FSHR – Spontaneous Ovarian Hyperstimulation Syndrome

Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare, often recurrent condition characterized by cystic ovarian enlargement and fluid shifts occurring in the absence of exogenous gonadotropin therapy. Heterozygous activating mutations in the follicle‐stimulating hormone receptor (FSHR) have been identified as a cause of familial sOHSS, demonstrating an autosomal dominant pattern of inheritance with variable expressivity and penetrance. Genetic testing of affected kindreds reveals a gain‐of‐function mechanism leading to inappropriate receptor activation by human chorionic gonadotropin (hCG) and, in some variants, thyroid‐stimulating hormone (TSH).

Genetic evidence comprises at least five unrelated probands harboring missense variants in either the serpentine transmembrane region (p.Thr449Ile ([PMID:15001619]), p.Asp567Asn ([PMID:15001619]), p.Thr449Ala ([PMID:15080154]), p.Ile545Thr ([PMID:16278261])) or the extracellular domain (p.Ser128Tyr ([PMID:17721928])). Each variant segregates with sOHSS in multiple affected relatives, confirming autosomal dominant transmission and recurrence within families.

The variant spectrum is limited to activating missense changes; no loss‐of‐function alleles have been associated with sOHSS. The recurrent p.Thr449Ala variant (c.1345A>G (p.Thr449Ala)) has been observed in at least two affected women in one pedigree and serves as a hallmark of sOHSS susceptibility.

Functional assays in heterologous cells demonstrate that these FSHR mutants exhibit increased basal activity and heightened sensitivity to hCG and, for some alleles, to TSH, resulting in ligand‐independent cAMP production and downstream signaling ([PMID:15166252]). Molecular modeling indicates that mutations disrupt key interhelical interactions that normally stabilize the inactive receptor conformation.

Confounding factors include cases of sOHSS without identifiable FSHR mutations, especially in contexts of elevated hCG or TSH, where promiscuous activation of wild-type FSHR may occur ([PMID:19499413]). No studies to date refute the causative role of activating FSHR variants in familial sOHSS.

In summary, autosomal dominant FSHR gain‐of‐function variants are a well‐established etiology of familial sOHSS. Identification of such variants informs risk assessment in pregnancy and guides IVF protocols to mitigate OHSS risk. Genetic screening of FSHR should be considered in recurrent or familial sOHSS to enable precision reproductive management.

References

• The Journal of clinical endocrinology and metabolism • 2004 • A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. PMID:15001619
• The Journal of clinical endocrinology and metabolism • 2004 • A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. PMID:15080154
• Human mutation • 2008 • Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome. PMID:17721928
• Molecular endocrinology (Baltimore, Md.) • 2004 • Modulation of ligand selectivity associated with activation of the transmembrane region of the human follitropin receptor. PMID:15166252
• The Journal of clinical endocrinology and metabolism • 2006 • Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. PMID:16278261
• Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology • 2009 • Ovarian hyper-stimulation syndrome after spontaneous conception. PMID:19499413

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