Association between estrogen and progesterone levels and premenstrual syndrome: a systematic review and meta-analysis

Premenstrual syndrome (PMS) is defined by the American College of Obstetricians and Gynecologists (ACOG) as a combination of cyclical physical, psychological, and behavioral symptoms occurring during the luteal phase of the menstrual cycle and resolving after menstruation. Prevalence estimates range from 15% to 50%, with a meta-analysis reporting 47.8%, contributing to reduced productivity and increased work absenteeism. Although hormonal variations, particularly estrogen and progesterone, have been implicated since Robert Frank’s 1931 description of premenstrual tension, underlying mechanisms remain debated due to inconsistent study findings. To assess the association between estrogen and progesterone concentrations across the menstrual cycle and PMS occurrence through a systematic review and meta-analysis. PRISMA-compliant systematic review, prospectively registered on PROSPERO (CRD42024629260), with searches from December 2024 to March 2025 in Medline (PubMed), Cochrane Library, Embase, and Lissa using MeSH terms for “Premenstrual Syndrome,” “Progesterone,” and “Estrogens”. Inclusion criteria: original observational studies in reproductive-age women, PMS diagnosis via ACOG criteria or validated scales (e.g., PAF, Premenstrual Assessment Form (PAF), Visual Analogue Scale (VAS) Daily Symptoms Reports (DSR), and the Prospective Record of the Impact and Severity of Menstrual Symptomatology (PRISM)), quantitative hormone assays (blood/saliva/urine). Exclusions: animal studies, hormonal treatments, PMDD, irrelevant hormone data. Independent dual selection and extraction by two reviewers; risk of bias via Newcastle-Ottawa Scale (NOS). Random-effects meta-analysis (SMD) for follicular and luteal phases using Jamovi v2.4. Of 681 identified articles, 27 studies were included (1959 women, mostly case-control, 13 countries), with 7 in progesterone meta-analysis and 5 for estrogen. Fifteen studies reported lower luteal progesterone in PMS cases, but meta-analysis showed no significant difference (luteal SMD: -1.07 [95%CI -2.51; 0.38], p = 0.14; I²=94.8%). For estrogen, 7 studies noted luteal elevations; meta-analysis confirmed significantly higher levels in PMS (luteal SMD: 0.42 [95%CI 0.08; 0.75], p = 0.014; I²=0%). Risk of bias was low to moderate (NOS mostly ≥ 7/9); publication bias controversial for progesterone. Elevated luteal-phase estrogen levels are associated with PMS, with no consistent progesterone differences, though limited by methodological heterogeneity (diagnostic criteria, mostly RIA assays). Multifactorial hormonal, psychological, and sociocultural interactions likely predominate; comprehensive biopsychosocial clinical approaches are recommended. PROSPERO Registration: CRD42024629260. Registered December 2024. Available at: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024629260 .