Effect of the Addition of an Oral Androgen (Dehydroepiandrosterone) on Hepatic Globulins in Users of an Antiandrogenic Combined Oral Contraceptive (Ethinyl Estradiol/Drospirenone)

While the pro-thrombotic effects of estrogens are well established in women using combined oral contraception (COC), controversy exists over whether the various synthetic progestogens (progestins) used in combination with ethinyl estradiol in COC formulations may modify the risk of venous thromboembolism (VTE). Several studies have demonstrated that different types of progestins used in COCs influence the magnitude of the estrogen-induced changes in coagulation pathway proteins. However, since hepatocytes do not express progesterone receptor, any activity of a progestin must be indirect. While all progestins on the market are strong agonists for the progesterone receptor (PR), most have variable affinity for the androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). Generations of progestins have been developed, each successive generation exhibiting decreasing levels of androgenicity. Recent epidemiologic studies have suggested an increased risk of VTE in women using low-androgen progestins relative to those using levonorgestrel-containing products. Although no pattern of hepatic globulin changes has been validated as a surrogate marker for thrombosis risk, the overall magnitude of change in various hepatic proteins involved in coagulation is greater with the newer low-androgenic progestins compared to levonorgestrel, leading some experts to suggest that a progestin's androgenic profile may influence the risk of thrombosis. However, a series of well-designed large prospective cohort studies have not confirmed the increased risk of VTE with low-androgen progestins.

A major problem with reconciling the conflicting results from epidemiologic and prospective studies has been the lack of a clear mechanism, as no studies have demonstrated whether these observed changes are mediated through androgen receptor activity. We hypothesize that androgen receptor activity opposes the estrogen receptor-mediated increase in hepatic clotting factors in women using combined oral contraceptives. To test this hypothesis, we propose a randomized clinical trial in which we will enroll healthy women using combined oral contraception containing ethinyl estradiol (EE) with an antiandrogenic progestin (drospirenone, DRSP). Participants will be randomized to treatment with oral androgen (dehydroepiandrosterone, DHEA) or placebo, and we will collect whole blood samples to measure coagulation pathway-related hepatic globulins (APC-r, Protein S, SHBG) before and after treatment.