Rare Genetic Variants Potentially Involved in Ovarian Hyperstimulation Syndrome

Overview

Journal J Assist Reprod Genet

Publisher Springer

Specialties Genetics
Reproductive Medicine

Date 2018 Nov 29

PMID 30483911

Citations 5

Authors

Katrien Stouffs

Sari Daelemans

Samuel Santos-Ribeiro

Sara Seneca

Alexander Gheldof

Ali Sami Gurbuz

Michel De Vos

Herman Tournaye

Christophe Blockeel

Affiliations

Soon will be listed here.

Abstract

Purpose: We aim to investigate whether there is a genetic predisposition in women who developed ovarian hyperstimulation syndrome (OHSS) after GnRH antagonist protocol with GnRH agonist trigger and freeze-all approach.

Methods: Four patients with OHSS after GnRH agonist trigger and freeze-all approach were gathered from the worldwide patient population. These patients were analyzed through Whole Exome Sequencing. In this study known causes of OHSS were investigated and new causes present in at least two individuals were searched for.

Results: In the first part of the study, we evaluated the presence of mutations in genes already known to be involved in OHSS. In PGR and TP53, heterozygous alterations were detected. PGR is predicted to be involved in progesterone resistance with a recessive inheritance pattern and is, therefore, not considered as being causal. The consequences of the variant detected in TP53 currently remain unknown. In part 2 of the study, we assessed the clinical significance of variants in genes previously not linked to OHSS. We especially focused on genes with variants present in ≥ 2 patients. Two patients have variants in the FLT4 gene. Mutations in this gene are linked to hereditary lymphedema, but no link to OHSS has been described.

Conclusions: Defining a genetic predisposition for OHSS is essential in view of prevention. In this study, a potential link between the FLT4 gene and OHSS has been suggested. Future functional studies are essential to define a more precise involvement of the detected variants in the development of OHSS.

Citing Articles

Peripheral blood transcriptome analysis of patients with ovarian hyperstimulation syndrome through high-throughput sequencing.

Yan B, Wu B, Wang Z, Wei Y, Ni Y Reprod Dev Med. 2023; 7(2):115-121.

PMID: 37519480 PMC: 10241322. DOI: 10.1097/RD9.0000000000000058.

Interventions to prevent or reduce the incidence and severity of ovarian hyperstimulation syndrome: a systematic umbrella review of the best clinical evidence.

Palomba S, Costanzi F, Nelson S, Caserta D, Humaidan P Reprod Biol Endocrinol. 2023; 21(1):67.

PMID: 37480081 PMC: 10360244. DOI: 10.1186/s12958-023-01113-6.

Severe Ovarian Hyperstimulation Syndrome in a Woman With Breast Cancer Under Letrozole Triggered With GnRH Agonist: A Case Report and Review of the Literature.

Iorio G, Rovetto M, Conforti A, Carbone L, Vallone R, Cariati F Front Reprod Health. 2022; 3:704153.

PMID: 36303992 PMC: 9580822. DOI: 10.3389/frph.2021.704153.

Severe ovarian hyperstimulation syndrome associated with long-acting GnRH agonist in oncofertility patients.

Christ J, Herndon C, Yu B J Assist Reprod Genet. 2021; 38(3):751-756.

PMID: 33471229 PMC: 7910346. DOI: 10.1007/s10815-020-02051-7.

Rare genetic variants suggest dysregulation of signaling pathways in low- and high-risk patients developing severe ovarian hyperstimulation syndrome.

Borgwardt L, Olsen K, Rossing M, Helweg-Larsen R, Toftager M, Pinborg A J Assist Reprod Genet. 2020; 37(11):2883-2892.

PMID: 32945993 PMC: 7642034. DOI: 10.1007/s10815-020-01941-0.

References

Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen M, Pulkkanen K . Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med. 2001; 7(2):199-205. DOI: 10.1038/84651. View

Walter J, North P, Waner M, Mizeracki A, Blei F, Walker J . Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer. 2002; 33(3):295-303. DOI: 10.1002/gcc.10028. View

Gomez R, Simon C, Remohi J, Pellicer A . Administration of moderate and high doses of gonadotropins to female rats increases ovarian vascular endothelial growth factor (VEGF) and VEGF receptor-2 expression that is associated to vascular hyperpermeability. Biol Reprod. 2003; 68(6):2164-71. DOI: 10.1095/biolreprod.102.010801. View

Delvigne A, Rozenberg S . Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update. 2003; 9(1):77-96. DOI: 10.1093/humupd/dmg005. View

Montanelli L, Delbaere A, Carlo C, Nappi C, Smits G, Vassart G . A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. J Clin Endocrinol Metab. 2004; 89(3):1255-8. View

Moron F, de Castro F, Royo J, Montoro L, Mira E, Saez M . Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulation hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS). Pharmacogenet Genomics. 2006; 16(7):485-95. DOI: 10.1097/01.fpc.0000215073.44589.96. View

Ling S, Chong K, Hwang J . Persistent megalocystic ovary following in vitro fertilization in a postpartum patient with polycystic ovarian syndrome. Taiwan J Obstet Gynecol. 2007; 45(1):70-2. DOI: 10.1016/S1028-4559(09)60196-0. View

Soares S, Gomez R, Simon C, Garcia-Velasco J, Pellicer A . Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Hum Reprod Update. 2008; 14(4):321-33. DOI: 10.1093/humupd/dmn008. View

Delvigne A . Symposium: Update on prediction and management of OHSS. Epidemiology of OHSS. Reprod Biomed Online. 2009; 19(1):8-13. DOI: 10.1016/s1472-6483(10)60040-5. View

10.

Rizk B . Symposium: Update on prediction and management of OHSS. Genetics of ovarian hyperstimulation syndrome. Reprod Biomed Online. 2009; 19(1):14-27. DOI: 10.1016/s1472-6483(10)60041-7. View

11.

Bahram F, Claesson-Welsh L . VEGF-mediated signal transduction in lymphatic endothelial cells. Pathophysiology. 2009; 17(4):253-61. DOI: 10.1016/j.pathophys.2009.10.004. View

12.

Hsu C, Chiang C, Cheng H, Chang W, Chou C, Tsai H . Identifying LRRC16B as an oncofetal gene with transforming enhancing capability using a combined bioinformatics and experimental approach. Oncogene. 2010; 30(6):654-67. DOI: 10.1038/onc.2010.451. View

13.

Griesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S . Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a "freeze-all" strategy: a prospective.... Fertil Steril. 2011; 95(6):2029-33, 2033.e1. DOI: 10.1016/j.fertnstert.2011.01.163. View

14.

Altmae S, Hovatta O, Stavreus-Evers A, Salumets A . Genetic predictors of controlled ovarian hyperstimulation: where do we stand today?. Hum Reprod Update. 2011; 17(6):813-28. DOI: 10.1093/humupd/dmr034. View

15.

Soares S . Etiology of OHSS and use of dopamine agonists. Fertil Steril. 2012; 97(3):517-22. DOI: 10.1016/j.fertnstert.2011.12.046. View

16.

Boudjenah R, Molina-Gomes D, Torre A, Bergere M, Bailly M, Boitrelle F . Genetic polymorphisms influence the ovarian response to rFSH stimulation in patients undergoing in vitro fertilization programs with ICSI. PLoS One. 2012; 7(6):e38700. PMC: 3372493. DOI: 10.1371/journal.pone.0038700. View

17.

OBrien T, Kalmin M, Harralson A, Clark A, Gindoff I, Simmens S . Association between the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) rs4073366 polymorphism and ovarian hyperstimulation syndrome during controlled ovarian hyperstimulation. Reprod Biol Endocrinol. 2013; 11:71. PMC: 3727944. DOI: 10.1186/1477-7827-11-71. View

18.

Fatemi H, Popovic-Todorovic B, Humaidan P, Kol S, Banker M, Devroey P . Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and "freeze-all" approach in GnRH antagonist protocol. Fertil Steril. 2014; 101(4):1008-11. DOI: 10.1016/j.fertnstert.2014.01.019. View

19.

Lledo B, Ortiz J, Llacer J, Bernabeu R . Pharmacogenetics of ovarian response. Pharmacogenomics. 2014; 15(6):885-93. DOI: 10.2217/pgs.14.49. View

20.

Gurbuz A, Gode F, Ozcimen N, Isik A . Gonadotrophin-releasing hormone agonist trigger and freeze-all strategy does not prevent severe ovarian hyperstimulation syndrome: a report of three cases. Reprod Biomed Online. 2014; 29(5):541-4. DOI: 10.1016/j.rbmo.2014.07.022. View