Changes in unbound sex steroids and sex hormone binding globulin--binding capacity during oral and vaginal progestogen administration.

Four groups of five cycling women each received either a contraceptive vaginal ring containing a combination of either levonorgestrel or norethindrone with estradiol or oral contraceptives containing a combination of either dl-norgestrel or norethindrone with ethinyl estradiol. Pretreatment as well as 2- and 7-week treatment serum samples were assayed for sex hormone binding globulin-binding capacity (SHBG-BC), estradiol, non-SHBG-bound estradiol, testosterone, and non-SHBG-bound testosterone, d-norgestrel, non-SHBG-bound d-norgestrel, and norethindrone. SHBG-BC was significantly increased in the norethindrone oral contraceptive group, unchanged in the norgestrel oral contraceptive group, and significantly reduced in both contraceptive vaginal ring groups. These findings indicate that the positive effect of oral ethinyl estradiol on SHBG-BC offsets the suppressive effects of d-norgestrel on SHBG-BC, while the estradiol in the d-norgestrel or norethindrone contraceptive vaginal rings is insufficient to alter the suppressive effect of d-norgestrel or norethindrone on SHBG-BC. In contrast, the ethinyl estradiol in the norethindrone oral contraceptive overcame the suppressive effect of norethindrone on SHBG-BC, resulting in a significantly increased SHBG-BC level. Although total circulating estradiol was significantly decreased in the contraceptive vaginal ring groups, the percentage of unbound serum estradiol was significantly increased in both contraceptive vaginal ring groups and significantly reduced in the norethindrone oral contraceptive group. Although total circulating testosterone was significantly reduced only in the norgestrel oral contraceptive group, the percentage and mass of unbound testosterone were significantly decreased in the norethindrone oral contraceptive group, while the percentage of unbound testosterone was significantly reduced in the norgestrel oral contraceptive group and significantly increased in the norethindrone contraceptive vaginal ring group. As levels of unbound (biologically active) steroid differ markedly from levels of total steroid, it is essential to measure levels of non-SHBG-bound estradiol and testosterone in order to determine effects of steroidal contraceptives on physiologically active circulating endogenous steroids.