The follicle-stimulating hormone receptor unmasked: insights drawn from a case of spontaneous ovarian hyperstimulation syndrome

This issue of F&S Reports features a case report of a woman with spontaneous ovarian hyperstimulation syndrome (sOHSS), the lesser-known “cousin” of iatrogenic OHSS (iOHSS) (1). Understanding the underlying mechanism of sOHSS, which operates in various ways through the follicle stimulating hormone (FSH) receptor (FSHR), has important implications for many different pathologic conditions encountered by reproductive endocrinologists.

Iatrogenic OHSS is an uncommon but potentially serious complication of ovarian stimulation with exogenous gonadotropins. The pathophysiology centers on vascular endothelial growth factor produced by the luteinized granulosa cells from multiple stimulated follicles.

Spontaneous OHSS is a rare condition in which OHSS develops in the absence of exogenous gonadotropin stimulation. Both conditions are characterized by enlarged multicystic ovaries, ascites, and a cascade of systemic complications including intravascular hypovolemia, hemoconcentration, thromboembolism, hepatorenal dysfunction, and coagulopathy.

As pointed out by Loheit et al (1), the molecular basis of sOHSS involves inappropriate activation of FSHR—either through promiscuous stimulation by supraphysiologic levels of human chorionic gonadotropin hormone (hCG) or thyroid-stimulating hormone (TSH) acting on the wild-type receptor, or through gain-of-function mutations that produce constitutive or ligand-hypersensitive receptor activity.

To understand this cross-reactivity, it is important to note that the three glycoprotein receptors (FSHR, luteinizing hormone/choriogonadotropin receptor (LH/CGR), and thyroid-stimulating hormone receptor [TSHR]) all belong to the rhodopsin-like G protein-coupled receptor family and share a similar architecture with large extracellular domains responsible for highly specific hormone binding, and a seven-transmembrane serpentine domain that couples to G proteins and activates intracellular signaling (2). Under normal circumstances, FSHR is highly specific for FSH and does not respond to hCG or TSH. Spontaneous OHSS, however, has been reported in patients with very high hCG levels (such as multiple pregnancies or molar pregnancies) or severe hypothyroidism with markedly elevated TSH, where the wild-type FSHR becomes “activated” by supraphysiologic hormone concentrations (3).Alternatively, sOHSS may occur as the result of mutations in the FSHR gene that cause promiscuous receptor activation by physiologic hCG levels during pregnancy, or by TSH levels in the setting of hypothyroidism (3). These mutations typically occur in the transmembrane domains of the receptor (particularly transmembrane helices III, V, and VI) or the extracellular loops connecting the domains (2).

Functional studies of these transmembrane domain mutations have examined both ligand-independent (constitutive) receptor activation and promiscuous stimulation by hCG and/or TSH, with increased cAMP production confirming receptor activation (4).

In the current report, Loheit et al (1) performed molecular genetic analysis on a young woman with well characterized OHSS and found a heterozygous variant in FSHR at position 460 leading to a leucine to glutamine substitution (1). They did not perform functional studies in this case report. Strictly speaking, unless and until L460Q (leucine -->glutamine) is found to be constitutively activating and has an exaggerated response to hCG, it should only be designated as a variant of interest and not a definitive mutation causing sOHSS. The fact that this variant was found in a woman with sOHSS in what is normally a highly conserved region is compelling evidence that this is indeed a causative mutation. On the other hand, previous reports have found that not all variants in this region, even those selected because they exhibit exaggerated activity in LHR, will exhibit similar activation in FSHR (4). Furthermore, constitutive activation and ligand responsiveness are not always linked—a mutant receptor that is constitutively active may nonetheless show reduced or absent cAMP response when stimulated by hCG or FSH. For example, in Zhang et al (4), the L460(3.43)R mutant in FSHR exhibits high constitutive activity but produces lower concentrations of FSH-stimulated cAMP compared with wild-type, demonstrating that mutations at this exact position can alter receptor function in complex ways—constitutive activation does not necessarily predict normal ligand-stimulated responses.

Understanding the effect of FSHR mutations is of particular importance for reproductive endocrinologists. As already noted, activating mutations put women at risk for sOHSS but may also identify those women who are at greater risk for iOHSS during treatment with gonadotropins (5). Constitutive activity of the D567N mutant receptor continuously recruits follicles, producing a polycystic appearance on ultrasound even outside of pregnancy (5).

Conversely, some inactivating or loss-of-function mutations in FSHR can result in recognizable pathologies more commonly seen by REIs, such as primary amenorrhea, primary ovarian insufficiency, and poor ovarian response to gonadotropins.

Further identification of novel FSHR mutations along with functional characterization of their phenotype is an important goal that may ultimately inform personalized approaches to ovarian stimulation and the management of related reproductive disorders.

Declaration of Interests

R.M. has nothing to disclose.