Two different entities of spontaneous ovarian hyperstimulation in a woman with FSH receptor mutation

Abstract

Spontaneous ovarian hyperstimulation syndrome (OHSS) is an extremely rare event. Normally OHSS is seen in the context of IVF. In 2003 a mutation of the FSH receptor (FSHR D567N) was identified for the first time as a cause of spontaneous OHSS. In most FSHR mutations, a hypersensitivity to human chorionic gonadotrophin (HCG) or thyroid-stimulating hormone (TSH) is described. This clinical case presents for the first time two occurrences of spontaneous OHSS in a single woman with a FSHR mutation and two different entities. Pathophysiology of both pregnancies was completely different. During the first pregnancy, elevated HCG and androgen concentrations led to spontaneous OHSS and finally to miscarriage. The second pregnancy with spontaneous OHSS was dominated by a latent hypothyroidism and normal HCG concentrations and ended in a delivery of a healthy female newborn. Due to the unusual courses of the pregnancies, the study looked for a mutation in the FSHR and surprisingly identified the same mutation previously described. This report confirms for the first time the in-vitro findings in a single clinical case that TSH as well as HCG leads to spontaneous OHSS in patients with FSHR D567N mutation. Hypothyroidism has to be treated or ruled out.

Structure, function and regulation of gonadotropin receptors – A perspective

“…Loss of function and gain of function mutations,associated with altered reproductive functions, have also been reported in human FSHR (Tao and Segaloff, 2009; Themmen, 2005). Specifically, mutations of FSHR have been linked to primary amenorrhea (Achrekar et al, 2010; Nakamura et al, 2008), ovarian hyperstimulation syndrome (De Leener et al, 2008; Dieterich et al, 2010; Montanelli et al, 2004; Rodien et al, 2010; Smits et al, 2003), primary ovarian failure (Doherty et al, 2002) and infertility (Peltoketo et al, 2010; Themmen and Huhtaniemi, 2000). …”

Effects of polymorphisms in gonadotropin and gonadotropin receptor genes on reproductive function

“…A few studies addressed the association between OHSS and polymorphisms in FSHR or LHCGR genes since they are direct targets of gonadotropins, but no consistent correlation was found. Since some cross-interaction between FSHR and heterologous ligands of the pituitary glycoprotein hormone family at high concentrations has been suggested [56][57][58], the pathogenesis of OHSS could indeed be associated to FSHR-mediated signals. In fact, some rare activating mutations of FSHR gene result in a predisposition to OHSS [58,59].…”

“…Since some cross-interaction between FSHR and heterologous ligands of the pituitary glycoprotein hormone family at high concentrations has been suggested [56][57][58], the pathogenesis of OHSS could indeed be associated to FSHR-mediated signals. In fact, some rare activating mutations of FSHR gene result in a predisposition to OHSS [58,59]. However, mutations in the FSHR are rare in OHSS [60] and polymorphisms could rather be involved.…”

Impact of follicle stimulating hormone receptor variants in fertility

“…All other cases were found in women. Some cases of ovarian hyperstimulation syndrome (OHSS) during pregnancy have been shown to be due to activating FSHR mutations, which cause either constitutive signaling or reduced specificity for FSH and concomitant increased sensitivity to human chorionic gonadotrophin (hCG) and/or TSH [19][20][21][22][23][24][25].…”