Changes in Physiologically Free Circulating Estradiol and Testosterone during Exposure to Levonorgestrel*

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Abstract
The biological activity of circulating sex steroids is dependent upon the relative binding to sex hormone-binding globulin (SHBG). Only that fraction which is not specifically bound to the high affinity binding protein is available to the receptors or for metabolism. Levonorgestrel (d-Ng), a synthetic gestagen used for contraception, decreases hepatic production of SHBG. Volunteers wearing contraceptive vaginal rings containing estradiol (E2) and d-Ng were studied to determine the changes in sex steroid binding which occur when d-Ng is administered in a sustained release fashion. The percentage of steroid not specifically bound to SHBG was measured by fractionating the serum proteins with ammonium sulfate precipitation. A binding capacity assay was used to quantitate SHBG. During normal menstrual cycles in control subjects, the unbound fractions of both E2 and testosterone (T) remained constant throughout the cycle at about 25% of total E2 and 10% of total T. During treatment with d-Ng the percentage of unbound E2 increased to about 80% of the total, and that of T increased to .apprx. 55% of the total, significantly greater than that in the control cycles (P < 0.01). SHBG was constant during the normal menstrual cycle, averaging 85.9 .+-. 1.92 nM, but was suppressed during the administration of d-Ng to 10.0 .+-. 2.6 nM. When SHBG concentration was greater than 50 nM, the percent binding of both E2 and T were independent of the concentration of this binding protein. When SHBG was suppressed below 50 nM, the percentage binding of E2 and T was directly related to the concentration of the binding protein. The affinity of SHBG for d-NG [apparent Ka (KA(app)) = 1.4 .times. 109 M-1] allows competition with E2 (KA(app) = 0.47 .times. 109 M-1) and T (KA(app) = 1.7 .times. 109 M-1) for SHBG-binding sites at concentrations of SHBG below 50 nM. The increase in physiologically free E2 and T may be due to the suppression of SHBG concentration by d-Ng, and the competition between d-Ng and endogenous sex steroids for the decreased number of available binding sites on SHBG.