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The N680S variant in the follicle-stimulating hormone receptor gene identifies hyperresponders to controlled ovarian stimulation

Nenonen, Hannah A; Lindgren, Ida A; Prahl, Alexandra S LU ; Trzybulska, Dorota LU ; Kharraziha, Isabella LU ; Hultén, Mathilda; Giwercman, Yvonne L LU and Henic, Emir LU (2019) In Pharmacogenetics and Genomics 29(5). p.114-120
Abstract

OBJECTIVE: To study if the follicle-stimulating hormone receptor (FSHR) variant asparagine/serine in amino acid 680 (N680S) can predict hypersensitivity to gonadotropins in women undergoing assisted reproduction.

PATIENTS AND METHODS: In this retrospective study, 586 women undergoing their first in-vitro fertilisation treatment were enroled, and their FSHR N680S genetic variant was analysed. The main outcome measures were number of retrieved oocytes and any grade of ovarian hyperstimulation syndrome (OHSS). Experimental studies were performed on FSHR variants transfected into eukaryotic cells treated with 1-90 IU recombinant follicle-stimulating hormone. The receptors' ability to induce a second messenger 3',5'-cyclic AMP was... (More)

OBJECTIVE: To study if the follicle-stimulating hormone receptor (FSHR) variant asparagine/serine in amino acid 680 (N680S) can predict hypersensitivity to gonadotropins in women undergoing assisted reproduction.

PATIENTS AND METHODS: In this retrospective study, 586 women undergoing their first in-vitro fertilisation treatment were enroled, and their FSHR N680S genetic variant was analysed. The main outcome measures were number of retrieved oocytes and any grade of ovarian hyperstimulation syndrome (OHSS). Experimental studies were performed on FSHR variants transfected into eukaryotic cells treated with 1-90 IU recombinant follicle-stimulating hormone. The receptors' ability to induce a second messenger 3',5'-cyclic AMP was measured.

RESULTS: The proportion of women who developed OHSS was 6% (n=36). None of the women who developed this condition had the homozygous serine variant. The N680S polymorphism in the FSHR was associated with the condition, P trend (genotype)=0.004 and P allelic (alleles)=0.04. Mean oocyte number was 11±6 in women without OHSS and 16±8 in women who developed OHSS (P=0.001), despite exposure to lower total hormonal dose in the latter group. The odds ratio for developing OHSS in carriers of the asparagine allele was 1.7 (95% confidence interval: 1.025-2.839, P=0.04). A higher receptor activity in cells expressing asparagine compared with the serine was also evident at all concentrations of recombinant follicle-stimulating hormone used (P<0.05 for all).

CONCLUSION: This study confirms previous findings regarding higher hormonal sensitivity in carriers of asparagine in the N680S position. These women are at higher risk for OHSS during in-vitro fertilisation. Genetic testing could identify those at highest risk to develop this adverse effect.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Pharmacogenetics and Genomics
volume
29
issue
5
pages
114 - 120
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85067126547
ISSN
1744-6872
DOI
10.1097/FPC.0000000000000374
language
English
LU publication?
yes
id
244dc2d8-bda5-43a0-b4c2-838430ad9e74
date added to LUP
2019-05-23 09:53:05
date last changed
2019-08-23 03:00:21
@article{244dc2d8-bda5-43a0-b4c2-838430ad9e74,
  abstract     = {<p>OBJECTIVE: To study if the follicle-stimulating hormone receptor (FSHR) variant asparagine/serine in amino acid 680 (N680S) can predict hypersensitivity to gonadotropins in women undergoing assisted reproduction.</p><p>PATIENTS AND METHODS: In this retrospective study, 586 women undergoing their first in-vitro fertilisation treatment were enroled, and their FSHR N680S genetic variant was analysed. The main outcome measures were number of retrieved oocytes and any grade of ovarian hyperstimulation syndrome (OHSS). Experimental studies were performed on FSHR variants transfected into eukaryotic cells treated with 1-90 IU recombinant follicle-stimulating hormone. The receptors' ability to induce a second messenger 3',5'-cyclic AMP was measured.</p><p>RESULTS: The proportion of women who developed OHSS was 6% (n=36). None of the women who developed this condition had the homozygous serine variant. The N680S polymorphism in the FSHR was associated with the condition, P trend (genotype)=0.004 and P allelic (alleles)=0.04. Mean oocyte number was 11±6 in women without OHSS and 16±8 in women who developed OHSS (P=0.001), despite exposure to lower total hormonal dose in the latter group. The odds ratio for developing OHSS in carriers of the asparagine allele was 1.7 (95% confidence interval: 1.025-2.839, P=0.04). A higher receptor activity in cells expressing asparagine compared with the serine was also evident at all concentrations of recombinant follicle-stimulating hormone used (P&lt;0.05 for all).</p><p>CONCLUSION: This study confirms previous findings regarding higher hormonal sensitivity in carriers of asparagine in the N680S position. These women are at higher risk for OHSS during in-vitro fertilisation. Genetic testing could identify those at highest risk to develop this adverse effect.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.</p>},
  author       = {Nenonen, Hannah A and Lindgren, Ida A and Prahl, Alexandra S and Trzybulska, Dorota and Kharraziha, Isabella and Hultén, Mathilda and Giwercman, Yvonne L and Henic, Emir},
  issn         = {1744-6872},
  language     = {eng},
  number       = {5},
  pages        = {114--120},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Pharmacogenetics and Genomics},
  title        = {The N680S variant in the follicle-stimulating hormone receptor gene identifies hyperresponders to controlled ovarian stimulation},
  url          = {http://dx.doi.org/10.1097/FPC.0000000000000374},
  volume       = {29},
  year         = {2019},
}