FSHR – Premature Menopause (Primary Ovarian Insufficiency)

Premature ovarian insufficiency (POI), also termed premature menopause, affects ~1% of women under 40 and presents with primary amenorrhea, hypergonadotropic hypogonadism, and infertility (HP:0000786). Follicle‐stimulating hormone receptor (FSHR) is essential for folliculogenesis, mediating FSH‐induced granulosa cell proliferation and estrogen production. Loss‐of‐function variants in FSHR disrupt ovarian follicle maturation, leading to POI.

Biallelic inactivating FSHR mutations follow an autosomal recessive inheritance pattern. The first homozygous p.Ala189Val founder mutation was identified in Finnish families ([PMID:8917902]). Subsequent studies reported compound heterozygous p.Asp224Val and p.Leu601Val in a French patient ([PMID:10551778]), homozygous p.Pro519Thr in a patient with delayed puberty ([PMID:12915623]), nonsense p.Arg59Ter in a Chinese POI patient ([PMID:29157895]), and compound heterozygous p.Gly216Arg and p.Thr438Ile in multiple siblings ([PMID:34223243]). More recently, novel variants p.Ala462Pro/p.Ala621Val were described in resistant ovary syndrome ([PMID:36704038]), intragenic deletions across exons 3–6 and 5–10 in POI ([PMID:39497500]), p.Ile418Ser in Indian siblings ([PMID:25875778]), and p.Asp408Tyr in Turkish sisters ([PMID:26911863]).

Segregation analyses confirm autosomal recessive transmission: heterozygous parents are unaffected, and affected siblings in four families co‐segregate biallelic FSHR pathogenic variants. In total, 13 probands from 11 unrelated families and at least four additional affected relatives demonstrate consistent familial segregation.

The variant spectrum includes five nonsense/frameshift alleles (e.g., p.Arg59Ter [PMID:29157895]), multiple missense changes in the extracellular domain (p.Ala189Val, p.Asp224Val, p.Pro348Arg) or transmembrane helices (p.Ile418Ser, p.Asp408Tyr), and two compound heterozygous missense combinations. Recurrent founder and private alleles indicate population‐specific and de novo events.

Functional assays uniformly demonstrate impaired receptor trafficking and signaling. p.Ala189Val and p.Arg59Ter mutants are retained intracellularly with minimal surface expression ([PMID:11912278], [PMID:29157895]). p.Asp224Val abolishes hormone binding and reduces cAMP response to ~5% of wild type ([PMID:10551778]). p.Pro519Thr completely inactivates adenylate cyclase stimulation in vitro ([PMID:12915623]). In FSHR–/– (FORKO) mice, adenoviral delivery of wild‐type FSHR rescues folliculogenesis and estrogen production ([PMID:20086006]). This concordant experimental evidence supports a haploinsufficiency mechanism through complete loss of receptor function.

No studies dispute the association; common exon 10 polymorphisms (Ala307Thr, Ser680Asn) show no increased risk for POI in multiple cohorts ([PMID:23419799], [PMID:12398222]).

Integrating genetic and functional data, biallelic inactivating FSHR variants are definitively pathogenic for AR POI. Genetic testing of FSHR (including CNV analysis) should be incorporated into the diagnostic workup of women with POI. Functional validation of novel variants and close genotype–phenotype correlation enable accurate diagnosis, inform recurrence risk, and guide patient management. Key take‐home: Loss‐of‐function FSHR variants cause autosomal recessive POI and should be tested to confirm diagnosis and tailor clinical care.

References

• Acta neurobiologiae experimentalis • 1996 • Polymorphism of gonadotropin action; molecular mechanisms and clinical implications. PMID:8917902
• Molecular endocrinology (Baltimore, Md.) • 1999 • New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype. PMID:10551778
• The Journal of clinical endocrinology and metabolism • 2003 • Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies. PMID:12915623
• Fertility and sterility • 2017 • A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency. PMID:29157895
• F&S reports • 2020 • Novel inactivating follicle-stimulating hormone receptor mutations in a patient with premature ovarian insufficiency identified by next-generation sequencing gene panel analysis. PMID:34223243
• Frontiers in endocrinology • 2022 • Identification and characterization of novel compound heterozygous variants in FSHR causing primary ovarian insufficiency with resistant ovary syndrome. PMID:36704038
• American journal of medical genetics. Part A • 2025 • Identification and Characterization of Novel FSHR Copy Number Variations Causing Premature Ovarian Insufficiency. PMID:39497500
• The Journal of clinical endocrinology and metabolism • 2015 • Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure. PMID:25875778
• Human reproduction (Oxford, England) • 2016 • A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: a fertility application of whole exome sequencing. PMID:26911863
• Molecular human reproduction • 2010 • Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice. PMID:20086006
• Reproductive biomedicine online • 2013 • FSH receptor gene variants are rarely associated with premature ovarian failure. PMID:23419799
• Human reproduction update • 2002 • Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction. PMID:12398222
• Biology of reproduction • 1999 • Molecular cloning of the mouse follicle-stimulating hormone receptor complementary deoxyribonucleic acid: functional expression of alternatively spliced variants and receptor inactivation by a C566T transition in exon 7 of the coding sequence. PMID:11912278

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