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Prg4.4
Progesterone Research
Mostly mechanism / observationalModerate safety
30 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Progesterone studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from high-quality meta-analyses and randomised trials published 1996–2026 with a typical study size of 266 participants.
Based on 30 studies · 11 meta-analyses · 6 RCTs · 53,320 total participants
Confidence
High
By outcome
Endometrial protection & menopause
Mostly mechanism / observational17 studies
Luteal support & early pregnancy
Mostly mechanism / observational8 studies
Safety profile
Mostly mechanism / observational6 studies
Sleep (menopausal)
Too few graded studies1 study
Depression & mood
Too few graded studies1 study
Active research area
23 studies in the last 5 years · Latest meta-analysis: 2026
199620112026
1Meta-Analysisn=4,341 · very large study2026
The addition of PD-1 or PD-L1 inhibitors probably increases immune-related SAEs.
Gao Y, Liu M, Li L, Zhang J, Song F, Tian J. · The Cochrane database of systematic reviews (2026)
Background Triple-negative breast cancer (TNBC), an aggressive subtype lacking oestrogen and progesterone receptors and amplification of HER2 receptors, accounts for 12% to 17% of breast cancers.
Adjuvant and neoadjuvant chemotherapy improve survival; however, 30% to 40% of early-stage TNBC cases progress to metastatic disease.
We calculated hazard ratios (HRs) for time-to-event data, risk ratios (RRs), odds ratios (ORs), or risk differences (RDs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes with corresponding 95% confidence intervals (CIs).
This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high-risk cohort.
Hodgetts Morton V, Morris K, Toozs-Hobson P, Middleton L, Pilarski N, Bell L, Hogg M, Man R, Israfil-Bayli F, Shennan A, Simpson N, Lees C, Moakes C. · PLoS medicine (2026)
From the 2,048 women recruited to C-STICH, 1943 (95%) women had a vaginal cerclage placed and available progesterone data.
Of these, 834 (43%) women received progesterone and 1,109 (57%) did not receive progesterone.
Further exploratory analysis excluding women who had termination of pregnancy for foetal anomaly demonstrated a nonsignificant reduction in the risk of pregnancy loss.
It also reduced gonadotropin (Gn) dose (P = 0.0002), Gn duration (P = 0.005), and OHSS incidence (P < 0.01).
Conclusions Our results showed that acupuncture therapy could increase the high-quality embryo rate, live birth rate and also the clinical pregnancy rate in PCOS patients undergoing IVF.
Conclusion Our study was able to demonstrate the benefit of progesterone in significantly reducing the risk of adverse neonatal outcomes.
Fernandes Dias M, Do O De Souto Neto M, Alves Duarte H, Gomes de Albuquerque Neto A, Medeiros Cabral IM. · International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics (2026)
Main results We included 12 randomized studies with 1557 participants, of whom 888 (57.3%) were randomized to receive progesterone therapy.
Conclusion Our study was able to demonstrate the benefit of progesterone in significantly reducing the risk of adverse neonatal outcomes.
The meta-analysis calculations were performed using the meta package in Rstudio, version 4.2.2 (R Foundation for Statistical Computing).
In conclusion, significant differences in serum progesterone concentration exist between different vaginal progesterone products and dosing regimens, which must be taken into account when performing HRT-FET.
Alsbjerg B, Humaidan P. · Reproductive biomedicine online (2025)
Significant differences were found when comparing Cyclogest (800 mg) with Crinone (180 mg or 270 mg) (P = 0.01); Cyclogest (800 mg) with Utrogestan/Progestan (600 mg or 800 mg) (P = 0.03); and Cyclogest (800 mg) with Lutinus (300 mg) (P = 0.01).
A random-effects proportional meta-analysis of five different vaginal micronized progesterone products was performed, including a total of 11,014 patients.
However, no significant differences were identified between products with an equivalent daily dose.
Protocol registration International Prospective Register of Systematic Reviews (PROSPERO), CRD42023476525.
Santiago FR, Celovska D, Thomis S, Blanc-Guillemaud V, Onselaer MB, Serifou S, Yaltirik HP, Bokuchava M. · Clinical drug investigation (2026)
Secondary outcomes included all dimensions of QoL score (pain, physical, social, and psychological) and CVD symptom scores (using 10-cm visual analog scale [VAS]) and percentage of patients with complete resolution for heaviness and cramps.
These studies conducted worldwide included 5654 patients allocated to MPFF treatment; nearly all (99.6%) were treated for at least 2 months.
Mean (standard deviation [SD]) age was 45.6 (6.7) years, with mostly females (81.3%) and overweight (body mass index [BMI] of 25.9 [3.5] kg/m 2 ) patients.
Conclusion L1 cell adhesion molecule overexpression, estrogen receptor positivity, and progesterone receptor status demonstrate considerable prognostic relevance in no specific molecular profile endometrial cancer, warranting consideration as potential markers for improving patient management, including fertility-sparing approach.
Ferrari F, Ferrari F, Gozzini E, Torroni L, Rota M, Soleymani Majd H, Dell'Avalle C, Ferrari FA, Odicino F. · American journal of obstetrics and gynecology (2026)
Collectively, these findings support the integration of precision medicine through SPRMs with the broader therapeutic benefits offered by plant-derived compounds.
Purnamasari HY, Rahmasari R, Gusmira A, A M Sitorus FL, Mun'im A, Elya B, Setiawan H, Khayrani AC. · Reproductive biology (2026)
Fully antagonistic SPRMs may provide potency and receptor selectivity, whereas partial antagonists may offer superior endometrial tolerability for long-term use.
All novel SPRMs are non-steroidal and lack the dimethylaminophenyl moiety, which may enhance their safety and tolerability.
Plant-derived agents could serve as adjunctive or alternative therapies through their multi-pathway actions.
This is important since the gene coding for PTHrP (PTHLH) has been consistently identified as a breast cancer susceptibility locus.
Clemenceau A, Bherer J, Grimshaw A, Durocher F, Diorio C, Wysolmerski JJ. · Endocrine-related cancer (2026)
Most studies interrogating the association between PTHrP expression and breast cancer prognosis or hypercalcemia were at a very high risk of bias.
Despite this, our results suggest associations between PTHrP and patient survival, the presence of bone metastases and the diagnosis of hypercalcemia of malignancy.
These meta-analyses underscore the need for robust multivariate analyses in women to rigorously re-evaluate the role of PTHrP in breast cancer.
The impact of testosterone and sex hormones in hemorrhagic stroke remain inconclusive due to lack of research.
Kung TFC, Suerte ACC, Khiabani E, Parranto M, Gannon Arnott S, Kalisvaart ACJ, Nakagawa S, Klahr AC, Colbourne F. · Biology of sex differences (2026)
Estrogen and progesterone improved all post-AIS outcomes (SMDs = 0.32-1.30, 95% CIs [0.02, 2.07], very low to moderate certainty of evidence), whereas testosterone had mostly null effects (very low to moderate certainty).
Sex and gonadal status were consistent moderators of these effects, and gonadal depletion length (i.e., the 'timing hypothesis') was a significant moderator of estrogen's effect on post-AIS injury volume.
Conclusions Estrogen and progesterone are promising cerebroprotectants for AIS.
This narrative review provides an updated overview of the clinical benefits of HRT regimens based on E2/P4, with a focus on their impact on endometrial thickness, venous thromboembolism (VTE), cardiovascular diseases (CVDs), breast cancer risk, cognitive effects, bone protection, and quality of life (QoL).
Foschi M, Groccia G, Rusce ML, Medaglia C, Aio C, Sponzilli A, Setti V, Battipaglia C, Genazzani AD. · Journal of clinical medicine (2025)
Standard regimens generally combine 17β-estradiol (E2) or conjugated equine estrogens (CEEs) with micronized progesterone (P4) or synthetic progestins.
While synthetic progestins ensure endometrial protection against estrogen-induced stimulation of the endometrium, their impact on metabolic, cardiovascular, skeletal, and cognitive systems is heterogeneous and not always beneficial.
In contrast, progesterone, as a micronized preparation (P4), allows for more physiological effects because it is chemically identical to endogenous progesterone.
Conclusions This comprehensive meta-analysis provides additional evidence supporting the effectiveness of MPFF in improving clinical signs of CVD across all stages of the disease.
Nicolaides A, Lobastov K, Mansilha A, Gonzalez-Ochoa AJ, Blanc-Guillemaud V, Onselaer MB, Serifou S, Yaltirik HP, Sriram N, Guo L, Kakkos S. · International angiology : a journal of the International Union of Angiology (2025)
Included participants were mainly females (84.1%) with a mean age (±SD) of 48.6 (±8.8) years, and overweight with a mean BMI of 26.3 (±4.5) kg/m 2 .
Significant reductions were observed in mean [95% confidence interval] ankle and calf circumferences (-7.6 mm [-9.1 to -6.2] and -8.0 mm [-11.2 to -4.8], respectively, P<0.001).
Venous ulcers were healed in 48.9% [30.3% to 67.8%] or regressed in 73.4% [63.3% to 82.3%] of the patients (P<0.001).
Conclusions Individualized luteal phase support with DYD supplementation in patients with low luteal serum P4 levels during an HRT cycle for FET achieves LBR comparable to those observed in patients with adequate serum P4 levels, both in this cohort study and in a complementary meta-analysis.
Cucchietti O, Mollevi C, Moulis L, Anahory T, Huberlant S, Brouillet S, Ranisavljevic N, Duraes M. · Journal of assisted reproduction and genetics (2025)
Results Insufficient P4 levels were observed in 28.9% (159/550) of the studied cycles.
LBR was comparable in both groups (24.16% [94/391] in group 1 and 27.22% [43/159] in group 2) and was not associated with the luteal support strategy (aOR 1.01, 95% CI [0.65-1.58], p = 0.96).
In the meta-analysis, the ongoing pregnancy rate was similar in both groups (aOR 1.14, 95% CI [0.91-1.42]).
Conclusions This systematic review and meta-analysis provide strong evidence of consistent and clinically significant improvements in venous leg symptoms associated with the use of the venoactive drug MPFF, across all stages of CVD.
Nicolaides A, Lobastov K, Mansilha A, Gonzalez-Ochoa AJ, Blanc-Guillemaud V, Onselaer MB, Serifou S, Yaltirik HP, Sriram N, Guo L, Kakkos S. · International angiology : a journal of the International Union of Angiology (2025)
Significant reductions in symptom intensity scores were observed for all outcomes (P<0.001), except for fatigue.
Improvement of symptoms was further supported by the resolution of pain, heaviness, cramps, discomfort, and burning sensation observed in pooled estimated proportion of patients (76.2%, 61.5%, 80.5%, 69.8%, and 67.2%, respectively; all P<0.001).
The overall level of patient satisfaction was estimated to be more than 90%.
Given the differences in pharmacological profiles, varying dosages and more frequent administration of DYD may also warrant exploration.
Roelens C, Mackens S, Drakopoulos P, Van Landuyt L, De Vos M, Tournaye H, Blockeel C. · Frontiers in endocrinology (2026)
OPR was 31·5% with DYD vs 45·2% with MVP (p=0·09; difference -13%, 95% CI -38 to 12).
ITT analysis was consistent (31·1% vs 44·7%).
Conclusion Although not statistically significant, the results of this pilot prospective randomized controlled trial may have clinical implications and highlight the need for larger studies investigating the ideal dose and administration route of different LPS medications in AC-FET cycles.
This combined therapy appears to be a safe and effective complementary approach for improving lactation in women with postpartum hypogalactia.
Li K, Cai D, Gao Z, Liang X, Zhang D, Niu Y. · African journal of reproductive health (2026)
Both groups showed significant post-treatment improvements (P<0.05).
Compared with the control group, the intervention group demonstrated lower estradiol and progesterone levels, higher prolactin levels, increased milk production, and reduced formula supplementation (P<0.05).
Symptom scores and anxiety/depression levels were also significantly improved.
Vaginal absorption of progesterone was similar regardless of whether a male condom was used.
Ranisavljevic N, Rolland A, Picot MC, Lotierzo M, Herman F, Duraes M, Brouillet S, Anahory T. · Reproductive biomedicine online (2026)
The linear mixed model showed no significant effect for condom use to affect the variation in progesterone levels (P = 0.08).
On average, serum progesterone levels were 0.21 ng/ml (± 5.26) lower after an unprotected intercourse compared with sexual abstinence; serum progesterone levels were 1.52 ng/ml (± 5.09) higher after an intercourse with a condom compared with sexual abstinence.
Conclusion Sexual intercourse did not significantly affect serum progesterone levels during an HRT cycle using vaginal progesterone suppositories.
Berlanda N, Bandini V, Croci GA, Dridi D, Nobili MV, Cipriani S, Vercellini P. · Human reproduction (Oxford, England) (2026)
Main results and the role of chance A histological morphological response to chronic progestogen treatment, defined by the presence of stromal atrophy and absence of active glands, was observed in 29/36 (80.5%) clinical responders and 16/19 (84.2%) non-responders.
Furthermore, no statistically significant between-group differences were observed in progesterone receptor (PR), oestrogen receptor (ER), and CD15 expression.
N.B. and P.V. have received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate, and both maintain a private gynaecological practice.
Clinical trial registration This study was registered with ClinicalTrials.gov, and its registration number is NCT06184438.
Tsai YW, Kiu KT, Chang TC. · Techniques in coloproctology (2026)
Additionally, the frequency of dressing changes was reduced in the MPFF group relative to the control group from day 1 to day 7 post-surgery, with statistically significant differences observed from day 4 onward (day 4, P = 0.036; day 5, P = 0.012; day 6, P = 0.012; day 7, P = 0.012).
Secondary outcomes, including analgesic use, wound healing, and postoperative complications such as infection, bleeding, urinary retention, delayed healing, and recurrence, showed no significant differences between groups.
No patient required re-intervention for hemorrhage.
Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.
Kantarci K, Kara F, Tosakulwong N, Fought AJ, Schwarz CG, Senjem ML, Kendall-Thomas J, Min P, Lowe VJ, Jack CR, Kapoor E, Fields JA, Bailey KR, James TT, Faubion L, Lobo RA, Manson JE, Pal L, Hammers DB, Brinton EA, Malek-Ahmadi M, Cedars MI, Naftolin FN, Santoro N, Miller VM, Harman SM, Dowling NM, Gleason CE. · Alzheimer's & dementia : the journal of the Alzheimer's Association (2026)
Findings support the long-term safety of short-term use of mHT on brain health.
Clinical trials registration NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) HIGHLIGHTS: There were no menopausal hormone therapy-related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term.
Apolipoprotein E ε4 carrier status did not modify these findings.