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Successful in vitro maturation of oocytes in a woman with gonadotropin-resistant ovary syndrome associated with a novel combination of FSH receptor gene variants: a case report

  • Genetics
  • Published:
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Abstract

Infertility due to Gonadotropin-Resistant Ovary Syndrome (GROS) is a rare type of hypergonadotropic hypogonadism. Here, we report an original case of GROS, associated with compound heterozygous follicle-stimulating hormone receptor (FSHR) variants, in a woman who achieved a live birth by in vitro maturation (IVM) of her oocytes. This 31-year-old woman consulted our assisted reproduction center for a second opinion after having been advised, because of pervasive high serum follicle-stimulating hormone (FSH) levels, to pursue in vitro fertilization (IVF) with donor oocytes. She presented with primary infertility and progressively prolonged menstrual cycles. Her serum FSH levels were indeed found to be high, but in discordance with a normal anti-Müllerian hormone (AMH) level and antral follicle count. Genetic investigation found the patient to be compound heterozygous for two FSHR variants: I160T, a known pathologic variant, and N558H, which has never been previously reported. As there was no ovarian response to high daily doses of exogenous gonadotropins, IVM was proposed to the patient with success and she finally delivered at term a healthy boy. Effects of the receptor variants were analyzed in heterologous cells. Whereas the I160T mutation blocked FSHR membrane trafficking and FSH-stimulated cAMP-dependent signaling in transfected CHO cells, the novel variant, N558H, functioned equivalently to wild-type FSHR in the assays employed. In conclusion, IVM should always be offered as a first-line therapy to infertile women presenting with GROS. The N558H variant discovered in FSHR is novel, but its functional significance, if any, is unresolved and merits further investigation as it may be associated with a recessive FSHR-related disorder.

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Acknowledgments

We would like to thank the personnel of FERTILYS, the Division of Medical Genetics, Centre hospitalier universitaire de Sherbrooke, and the McGill Centre for Research in Reproduction and Development. We also thank Cook Medical and its representative, Benoît Quezel, who kindly provided the IVM follicle aspiration needle. We finally want to thank Dr. Étienne Audet-Walsh for his help and his critical reading of the manuscript.

Funding

DJB was supported by operating grants from Canadian Institutes of Health Research (CIHR) (MOP-133557 and -123447) and Natural Sciences and Engineering Research Council of Canada NSERC (2015-05178).

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Authors and Affiliations

  1. Centre d’aide médicale à la procréation FERTILYS, Laval, Québec, Canada

    C. Flageole, S. Ates, V. Blais, M. Benkhalifa & P. Miron

  2. Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada

    C. Toufaily & D. J. Bernard

  3. Department of Pediatrics, Division of Medical Genetics, Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada

    S. Chénier

  4. Department of Medicine and Reproductive Genetics, Faculty of Medicine, Université de Picardie Jules-Verne, Amiens, France

    M. Benkhalifa

  5. Institut National de la Recherche Scientifique (INRS) – Institut Armand-Frappier, Laval, Québec, Canada

    P. Miron

Authors
  1. C. Flageole
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  2. C. Toufaily
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  3. D. J. Bernard
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  4. S. Ates
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  5. V. Blais
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  6. S. Chénier
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  7. M. Benkhalifa
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  8. P. Miron
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Contributions

CF was responsible for the laboratory procedures, literature review, writing, and coordinating the submission of the manuscript. VB developed the IVM procedure and participated in the laboratory procedures. SC provided genetic consultation, interpretation of genetic testing, and contributed to manuscript writing. SA participated in the reflection and writing of the manuscript. MB supervised the IVM procedures. CT and DJB studied the in vitro effects of the identified mutations on FSHR function and wrote parts of the manuscript. PM was responsible for the diagnostic evaluation and clinical management of the couple, wrote parts of the manuscript, and coordinated its preparation.

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Correspondence to P. Miron.

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Flageole, C., Toufaily, C., Bernard, D.J. et al. Successful in vitro maturation of oocytes in a woman with gonadotropin-resistant ovary syndrome associated with a novel combination of FSH receptor gene variants: a case report. J Assist Reprod Genet 36, 425–432 (2019). https://doi.org/10.1007/s10815-018-1394-z

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  • DOI: https://doi.org/10.1007/s10815-018-1394-z

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