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Presence and Absence of Follicle-Stimulating Hormone Receptor Mutations Provide Some Insights into Spontaneous Ovarian Hyperstimulation Syndrome Physiopathology

Interdisciplinary Research Institute for Human and Molecular Biology, Faculty of Medicine, and Department of Genetics, Erasme Hospital (G.S., G.V.), Free University of Brussels (A.D.L., L.M., J.V.D., G.S., G.V., S.C.), B-1070, Brussels, Belgium; and Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center (H.C.), Seoul, 138-736, Korea

Address all correspondence and requests for reprints to: Dr. S. Costagliola, Interdisciplinary Research Institute for Human and Molecular Biology, Free University of Brussels, 808 Lennik Street, B-1070 Brussels, Belgium. E-mail: scostag{at}ulb.ac.be.

Context: Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of ovarian stimulation treatments. Moreover, four mutations of the FSH receptor (FSHr) were recently described in patients presenting with spontaneous OHSS (sOHSS) of the first trimester of pregnancy with normal levels of human chorionic gonadotropin (hCG).

Objective: The objective of this study was to look for novel FSHr mutations in patients with sOHSS associated with different levels of hCG and TSH to 1) find new residues important for FSHr activation and specificity, and 2) better delineate the pathophysiology of the different presentations of sOHSS.

Design, Intervention, and Patients: After blood sampling, we sequenced the FSHr from genomic leukocytes DNA from eight patients with sOHSS of the first or second trimester of pregnancy with normal or high hCG levels or with high TSH levels associated with severe hypothyroidism.

Setting: This study was performed at a university laboratory.

Main Outcome Measure: The main outcome measure was FSHr sequencing and in vitro evaluation of the variation of cAMP production of FSHr mutants.

Results: A new mutation was found in the patient with sOHSS of the first trimester of pregnancy with a normal hCG level: I5.54⁵⁴⁵T, in transmembrane helix V of the FSHr. When tested functionally, this mutant displayed promiscuous activation by both hCG and TSH together with detectable constitutive activity. In contrast, no mutations were found in the FSHr from patients with high hCG or TSH levels, indicating that for those seven patients, sOHSS results from the natural promiscuous stimulation of a wild-type FSHr by very high concentrations of hCG or TSH.

Conclusions: sOHSS can occur by at least three different pathophysiological mechanisms.