CLINICAL STUDY The early luteal phase administration of estrogen and progesterone does not induce premature luteolysis in normo-ovulatory women Nicole G M Beckers 1 , Peter Platteau 4 , Marinus J Eijkemans 2 , Nicholas S Macklon 5 , Frank H de Jong 3 , Paul Devroey 4 and Bart C J M Fauser 5 1 Division of Reproductive Medicine, Department of Obstetrics and Gynecology, 2 Department of Public Health and 3 Department of Medicine, Erasmus MC University Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands, 4 Center for Reproductive Medicine, Dutch-Speaking Brussels Free University Brussels, Laarbeeklaan 101, 1090, Brussels, Belgium and 5 Department of Reproductive Medicine and Gynecology, University Medical Center, Hiedelberglaan 100, 3584 CX, Utrecht, The Netherlands (Correspondence should be addressed to N G M Beckers; Email: n.beckers@erasmusmc.nl) Abstract Objective: The luteal phase after ovarian hyperstimulation for in vitro fertilization (IVF) is insufficient. Therefore, luteal phase supplementation is routinely applied in IVF. It may be postulated that premature luteolysis after ovarian hyperstimulation is due to supraphysiological steroid levels in the early luteal phase. In the present study, high doses of steroids are administered after the LH surge in normo-ovulatory volunteers in order to investigate whether this intervention gives rise to endocrine changes and a shortening of the luteal phase. Design: Randomized controlled trial. Methods: Forty non-smoking, normal weight women, between 18 and 37 years of age, with a regular menstrual cycle (24–35 days), received either high dosages of estradiol (E 2 ), progesterone (P), E 2 CP or no medication. Blood sampling was performed every other day from the day of the LH surge until LHC 14. Duration of the luteal phase and endocrine profiles were the main study outcomes. Results: Early luteal phase steroid concentrations achieved by exogenous administration were comparable with levels observed following ovarian hyperstimulation for IVF. No difference in the luteal phase length was observed comparing all groups. However, a significant decrease in LH levels could be observed 6 days after the mid-cycle LH surge (P!0.001) in women receiving P, resulting in accelerated decrease of inhibin A production by the corpus luteum (PZ0.001). Conclusion: The present intervention of high-dose steroid administration shortly after the LH surge failed to induce a premature luteolysis regularly in cyclic women. It seems that the induced transient suppression in LH allowed for a timely recovery of corpus luteum function. Other additional factors may be held responsible for the distinct reduction in luteal phase length observed after ovarian hyperstimulation for IVF. European Journal of Endocrinology 155 355–363 Introduction During normo-ovulatory cycles, the corpus luteum remains dependent on support by the pituitary gonadotropins throughout the luteal phase (1–3). Slowing down of the gonadotropin releasing hormone (GnRH) pulse generator along with diminished luteiniz- ing hormone (LH) pulse amplitude, is responsible for the demise of the corpus luteum both in the monkey and the human (1, 4). Luteolysis can only be prevented by rising doses of LH (5) or by human chorionic gonadotropin (hCG) (either exogenously administered or produced by the placenta in the case of pregnancy) (6). Under normal conditions, a tight balance is operative between negative-feedback activity of estradiol (E 2 ), progesterone (P) and the periodic secretion of pituitary LH for corpus luteum support and demise (7, 8). Indeed, under normal conditions, luteolysis can be induced by the luteal phase administration of either GnRH agonist (9) or antagonist (10). Since the early days of in vitro fertilization (IVF), it has been described that the luteal phase of stimulated cycles is abnormal. In fact, it was already stated in the first extended report on IVF by Edwards et al. (11) that ‘the luteal phase of virtually all patients was shortened considerably after treatment with gonadotropins’ and it was suggested that high-follicular phase E 2 levels caused by ovarian hyperstimulation might be involved. Initial studies in 1983 also confirmed the occurrence of an abnormal luteal phase in IVF cycles with the characteristic European Journal of Endocrinology (2006) 155 355–363 ISSN 0804-4643 q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02199 Online version via www.eje-online.org