Evaluating the roles of follicle-stimulating hormone receptor polymorphisms in gonadal hyperstimulation associated with severe juvenile primary hypothyroidism.
BACKGROUND
Rare activating mutations of the human (h)FSHR have been reported in some women with spontaneous ovarian hyperstimulation in pregnancy, where follicular growth is inappropriately stimulated by elevated concentrations of human chorionic gonadotropin acting through the hFSHR. It is not known whether ovarian hyperstimulation in peripubertal girls with untreated primary hypothyroidism is caused by hFSHR mutations and/or influenced by hFSHR allelic variants, rendering the hFSHR more sensitive to circulating TSH.


OBJECTIVE
The aim of the study was to determine whether mutations of the hFSHR and/or hFSHR allelic variants are associated with greater sensitivity of the hFSHR to TSH.


METHODS
The hFSHR gene was sequenced from eight pediatric patients displaying gonadal hyperstimulation due to primary hypothyroidism. HEK293 cells expressing different hFSHR allelic combinations were studied for their responsiveness to recombinant (r)hTSH.


METHODS
The study was conducted at university research centers.


METHODS
Eight unrelated patients (seven girls and one boy) who exhibited primary hypothyroidism and gonadal hyperstimulation were included in the study.


METHODS
There were no interventions.


METHODS
DNA sequencing of the hFSHR gene was the main outcome measure. Basal, rhFSHR- and rhTSH receptor-stimulated cAMP levels were assayed in HEK293 cells transfected with the hTSH receptor or different hFSHR allelic combinations. Cell surface receptor numbers were also determined.


RESULTS
No hFSHR mutations were identified in the patient population, but we did identify two known polymorphisms. In vitro experiments demonstrated a dose-dependent and specific rhTSH-dependent increase in cAMP production in HEK293 cells expressing the wild-type hFSHR, regardless of hFSHR isoform.


CONCLUSIONS
Pediatric gonadal hyperstimulation associated with severe primary hypothyroidism is likely due to the actions of the elevated concentrations of TSH on the wild-type hFSHR, and this response is not dependent upon the hFSHR isoform.
Ryan
Ginny L
GL
Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, The University of Iowa, Iowa City, IA 52246, USA.
Feng
Xiuyan
X
d'Alva
Catarina Brasil
CB
Zhang
Meilin
M
Van Voorhis
Bradley J
BJ
Pinto
Emilia Modolo
EM
Kubias
Ana Elisa F
AE
Antonini
Sonir R
SR
Latronico
Ana Claudia
AC
Segaloff
Deborah L
DL
D000293:Adolescent; D000483:Alleles; D002460:Cell Line; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D007457:Iodine Radioisotopes; D007668:Kidney / Q000166:cytology; D008297:Male; D009154:Mutation; D016471:Ovarian Hyperstimulation Syndrome / Q000150:complications* / Q000235:genetics*; D011869:Radioligand Assay; D011962:Receptors, FSH / Q000235:genetics*; D012720:Severity of Illness Index; D013972:Thyrotropin / Q000097:blood; D014162:Transfection
D007457:Iodine Radioisotopes; D011962:Receptors, FSH; D013972:Thyrotropin; D000242:Cyclic AMP