Identification and in Vitro Characterization of Follicle Stimulating Hormone (FSH) Receptor Variants Associated with Abnormal Ovarian Response to FSH

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2010 Jan 12

PMID 20061434

Citations 21

Authors

Tsilya Gerasimova

Maria N Thanasoula

Dimitrios Zattas

Emre Seli

Denny Sakkas

Maria D Lalioti

Affiliations

Soon will be listed here.

Abstract

Context: FSH mediates cyclic follicle growth and development and is widely used for controlled ovarian stimulation in women undergoing infertility treatment. The ovarian response of women to FSH is variable, ranging from poor response to ovarian hyperstimulation.

Objective: We investigated whether genetic alterations of the FSH receptor (FSHR) contribute to this variability.

Design And Patients: Our approach was to study women undergoing treatment with in vitro fertilization falling into the edges of the normal distribution of ovarian response to FSH, with respect to age.

Setting: We conducted the study at the Yale Fertility Clinic.

Methods: We extracted RNA from cumulus cells surrounding the oocytes of women undergoing in vitro fertilization and analyzed the FSHR mRNA by RT-PCR and sequencing.

Results: We identified four abnormal FSHR splicing products (three exon deletions and one intron insertion) in the FSHR mRNA in 37% (13 of 35) of women tested. All alterations affected the extracellular ligand-binding portion of the receptor without causing a frameshift. When transfected in HEK293T cells, all four splicing variants showed markedly decreased cAMP activation compared to controls. Untransfected cells showed no response to FSH, whereas all the cell lines showed normal cAMP activation when treated with forskolin, a nonreceptor-mediated cAMP stimulant. None of the normal or mutant forms showed any response to LH or TSH.

Conclusions: Our findings strongly indicate FSHR variants as being an intrinsic genetic cause of some forms of infertility and identify a need for functional characterization of these variants and the investigation of more individualized ovarian stimulation protocols.

Citing Articles

Serum miR-329-3p as a potential biomarker for poor ovarian response in an in vitro fertilization.

Kim J, Kim H, Lee S, Park E, Choi K, Kang K Clin Exp Reprod Med. 2025; 52(1):44-55.

PMID: 40018792 PMC: 11900665. DOI: 10.5653/cerm.2024.07094.

An update review of the application of single-cell RNA sequencing in pregnancy-related diseases.

Zhou Z, Yang X Front Endocrinol (Lausanne). 2024; 15:1415173.

PMID: 39717096 PMC: 11663665. DOI: 10.3389/fendo.2024.1415173.

Single-cell RNA-seq analysis and cell-cluster deconvolution of the human preovulatory follicular fluid cells provide insights into the pathophysiology of ovarian hyporesponse.

Roos K, Rooda I, Keif R, Liivrand M, Smolander O, Salumets A Front Endocrinol (Lausanne). 2022; 13:945347.

PMID: 36339426 PMC: 9635625. DOI: 10.3389/fendo.2022.945347.

An overview of FSH-FSHR biology and explaining the existing conundrums.

Bhartiya D, Patel H J Ovarian Res. 2021; 14(1):144.

PMID: 34717708 PMC: 8557046. DOI: 10.1186/s13048-021-00880-3.

Endogenous, tissue-resident stem/progenitor cells in gonads and bone marrow express FSHR and respond to FSH via FSHR-3.

Bhartiya D, Patel H, Kaushik A, Singh P, Sharma D J Ovarian Res. 2021; 14(1):145.

PMID: 34717703 PMC: 8556987. DOI: 10.1186/s13048-021-00883-0.

References

Sprengel R, Braun T, Nikolics K, Segaloff D, Seeburg P . The testicular receptor for follicle stimulating hormone: structure and functional expression of cloned cDNA. Mol Endocrinol. 1990; 4(4):525-30. DOI: 10.1210/mend-4-4-525. View

Sudo S, Kudo M, Wada S, Sato O, Hsueh A, Fujimoto S . Genetic and functional analyses of polymorphisms in the human FSH receptor gene. Mol Hum Reprod. 2002; 8(10):893-9. DOI: 10.1093/molehr/8.10.893. View

Dierich A, Sairam M, Monaco L, Fimia G, Gansmuller A, Lemeur M . Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci U S A. 1998; 95(23):13612-7. PMC: 24867. DOI: 10.1073/pnas.95.23.13612. View

Lifton R, Gharavi A, Geller D . Molecular mechanisms of human hypertension. Cell. 2001; 104(4):545-56. DOI: 10.1016/s0092-8674(01)00241-0. View

Layman L, Lee E, Peak D, Namnoum A, Vu K, van Lingen B . Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone beta-subunit gene. N Engl J Med. 1997; 337(9):607-11. DOI: 10.1056/NEJM199708283370905. View

Ulloa-Aguirre A, Zarinan T, Pasapera A, Casas-Gonzalez P, Dias J . Multiple facets of follicle-stimulating hormone receptor function. Endocrine. 2008; 32(3):251-63. DOI: 10.1007/s12020-008-9041-6. View

Uribe A, Zarinan T, Perez-Solis M, Gutierrez-Sagal R, Jardon-Valadez E, Pineiro A . Functional and structural roles of conserved cysteine residues in the carboxyl-terminal domain of the follicle-stimulating hormone receptor in human embryonic kidney 293 cells. Biol Reprod. 2008; 78(5):869-82. DOI: 10.1095/biolreprod.107.063925. View

Sun L, Peng Y, Sharrow A, Iqbal J, Zhang Z, Papachristou D . FSH directly regulates bone mass. Cell. 2006; 125(2):247-60. DOI: 10.1016/j.cell.2006.01.051. View

Laven J, Mulders A, Suryandari D, Gromoll J, Nieschlag E, Fauser B . Follicle-stimulating hormone receptor polymorphisms in women with normogonadotropic anovulatory infertility. Fertil Steril. 2003; 80(4):986-92. DOI: 10.1016/s0015-0282(03)01115-4. View

10.

Perez Mayorga M, Gromoll J, Behre H, Gassner C, Nieschlag E, Simoni M . Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab. 2000; 85(9):3365-9. DOI: 10.1210/jcem.85.9.6789. View

11.

Smits G, Olatunbosun O, Delbaere A, Pierson R, Vassart G, Costagliola S . Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor. N Engl J Med. 2003; 349(8):760-6. DOI: 10.1056/NEJMoa030064. View

12.

Vasseur C, Rodien P, Beau I, Desroches A, Gerard C, de Poncheville L . A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome. N Engl J Med. 2003; 349(8):753-9. DOI: 10.1056/NEJMoa030065. View

13.

Allen L, Achermann J, Pakarinen P, Kotlar T, Huhtaniemi I, Jameson J . A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics. Hum Reprod. 2003; 18(2):251-6. DOI: 10.1093/humrep/deg046. View

14.

Rajapaksha W, Robertson L, OShaughnessy P . Expression of follicle-stimulating hormone-receptor mRNA alternate transcripts in bovine granulosa cells during luteinization in vivo and in vitro. Mol Cell Endocrinol. 1996; 120(1):25-30. DOI: 10.1016/0303-7207(96)03816-6. View

15.

Kelton C, Cheng S, Nugent N, Schweickhardt R, ROSENTHAL J, Overton S . The cloning of the human follicle stimulating hormone receptor and its expression in COS-7, CHO, and Y-1 cells. Mol Cell Endocrinol. 1992; 89(1-2):141-51. DOI: 10.1016/0303-7207(92)90220-z. View

16.

Gromoll J, Simoni M, Nieschlag E . An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab. 1996; 81(4):1367-70. DOI: 10.1210/jcem.81.4.8636335. View

17.

Matthews C, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G . Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet. 1993; 5(1):83-6. DOI: 10.1038/ng0993-83. View

18.

Phillip M, Arbelle J, Segev Y, Parvari R . Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone. N Engl J Med. 1998; 338(24):1729-32. DOI: 10.1056/NEJM199806113382404. View

19.

Beau I, Touraine P, Meduri G, Gougeon A, Desroches A, Matuchansky C . A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. J Clin Invest. 1998; 102(7):1352-9. PMC: 508982. DOI: 10.1172/JCI3795. View

20.

Camp T, Rahal J, Mayo K . Cellular localization and hormonal regulation of follicle-stimulating hormone and luteinizing hormone receptor messenger RNAs in the rat ovary. Mol Endocrinol. 1991; 5(10):1405-17. DOI: 10.1210/mend-5-10-1405. View