FSHR polymorphism p.N680S mediates different responses to FSH in vitro

Casarini, Livio; Moriondo, Valeria; Marino, Marco; Adversi, Francesca; Capodanno, Francesco; Grisolia, Chiarina; Marca, Antonio La; Sala, Giovanni Battista La; Simoni, Manuela

doi:10.1016/j.mce.2014.06.013

Cited by 87 publications

(66 citation statements)

References 60 publications

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“…Total cAMP levels were evaluated using the Cyclic AMP Direct EIA kit (Arbor Assays, Ann Arbor, MI, USA), following the supplier’s instructions and signals were measured by a Victor3 multilabel plate reader (PerkinElmer Inc., Waltham, MA, USA). Data were entered into a curve fitting software and represented using a log regression analysis, as previously described [29]. …”

Section: Methodsmentioning

confidence: 99%

Human LH and hCG stimulate differently the early signalling pathways but result in equal testosterone synthesis in mouse Leydig cells in vitro

Riccetti

Pascali

Gilioli

et al. 2017

Reprod Biol Endocrinol

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BackgroundHuman luteinizing hormone (LH) and chorionic gonadotropin (hCG) are glycoprotein hormones regulating development and reproductive functions by acting on the same receptor (LHCGR). We compared the LH and hCG activity in gonadal cells from male mouse in vitro, i.e. primary Leydig cells, which is a common tool used for gonadotropin bioassay. Murine Leydig cells are naturally expressing the murine LH receptor (mLhr), which binds human LH/hCG.MethodsCultured Leydig cells were treated by increasing doses of recombinant LH and hCG, and cell signaling, gene expression and steroid synthesis were evaluated.ResultsWe found that hCG is about 10-fold more potent than LH in cAMP recruitment, and slightly but significantly more potent on cAMP-dependent Erk1/2 phosphorylation. However, no significant differences occur between LH and hCG treatments, measured as activation of downstream signals, such as Creb phosphorylation, Stard1 gene expression and testosterone synthesis.ConclusionsThese data demonstrate that the responses to human LH/hCG are only quantitatively and not qualitatively different in murine cells, at least in terms of cAMP and Erk1/2 activation, and equal in activating downstream steroidogenic events. This is at odds with what we previously described in human primary granulosa cells, where LHCGR mediates a different pattern of signaling cascades, depending on the natural ligand. This finding is relevant for gonadotropin quantification used in the official pharmacopoeia, which are based on murine, in vivo bioassay and rely on the evaluation of long-term, testosterone-dependent effects mediated by rodent receptor.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0224-3) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Human LH and hCG stimulate differently the early signalling pathways but result in equal testosterone synthesis in mouse Leydig cells in vitro

Riccetti

Pascali

Gilioli

et al. 2017

Reprod Biol Endocrinol

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“…Perez Mayorga et al [20] was the first group that observed differences in Asn680Ser genotypes with dose of rFSH in COH. Other groups observed that the FSHR variants influence the basal FSH and estradiol levels with conflicting results [23,24,25,26,27], for this reason, the FSHR gene and others gene variations may play a role in modulating receptor sensitivity and intracellular second messenger cascades to exogenous hCG and other gonadotrophins [24,28], thus the FSHR SNPs may cause changes in the phosphorylation and glycosylation molecular mechanisms [29,30]. …”

Section: Introductionmentioning

confidence: 99%

Ala307Thr and Asn680Ser Polymorphisms ofFSHRGene in Human Reproduction Outcomes

Trevisan¹,

Peluso²,

Cordts³

et al. 2014

Cell Physiol Biochem

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Background/Aims: It is known that some markers of ovarian stimulation can help to personalize the treatment, adjusting the dose of exogenous rFSH, thus preventing excessive wear of the patient. We aimed to evaluate Ala307Thr and Asn680Ser genotypes of the FSHR gene in infertile women and correlate the findings with the results of ovarian response and assisted reproduction outcomes. Methods: Cross-sectional study covering 149 infertile women submitted to assisted reproduction treatment. Genotyping of FSHR variants were performed using TaqMan methodology by real time PCR. FSH and estradiol were measured by ELFA. The data was analyzed statistically. Results: The frequencies of the FSHR Ala307Thr and Asn680Ser genotypes considering the ovarian hyper stimulation response also did not differ statistically. Considering assisted reproduction outcomes, we observed that the polymorphism Ala307Thr have a statistical difference for the number of MII oocytes and embryos (p=0,051 and p=0.037, respectively), which the genotype Ala/Ala showed more embryos. The polymorphisms did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. Conclusions: The polymorphisms Ala307Thr and Asn680Ser did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. However, we observed that the Ala307Thr may influence the number of embryos produced.

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“…Carriers of FSHR 2039GG have slower intracellular cAMP production (assessed in human granulosa cells)22 and they need more exogenous FSH for sufficient ovarian stimulation than FSHR 2039AA homozygotes2324.…”

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Pubertal Onset in Girls is Strongly Influenced by Genetic Variation Affecting FSH Action

Hagen

Sørensen

Aksglæde

et al. 2014

Sci Rep

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Age at pubertal onset varies substantially in healthy girls. Although genetic factors are responsible for more than half of the phenotypic variation, only a small part has been attributed to specific genetic polymorphisms identified so far. Follicle-stimulating hormone (FSH) stimulates ovarian follicle maturation and estradiol synthesis which is responsible for breast development. We assessed the effect of three polymorphisms influencing FSH action on age at breast deveopment in a population-based cohort of 964 healthy girls. Girls homozygous for FSHR -29AA (reduced FSH receptor expression) entered puberty 7.4 (2.5–12.4) months later than carriers of the common variants FSHR -29GG+GA, p = 0.003. To our knowledge, this is the strongest genetic effect on age at pubertal onset in girls published to date.

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FSHR polymorphism p.N680S mediates different responses to FSH in vitro

Cited by 87 publications

References 60 publications

Human LH and hCG stimulate differently the early signalling pathways but result in equal testosterone synthesis in mouse Leydig cells in vitro

Human LH and hCG stimulate differently the early signalling pathways but result in equal testosterone synthesis in mouse Leydig cells in vitro

Ala307Thr and Asn680Ser Polymorphisms ofFSHRGene in Human Reproduction Outcomes

Pubertal Onset in Girls is Strongly Influenced by Genetic Variation Affecting FSH Action

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