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Case Reports
, 36 (3), 425-432

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

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Case Reports

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

C Flageole et al. J Assist Reprod Genet.

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.

Keywords: FSH receptor; Follicle-stimulating hormone (FSH); Gonadotropins; In vitro maturation (IVM); Ovarian resistance.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
FSH receptor, showing the locations of the patient’s variants. Representation of allelic variants of FSHR as described in OMIM (Online Mendelian Inheritance in Man). The information regarding loss-of-function and gain-of-function was taken from the NCBI database (www.pubmed.com – the ClinVar section). Note that only variants with demonstrated clinical significance were included. On top of the figure are shown variants leading to ovarian hyperstimulation (gain-of-function). Under the figure are variants leading to loss-of-function (ovarian dysgenesis). The two variants sequenced in our patient: I160T variant (in orange) localized in exon 6 and N558H variant (in blue) localized in exon 10. The different domains of the receptor were based on Fan 2005, Jiang 2012 and Ulloa-Aguirre 2016. [–16]
Fig. 2
Fig. 2
Oocyte maturation and embryo development. a Expulsion of first polar body confirming MII maturation. b Embryo used for transfer on day 3 after ICSI
Fig. 3
Fig. 3
Cell surface expression of wild-type and variant human FSH receptors. CHO cells were either left untransfected (mock), or transiently transfected with empty vector, or expression vectors encoding wild-type (WT), I160T, N558H, or I160T and N558H human FSHR receptor(s). Forty-eight hours post-transfection, cells were fixed and whole cell ELISAs were performed using mAb 106.105 against human FSH receptor to measure relative surface receptor expression. Results are shown as ratio of OD 450 nm for expression vectors over the value for non-transfected cells. Data represent the mean ± SEM of three independent experiments, each performed with three technical replicates. *p < 0.05, ns non-significant
Fig. 4
Fig. 4
FSH activation of a cAMP responsive reporter via wild-type and variant human FSH receptors. CHO cells were transfected with pCRE-Luc plasmid along with expression vectors encoding wild type (WT), I160T, N558H, or with both I160T and N558H FSHR receptor(s). Twenty-four hours post-transfection, cells were either left untreated or treated with human FSH at the indicated concentrations. Six hours post-treatment, cells were lysed and luciferase activity was assessed. Results are shown as the fold induction of treated conditions over the untreated condition expressing the WT receptor. Data represent the mean ± SEM of three independent experiments, each performed with two technical replicates. *p < 0.05, ns non-significant
Fig. 5
Fig. 5
Modifications proposed to WHO classification for chronic anovulation

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