulators-Mechanisms and Therapeutic Utility.
    Md Soriful Islam, Sadia Afrin, Sara Isabel Jones, James Segars (2020) - Endocrine reviews
  7. Progesterone: The Key Factor of the Beginning of Life.
    Carlo Bulletti, Francesco Maria Bulletti, Romualdo Sciorio, Maurizio Guido (2022) - International journal of molecular sciences
  8. Meta-analysis of progesterone supplementation during timed artificial insemination programs in dairy cows.
    R S Bisinotto, I J Lean, W W Thatcher, J E P Santos (2015) - Journal of dairy science
  9. Using estrogen and progesterone to treat premenstrual dysphoric disorder, postnatal depression and menopausal depression.
    Eveline Mu, Lauren Chiu, Jayashri Kulkarni (2025) - Frontiers in pharmacology
  10. The inadequate corpus luteum.
    W Colin Duncan (2021) - Reproduction & fertility
  11. Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT.
    Arri Coomarasamy, Hoda M Harb, Adam J Devall, Versha Cheed, Tracy E Roberts, Ilias Goranitis, Chidubem B Ogwulu, Helen M Williams, Ioannis D Gallos, Abey Eapen, Jane P Daniels, Amna Ahmed, Ruth Bender-Atik, Kalsang Bhatia, Cecilia Bottomley, Jane Brewin, Meenakshi Choudhary, Fiona Crosfill, Shilpa Deb, W Colin Duncan, Andrew Ewer, Kim Hinshaw, Thomas Holland, Feras Izzat, Jemma Johns, Mary-Ann Lumsden, Padma Manda, Jane E Norman, Natalie Nunes, Caroline E Overton, Kathiuska Kriedt, Siobhan Quenby, Sandhya Rao, Jackie Ross, Anupama Shahid, Martyn Underwood, Nirmala Vaithilingham, Linda Watkins, Catherine Wykes, Andrew W Horne, Davor Jurkovic, Lee J Middleton (2020) - Health technology assessment (Winchester, England)
  12. Allopregnanolone: state of the art.
    Roberto Cosimo Melcangi, Gian Carlo Panzica (2014) - Progress in neurobiology
  13. Clostridium innocuum, an opportunistic gut pathogen, inactivates host gut progesterone and arrests ovarian follicular development.
    Mei-Jou Chen, Chia-Hung Chou, Tsun-Hsien Hsiao, Tien-Yu Wu, Chi-Ying Li, Yi-Lung Chen, Kuang-Han Chao, Tzong-Huei Lee, Ronnie G Gicana, Chao-Jen Shih, Guo-Jie Brandon-Mong, Yi-Li Lai, Po-Ting Li, Yu-Lin Tseng, Po-Hsiang Wang, Yin-Ru Chiang (2024) - Gut microbes
  14. Progesterone Receptor Activation Regulates Sensory Sensitivity and Migraine Susceptibility.
    Suchitra Joshi, John Williamson, Shayan Moosa, Jaideep Kapur (2024) - The journal of pain
  15. Sporadic pregnancy loss and recurrent miscarriage.
    Adam J Devall, Arri Coomarasamy (2020) - Best practice & research. Clinical obstetrics & gynaecology
  16. Hormonal modulation of the immune system - A spotlight on the role of progestogens.
    Irene J Tan, Elena Peeva, Gisele Zandman-Goddard (2015) - Autoimmunity reviews
  17. Progesterone use in assisted reproductive technology.
    Elena Labarta, Cristina Rodríguez (2020) - Best practice & research. Clinical obstetrics & gynaecology
  18. Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study.
    Bushra Wali, Tauheed Ishrat, Soonmi Won, Donald G Stein, Iqbal Sayeed (2014) - Brain : a journal of neurology
  19. FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer.
    Darcie D Seachrist, Lindsey J Anstine, Ruth A Keri (2021) - Cancers
  20. Centering the Needs of Transgender, Nonbinary, and Gender-Diverse Populations in Neuroendocrine Models of Gender-Affirming Hormone Therapy.
    Krisha Aghi, Teddy G Goetz, Daniel R Pfau, Simón E D Sun, Troy A Roepke, Eartha Mae Guthman (2022) - Biological psychiatry. Cognitive neuroscience and neuroimaging


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