How DHEA Supplements Affect Coagulation in Women Using Birth Control Pills

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.

Inclusion Criteria:

- Women of reproductive age (18-44 years) in generally good health and with body mass
index (BMI) between 18 and 35kg/m2

- Premenopausal, with uterus and at least one ovary intact

- Current users (at least 3 months) of combined oral contraception consisting of 0.02 mg
(milligram) ethinyl estradiol and 3 mg drospirenone

- Willing to continue use of current combined oral contraception for the next three
menstrual cycles

- Have a prescription for combined oral contraception consisting of ethinyl estradiol
and drospirenone for the next four cycles

- Not currently using androgen supplementation

- Willing and able to sign the informed consent

- Willing to comply with the study requirements and visit schedule

- No desire to conceive during study participation, approximately 3 months

Exclusion Criteria:

- Currently enrolled in another clinical trial

- Contraindications to androgen supplementation; history of polycystic ovarian syndrome
(PCOS)

- Known or suspected pregnancy, pregnancy within 3 months before study enrollment, or
desire to conceive during study participation

- Currently breastfeeding

- Known or suspected alcoholism or drug abuse