Abstract
Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare event that may result from a FSH-producing pituitary adenoma (FSHoma), activating mutations of the FSH receptor (FSHR), and cross-reactivity of the FSHR to elevated hCG and TSH in the setting of pregnancy or hypothyroidism. The objective of this study was to investigate whether an aberrant FSHR was present in a woman with sOHSS and a non-surgically diagnosed FSHoma whose serum FSH levels and FSH bioactivity were nearly normal. Sequencing of the patient’s FSHR gene revealed a heterozygous novel missense mutation c. 1536G>A resulting in an amino acid substitution M512I. We asked whether this mutant FSHR affected FSHR-mediated signaling pathways involving cAMP/protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog kinase (SRC)/ p42/p44 extracellular signal-regulated protein kinases (ERK1/2). Thus, 293T cells expressing wild-type (FSHRwt), the mutant FSHR (FSHRmt), or both (FSHRwt/mt) were treated with FSH and subjected to measurements of intracellular cAMP, cAMP-induced CRE (cAMP response element)-mediated luciferase assays and immunoblot analyses of phosphorylated PI3K and ERK1/2. There were no differences in luciferase activities or phosphorylation levels of ERK1/2 among FSHRwt, FSHRmt cells and FSHwt/mt cells. However, FSHRmt cells showed a significant reduction in both cAMP production and PI3K phosphorylation levels with unchanged phosphorylation of ERK1/2 upon FSH stimulation in comparison to FSHwt cells. Also, FSH treatment did not provoke PI3K phosphorylation in FSHwt/mt cells. These results indicate that the novel missense M512I FSHR mutation identified herein did not participate in hyperactivation of FSHR-mediated signaling pathways but rather in hypoactivation of the FSH-mediated PI3K/AKT pathway. Thus, this study demonstrates a new functional property of this novel mutatnt FSHR, which, however, might not be involved in the pathogenesis of sOHSS in this FSHoma patient.
Highlights
Ovarian hyperstimulation syndrome (OHSS) is most often an iatrogenic complication of ovulation induction and controlled ovarian hyperstimulation using gonadotropin(s) in infertile patients
Reproductive-aged women with an FSH-producing adenoma (FSHoma) exhibit spontaneous ovarian hyperstimulation syndrome (sOHSS) characterized by high serum levels of FSH and estradiol (E2) together with enlarged multicystic ovaries [8,9,10,11,12,13,14,15]
In the present study we identified a novel missense mutation of the FSH receptor (FSHR) in the same patient and performed an in vitro functional analysis on the mutated FSHR to elucidate the molecular mechanism(s) underlying sOHSS caused by this FSHoma
Summary
Ovarian hyperstimulation syndrome (OHSS) is most often an iatrogenic complication of ovulation induction and controlled ovarian hyperstimulation using gonadotropin(s) in infertile patients. Cases of sOHSS together with its possible underlying mechanisms have been reported, and include the cross-reactivity of the FSH receptor (FSHR) to a pregnancy- or hypothyroidism-induced elevation of hCG, in response to TSH in which the specific β-subunits are similar to that of FSH [5,6,7], activating mutations of the FSHR [5,6,7], or hypergonadotropinemia caused by gonadotropin-producing pituitary adenomas [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] Among these pituitary adenomas, reproductive-aged women with an FSH-producing adenoma (FSHoma) exhibit sOHSS characterized by high serum levels of FSH and estradiol (E2) together with enlarged multicystic ovaries [8,9,10,11,12,13,14,15]. In the present study we identified a novel missense mutation of the FSHR in the same patient and performed an in vitro functional analysis on the mutated FSHR to elucidate the molecular mechanism(s) underlying sOHSS caused by this FSHoma
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