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NEJM 
Prespective

The ovarian hyperstimulation syndrome is an iatrogenic complication of ovulation-induction therapy. In its most severe form, this syndrome involves massive ovarian enlargement and the formation of multiple ovarian cysts, fluid shifts resulting in extravascular fluid accumulation and intravascular volume depletion, renal failure, hypovolemic shock, and in some cases, death. The severe form is rare, with a reported incidence of 0.5 to 5 percent among patients undergoing ovulation-induction therapy.

Ovulation-induction therapy is generally initiated with gonadotropins to stimulate follicle development and growth. The intensity of the ovarian hyperstimulation syndrome is related to the degree of ovarian follicular response. Estrogens, produced by the developing follicles, can reach high levels and serve as markers of the degree of ovarian hyperstimulation. The ovarian hyperstimulation syndrome will not develop until final follicular maturation and luteinization occur in response to human chorionic gonadotropin or luteinizing hormone; this process results in the ovarian secretion of vasoactive substances that cause increased capillary permeability, triggering this syndrome. Possible mediators of increased vascular permeability include vascular endothelial growth factor, components of the renin�angiotensin system, and cytokines.

Although the ovarian hyperstimulation syndrome most commonly occurs as a complication of ovulation-induction therapy, spontaneous ovarian hyperstimulation syndrome has been reported in rare instances during pregnancy, most often in situations in which there is supraphysiologic production of chorionic gonadotropin, such as multiple gestations or molar pregnancies. Chorionic gonadotropin production typically peaks around the ninth week of gestation and decreases thereafter. In parallel with this course, the spontaneous ovarian hyperstimulation syndrome is usually most severe during the first trimester of pregnancy.

In this issue of the Journal, recurrent, spontaneous, pregnancy-associated ovarian hyperstimulation syndrome is described in two separate reports. In one case, described by Vasseur et al. (pages 753�759), typical manifestations of the ovarian hyperstimulation syndrome developed in a woman during all four of her pregnancies that extended beyond six weeks of gestation; two of her four sisters had also had pregnancy-associated ovarian hyperstimulation syndrome. This familial pattern suggested a genetic cause, and a heterozygous mutation in the follicle-stimulating hormone receptor was identified in the affected family members. In the second report, by Smits et al. (pages 760�766), spontaneous ovarian hyperstimulation syndrome also developed in a woman during each of four pregnancies, and she was found to have a distinct heterozygous mutation in the follicle-stimulating hormone receptor.

Together with thyroid-stimulating hormone, the gonadotropins follicle-stimulating hormone, luteinizing hormone, and chorionic gonadotropin form a family of glycoprotein hormones, each consisting of a common alpha subunit and a hormone-specific beta subunit. Similarly, the glycoprotein hormone receptors have related structures. These receptors belong to the family of G-protein�coupled receptors, which are characterized by a serpentine domain that contains seven transmembrane alpha helixes and binds to G proteins to activate downstream intracellular signaling. The glycoprotein hormone receptors form a separate subgroup within this family, having a large N-terminal extracellular domain that is responsible for high-affinity binding and ligand specificity. Follicle-stimulating hormone and thyroid-stimulating hormone bind to and activate follicle-stimulating hormone and thyroid-stimulating hormone receptors, respectively, and luteinizing hormone and chorionic gonadotropin both bind to the luteinizing hormone receptor. It has been hypothesized that specific high-affinity ligand binding to the extracellular domain stabilizes the active conformation of the receptors, stimulating downstream signaling events.

In both cases reported in this issue, germ-line mutations in the follicle-stimulating hormone receptor led to the reduction of ligand specificity, permitting activation by chorionic gonadotropin. Unexpectedly, in both cases, the mutations were not in the hormone-binding ectodomain but, rather, in the serpentine domain that is responsible for the activation of signaling. The affinity for follicle-stimulating hormone was not affected, and no direct binding of chorionic gonadotropin could be detected � findings that argue against changes in ligand binding. Rather, it seems likely that the mutations affect the specificity of ligand recognition by allowing the low-affinity interaction of chorionic gonadotropin with the ectodomain of the follicle-stimulating hormone receptor to be sufficient to "flip the switch," inducing an active conformation of the serpentine domain and the induction of downstream signaling events (see Figure). In addition, in the case reported by Smits et al., the mutation in the follicle-stimulating hormone receptor was such that ligand specificity was reduced to an even greater extent, permitting the induction of downstream signaling events by thyroid-stimulating hormone in addition to chorionic gonadotropin and follicle-stimulating hormone and permitting some constitutive activity in the absence of ligand.

View larger version (58K): [in this window] [in a new window]   Pathogenesis of Familial Gestational Spontaneous Ovarian Hyperstimulation Syndrome. Chorionic gonadotropin (hCG) is synthesized by the syncytiotrophoblast cells of the developing placenta in pregnancy and circulates to act at the level of the ovary. In the normal pregnant state, its activity is limited to the luteinizing hormone (LH) receptors. Stimulation of LH receptors in the corpus luteum results in continued progesterone production to allow the maintenance of pregnancy. Either of the two mutations (depicted in red and orange) in the follicle-stimulating hormone (FSH) receptor allows activation of downstream signaling events by hCG (modeled as a change in the conformation of the mutant FSH receptor, so that the low-affinity binding of hCG to the receptor ectodomain leads to activation of the serpentine domain). This conformational change results in the stimulation of FSH receptors by hCG in the granulosa cells of developing follicles, leading in turn to excessive follicular recruitment and enlargement. AC denotes adenylyl cyclase and , , and G-protein subunits.

 
How do these mutations lead to the ovarian hyperstimulation syndrome? Normally, the activity of chorionic gonadotropin is limited to luteinizing hormone receptors, expressed in the corpus luteum, allowing the maintenance of pregnancy. The described mutations in the follicle-stimulating hormone receptor result in "promiscuous" stimulation by chorionic gonadotropin of the follicle-stimulating hormone receptors in the granulosa cells of developing follicles, resulting in excessive follicular recruitment and enlargement. The hypothesis is that this excessive follicular recruitment, in association with luteinization mediated by the luteinizing hormone receptors, results in the ovarian hyperstimulation syndrome (see Figure). In contrast, in women with normal follicle-stimulating hormone receptors, spontaneous pregnancy-induced ovarian hyperstimulation syndrome occurs only when chorionic gonadotropin production is abnormally high, thus overcoming the hormone specificity of the wild-type receptor.

What other effects might such activating mutations in the follicle-stimulating hormone receptor be expected to cause? The possibility that such mutations may lead to increased susceptibility to iatrogenic ovarian hyperstimulation syndrome in patients undergoing induction of ovulation must be considered. Similarly, a predisposition to multiple gestations due to increased stimulation of ovarian-follicle development would not be unexpected, although such a predisposition was not observed in these cases. Finally, the as-yet-unresolved concern that ovulation-induction therapy may increase the risk of ovarian, breast, or uterine neoplasms suggests that patients with activating mutations of the follicle-stimulating hormone receptor require careful long-term follow-up.

The identification of mutations in the follicle-stimulating hormone receptor as a cause of spontaneous ovarian hyperstimulation syndrome illustrates the critical functional importance of maintaining the ligand specificity of the glycoprotein hormone receptors. The revelation that mutations outside of the ligand-binding domain can affect the ligand specificity of G-protein�coupled receptors was completely unexpected and highlights the insights into biology that can be gained from studies of mutations identified in patients with genetic diseases.

Source Information

From the Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston.