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Submitted on July 15, 2005
Accepted on November 2, 2005
I.R.I.B.H.M., Faculty of Medicine, Free University of Brussels, 808 Route de Lennik, B-1070, Brussels, Belgium; Department of Obstetrics and Gynaecology, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea; Department of Genetics, Erasme Hospital, Free University of Brussels, 808 Route de Lennik, B-1070, Brussels, Belgium
* To whom correspondence should be addressed. 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 hCG.
Objective: 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, 2) better delineate the pathophysiology of the different presentations of sOHSS.
Design, intervention, patients: After blood sampling, we sequenced the FSHr from genomic Leukocytes DNA, from eight patients with the 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: University laboratory
Main outcome measure: 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 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 the 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 at least occur by three different pathophysiological mechanisms.
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