The effect of micronized progesterone and medroxyprogesterone acetate in combination with transdermal estradiol on hemostatic biomarkers in postmenopausal women diagnosed with POI and early menopause: a randomized trial

Abstract

Objective: To compare the impact of micronized progesterone (MP) or medroxyprogesterone acetate (MPA) in combination with transdermal estradiol (t-E 2 ) on traditional coagulation factors and thrombin generation parameters in postmenopausal women diagnosed with premature ovarian insufficiency or early menopause.Method: Randomized prospective trial conducted in women diagnosed with premature ovarian insufficiency or early menopause and an intact uterus, recruited over 28 months. All participants were prescribed t-E 2 and randomized to either cyclical MP or MPA using a web-based computer randomization software, Graph Pad. Thrombin generation parameters were measured at baseline and repeated after 3-months. Traditional hemostatic biomarkers were measured at baseline and repeated after 3, 6, and 12-months. Seventy-one participants were screened for the study, of whom 66 met the inclusion criteria. In total, 57 participants were randomized: 44 completed the thrombin generation assessment arm of the study, whilst 32 completed 12-months of the traditional coagulation factor screening component of the trial.Results: Thrombin generation parameters did not significantly change from baseline after 3-months duration for either progestogen component when combined with t-E 2 , unlike the traditional coagulation factors. Protein C activity, free Protein S, and Antithrombin III levels decreased with time in both treatment arms.Conclusion: Fluctuations in traditional hemostatic biomarkers were not reproduced by parallel changes in thrombin generation parameters that remained neutral in both groups compared with baseline. The absence of statistically significant changes in thrombin generation for the first 3-months of hormone therapy use is reassuring and would suggest a neutral effect of both progestogens on the global coagulation assay.

Hormone replacement therapy in women with history of thrombosis or a thrombophilia

“…30 A RCT comparing the effect of micronized progesterone and medroxyprogesterone acetate on coagulation pathway factors when combined with transdermal estradiol found both progestogens had a neutral effect. 31 These data provide a biological explanation for the epidemiological evidence that the progesterone component of HRT remains an important consideration even when prescribing non-oral HRT. 26 Although there is no robust RCT evidence available for the risk of VTE comparing the route of HRT administration in specific populations (such as women with thrombophilia), there is high quality, large scale epidemiological evidence which demonstrates that transdermal HRT, with micronised progesterone, does not seem to be associated with an increased risk of VTE in such women.…”

“…30 A RCT comparing the effect of micronized progesterone and medroxyprogesterone acetate on coagulation pathway factors when combined with transdermal estradiol found both progestogens had a neutral effect. 31 These data provide a biological explanation for the epidemiological evidence that the progesterone component of HRT remains an important consideration even when prescribing non-oral HRT. 26…”