Progestins

BackgroundPublished 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 We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.MethodsPrincipal analyses used individual participant data from all eligible prospective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.FindingsDuring 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 pInterpretationIf 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.FundingCancer Research UK and the Medical Research Council.

Sex hormones are key determinants of gender-related differences and regulate growth and development during puberty. They also exert a broad range modulation of immune cell functions, and a dichotomy exists in the immune response between the sexes. Both clinical and animal models have demonstrated that androgens, estrogens, and progestogens mediate many of the gender-specific differences in immune responses, from the susceptibility to infectious diseases to the prevalence of autoimmune disorders. Androgens and progestogens mainly promote immunosuppressive or immunomodulatory effects, whereas estrogens enhance humoral immunity both in men and in women. This study summarizes the available evidence regarding the physiological effects of sex hormones on human immune cell function and the underlying biological mechanisms, focusing on gender differences triggered by different amounts of androgens between males and females.

BackgroundThere remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes.Methods and findingsWe searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p ConclusionsMHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

Uterine fibroids are benign tumors with high incidence and recurrence rates that still pose significant treatment challenges. Traditionally, it has been believed that estrogen and progesterone primarily drive the development and progression of uterine fibroids. Recent studies have revealed that hormonal imbalance can affect reactive oxygen species production and trigger a significant oxidative stress (OS) state. The OS status in uterine fibroids can further amplify the pathological effects caused by hormonal imbalance. This suggests that estrogen, progesterone, and OS may interact to form an estrogen-progesterone-oxidative stress (E-P-OS) network, collectively promoting the progression of uterine fibroids. This network model provides a theoretical basis for the high recurrence rates following hormone monotherapy or surgery. Therefore, we reviewed the molecular mechanisms underlying hormone-OS interactions within the E-P-OS network and elucidated its pathological effects in promoting uterine fibroid progression. The integrated perspective lays the theoretical foundation for developing novel therapies that simultaneously block hormone signaling and counteract oxidative damage. Additionally, we summarized current clinical strategies for hormone therapy and antioxidant treatment, identified potential combination therapy approaches, and explored key challenges in their clinical translation. This aims to provide new directions and evidence for advancing the precision treatment of uterine fibroids.