Progestogen safety and tolerance in hormonal replacement therapy.

Introduction: Today, it is a mandatory practice to prescribe a combination of estrogens and progestogens for menopausal women requiring hormone therapy and with a uterus. The WHI study and its reanalysis demonstrate a big difference in results between the conjugated equin estrogen (CEE) only vs.CEE plus medroxyprogesterone acetate (MPA) arms in relation with breast cancer and cardiovascular risk. The conclusion is that risk is clearly higher in the arm with MPA than in the CEE only arm. Although the only progestogen used in the WHI study was medroxyprogesterone acetate, side effects and intolerance have been extrapolated as a class effect to all progestogens. Areas covered: Progestogen tolerance and side effects in hormone therapy were reviewed. For that purpose, a limited literature search was conducted on key resources including Pubmed, the Cochrane Library, ECRI, and major international health technology agencies. Expert opinion: Many of the tolerance effects are based on limited data. There are no double-blind randomized trials comparing long-term safety for breast cancer and cardiovascular risk among different progestogens. Short-term clinical studies, observational, and in animal and in vitro studies indicate that both micronized progesterone and dydrogesterone are the safer progestogens with an acceptable metabolic profile.