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Late follicular phase administration of mifepristone suppresses circulating leptin and FSH – mechanism(s) of action in emergency contraception?

¹ Department of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland, ² Biomedicum Helsinki, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland, ³ Hospital for Children and Adolescents, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, ⁴ Biomedicum Helsinki, Institute of Biomedicine/Biochemistry, University of Helsinki, Helsinki, Finland, ⁵ The Concept Foundation, Bangkok, Thailand, ⁶ WHO, UNDP/UNFPA, Geneva, Switzerland and ⁷ Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland

(Correspondence should be addressed to O Heikinheimo, Department of Obstetrics and Gynaecology, University of Helsinki, PO Box 140, FI-00029, HUS, Finland; Email: oskari.heikinheimo{at}helsinki.fi)

Objective: Low dose mifepristone (RU486) is highly effective in emergency post-coital contraception (EC), although the mechanism(s) of action remains unclear. We studied the endocrine actions of 10 mg mifepristone administered orally as a single dose to eight healthy volunteers (aged 20–45 years) during the late follicular phase.

Methods: Serum levels of LH, FSH, oestradiol, progesterone, leptin, mifepristone, cortisol, and gluco-corticoid bioactivity (GBA) were measured before and 1, 2, 4 and 8 h after ingestion of mifepristone on cycle day 10 or 11 (study day 1), and follow-up was continued for 10 days. Ovarian ultrasonography was performed on study days 1 and 7. Similar measurements were carried out during a control cycle.

Results: Mifepristone postponed ovulation, as evidenced by a 3.4±1.1 day (means±S.D.) delay (P < 0.005) in the LH surge and 3.6±4.0 day prolongation of the treatment cycle (P = 0.08). During the mifepristone cycle, an LH surge was displayed by five subjects when serum mifepristone levels had declined to 9.5±7.1 nmol/l. During the day of mifepristone administration, circulating GBA (P < 0.001) and leptin (P < 0.001) levels declined. On the day after mifepristone administration, mean serum FSH and leptin levels were lower than pretreatment values (3.8±1.8 IU/l vs 5.2±1.1 IU/l, n = 7, P < 0.05; 28.9±6.7 µg/l vs 33.2±9.0 µg/l, n = 7, P < 0.05 respectively), and the corresponding difference in the mean serum oestradiol concentration was borderline (452±252 pmol/l vs 647±406 pmol/l, n = 7, P = 0.056). In contrast to the control cycle, individual leptin levels declined during the follow-up after ingestion of mifepristone (n = 8, P < 0.01).

Conclusions: These data showed that the commonly employed dose of mifepristone for EC delays ovulation and prolongs the menstrual cycle, when given during the late follicular phase. The mechanism of action of mifepristone may include a reduction of FSH secretion via a decrease in circulating leptin.