Follicular development induced by recombinant luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in anovulatory women with LH and FSH deficiency: evidence of a threshold effect

ABSTRACTObjective: To assess the requirement for luteinizing hormone (LH) in women deficient in LH and follicle-stimulating hormone (FSH).Research design and methods: A prospective, randomized, parallel-group, multicentre study was carried out in tertiary care and academic medical centres. Women with anovulatory amenorrhoea ≥ 1 year, serum oestradiol (E2) < 60 pg/mL (< 220 pmol/L) and low normal serum gonadotrophins were randomized in cycle A to a fixed daily dose of recombinant human (r-h) FSH (150 IU) and r-hLH 0, 25, 75 or 225 IU. Cycles B and C were not randomized.Main outcome measures: Follicular development, ovulation and luteinization.Results: In cycle A, follicular development was achieved by 63.6% (7/11), 100% (9/9), 72.7% (8/11) and 66.7% (6/9) of patients who received r-hFSH and r-hLH 0, 25, 75 or 225 IU/day, respectively ( p = not significant). Among patients with basal serum LH of < 1.2 IU/L, a dose-response relationship of r-hLH to follicular development was observed ( p = 0.039). Fourteen of 34 patients (41.2%) wishing to conceive became pregnant. Among patients with hypogonadotrophic hypogonadism (HH) treated with r-hFSH alone, a transition from LH dependence to independence was observed between basal LH values of ≥ 1.2 IU/L and ≤ 1.6 IU/L. The r-hLH was well tolerated and no serious adverse events occurred during treatment. The most common treatment-related events were related to the reproductive system and the gastrointestinal tract.Conclusions: Recombinant human LH provides a safe treatment option for women with HH. This small study also provided evidence suggestive of an LH threshold: follicular development was suboptimal when less than 75 IU/day r-hLH was administered.Key words: : AnovulationFollicular developmentHypogonadotrophic hypogonadismRecombinant luteinizing hormoner-hFSHr-hLHThreshold effect AcknowledgementsDeclaration of interest: This work was funded by Clinical Development, EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany and Merck Serono International S.A., an affiliate of Merck KGaA, Darmstadt, Germany; Rockland, MA, USA but was made possible by the members of the US Recombinant Human LH Study Group: Sarah Berga, Magee Women's Hospital, Pittsburgh, PA, USA; Gary W. DeVane, Center for Infertility & Reproductive Medicine, Orlando, FL, USA; Seth Feigenbaum, Kaiser Permanente Medical Center, San Francisco, CA, USA; Keith A. Hansen, The Medical College of Georgia, Augusta, GA, USA; Kathryn Martin, Massachusetts General Hospital, Boston, MA, USA; Joe B. Massey, Southeastern Fertility Institute, Atlanta, GA, USA; Randall Odem, Washington University School of Medicine, St. Louis, MO, USA; Nanette Santoro, New Jersey Medical School, Newark, NJ, USA; Michael Soules, University of Washington School of Medicine, Seattle, WA, USA; Daniel Spratt, Maine Medical Center, Portland, ME, USA; Emil Steinberger, Texas Foundation for Research in Reproductive Medicine, Houston, TX, USA; Michael P. Steinkampf, University of Alabama, Birmingham, AL, USA; David K. Walmer, Duke University Medical Center, Durham, NC, USA; Carol A. Wheeler, Women & Infants Hospital of Rhode Island, Providence, RI, USA.Thanks also go to the Investigators who contributed to the study, their study staff, and to Joan Schertz of EMD Serono Inc., Philippe Fonjallaz and Beatrice De Moustier of Merck Serono International S.A. and Hannah Wills (supported by Merck Serono International S.A.) for editorial support.L.O. was previously employed by EMD Serono, Inc. and is now employed by Radius Health, Inc. F.O. was previously employed by EMD Serono, Inc. and is now employed by Biomedical Operations, Genzyme Corp. K.C. was previously employed by EMD Serono, Inc. and is now employed by Citeline, Inc. GH is currently employed by EMD Serono, Inc.Notes* Some of the material contained in the manuscript has been presented, as an oral presentation, at the American Society of Reproductive Medicine 56th Annual Meeting, 21–26 October 2000, San Diego, California, USA