ORIGINAL ARTICLE The effect of LH supplementation to the GnRH antagonist protocol in advanced reproductive ageing women: a prospective randomized controlled study Johnny S. Younis* , †, Ido Izhaki‡ and Moshe Ben-Ami* , † *Reproductive Medicine Unit, Department of Obstetrics & Gynecology, Poriya Medical Center, Tiberias, †Faculty of Medicine in Galilee, Bar-Ilan University, and ‡Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel Summary Objective Although the fundamental significance of both LH and FSH for adequate ovarian folliculogenesis and steroidogene- sis has been extensively discussed, the clinical implication of recombinant (r) LH to rFSH for ovarian stimulation employing the GnRH antagonist protocol remains to be elucidated. The aim of this prospective randomized controlled study was to explore whether rLH supplementation to rFSH following GnRH antagonist has an added value to the late follicular ovarian steroidogenesis in the advanced reproductive aged women. Design and Subjects Sixty-three consecutive infertile women above 35 years of age and/or with a previous low ovarian response admitted for IVF/ICSI treatment were prospectively randomized. Women in the study and control groups were simi- larly treated employing the rFSH 300 IU/day and the flexible GnRH antagonist 0 25 mg/day protocol. On the day of antago- nist initiation, rLH 150 IU/day was added only to the study group and continued till the hCG day. Results Serum E 2 level on hCG day did not significantly differ between the study and control groups, corresponding to 1268 1006 and 1113 669 pg/mL, respectively (P = 0 9). In the study group, the duration of GnRH antagonist administra- tion was significantly lower than the control group correspond- ing to 5 0 1 5 to 4 0 1 5 days, respectively (P < 0 05). The total dosage of rFSH administration did not differ between the two groups. Conclusions rLH supplementation to rFSH following GnRH antagonist administration employing the flexible protocol does not seem to significantly augment serum E 2 level on the day of hCG administration in the advanced reproductive ageing women. This suggests that endogenous serum LH levels follow- ing GnRH antagonist initiation are sufficient for adequate late follicular ovarian steroidogenesis in this setting. (Received 29 May 2015; returned for revision 28 June 2015; finally revised 6 July 2015; accepted 19 August 2015) Introduction Although the fundamental significance of both LH and FSH for adequate ovarian folliculogenesis and steroidogenesis has been lengthily discussed, the clinical implication of recombinant (r) LH for ovarian stimulation remains to be elucidated. Specifically, the extent and duration of endogenous LH suppression, follow- ing GnRH analogues employment, requiring exogenous rLH administration remains to be established. It has been reported that there is no increase in pregnancy rate following rLH supplementation to the long GnRH agonist and rFSH protocol in the general infertile women undergoing IVF-ET. 1–3 However, pooled pregnancy estimates of clinical tri- als including only advanced reproductive ageing women showed significant increase in pregnancy rate, in favour of rLH co- administration. 3,4 Although the issue of rLH supplementation to the GnRH antagonist in the general infertile population 5,6 and in the advanced reproductive ageing has been investi- gated, 7,8 the topic is still controversial and debated. There is insufficient evidence to make definitive conclusions on the need for exogenous rLH in GnRH antagonist cycles. 9 Those in sup- port of LH supplementation argue that GnRH analogues cause profound LH suppression which prevents adequate steroidogen- esis, folliculogenesis and oocyte maturation while others con- tend that marginal endogenous serum LH levels, under the same GnRH analogues, are ample for adequate follicular and oocyte development. GnRH antagonist therapy has major effects on ovarian follic- ular steroidogenesis. It has been shown that GnRH antagonist causes more profound LH than FSH blockage, reduces follicular fluid E 2 level as compared to agonist cycles and demonstrates serum E 2 decrease following its initiation in a considerable part of treated women. 10–12 Moreover, in an oocyte donation set- ting, rLH supplementation improved pregnancy achievement for recipients whose embryos originated from GnRH-antago- nist-treated donors. 13 Consequently, it may be speculated that Correspondence: Johnny S. Younis, Reproductive Medicine Unit, Department of Obstetrics & Gynecology, Poriya Medical Center, Tiberias, 15208, Israel. Tel.: 972-40-6652275; Fax: 972-4-6080405; E-mail: jsy@ netvision.net.il © 2015 John Wiley & Sons Ltd 99 Clinical Endocrinology (2016) 84, 99–106 doi: 10.1111/cen.12886