Minimal androgenic activity of a new oral contraceptive containing norethindrone acetate and graduated doses of ethinyl estradiol.
The pharmacokinetics and androgenic activity of Estrostep, a new oral contraceptive providing low-dose estrogen in a graduated sequence with a constant dose of progestin, were characterized in an open-label, nonrandomized study in 17 normally cycling women treated for three cycles with Estrostep. Women received 1 mg of norethindrone acetate daily combined with 20 microg of ethinyl estradiol daily for the first 5 days (1/20), 30 microg of ethinyl estradiol daily for the next 7 days (1/30), and 35 microg of ethinyl estradiol daily for 9 days (1/35). No medication was given for 7 days in each cycle to allow for withdrawal bleeding. Serial blood samples for the measurement of ethinyl estradiol and norethindrone concentrations were collected on days 5, 12, and 21 of the third treatment cycle for the 1/20, 1/30, and 1/35 dose, respectively. Sex hormone-binding globulin (SHBG) and free testosterone were measured at baseline, on day 1 of cycles 2 and 3 (SHBG only), and on days 5, 12, and 21 of cycle 3. Mean steady-state plasma ethinyl estradiol and norethindrone concentrations increased over cycle 3. The increases in ethinyl estradiol concentrations were proportional to dose. The increases in norethindrone concentrations were related to ethinyl estradiol-dependent increases in SHBG concentrations, which were 218%, 253%, and 296% of baseline values on days 5, 12, and 21, respectively. Mean plasma free testosterone concentrations decreased 47%, 60%, and 64% below baseline on days 5, 12, and 21 of cycle 3, respectively. Graduated ethinyl estradiol doses combined with a constant norethindrone acetate dose progressively increase SHBG and decrease free testosterone, which overrides any theoretic concerns of androgenic activity of norethindrone acetate. Although true androgenic activity can be determined only by assessing endpoints such as acne, hirsutism, and lipids in large controlled trials, the observed changes in circulating SHBG and free testosterone concentrations indicate that Estrostep has little, if any, intrinsic androgenic activity.
Boyd
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RA
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research & Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA. Rebecca.Boyd@pfizer.com
Zegarac
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EA
Posvar
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Flack
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MR
D000328:Adult; D000728:Androgens / Q000097:blood* / Q000494:pharmacology*; D003276:Contraceptives, Oral / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D009640:Norethindrone / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000077563:Norethindrone Acetate; D012738:Sex Hormone-Binding Globulin / Q000032:analysis; D013739:Testosterone / Q000097:blood
D000728:Androgens; D003276:Contraceptives, Oral; D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D004997:Ethinyl Estradiol; D000077563:Norethindrone Acetate; D009640:Norethindrone