Follicle-stimulating hormone receptors (FSHRs) are almost exclusively expressed on granulosa cells, and FSH action is probably most clearly reflected in intrafollicular hormone milieu of antral follicles. Little is known about the possible effects of the common single nucleotide polymorphism (SNP) FSHR -29G > A (rs1394205) on hormonal conditions in humsan small antral follicles (hSAFs) obtained from women in the natural menstrual cycle. This study investigated the follicle fluid (FF) concentrations of anti-Müllerian hormone, estradiol, progesterone, androstenedione, and testosterone in hSAF in relation to the different genotypes of FSHR -29G > A. FF from 362 follicles was collected in 95 women undergoing fertility preservation, who did not suffer from a disease that directly affected ovarian function. The testosterone levels of the minor A/A genotype were significantly increased compared to the A/G and the G/G genotype. Furthermore, significantly reduced androstenedione levels were observed for the G/G genotype, as compared to the A/G genotype, while the other hormones did not show statistical significant differences. In conclusion, the androgen levels of hSAF were significantly elevated in the minor SNP genotype in the FSHR promoter polymorphism FSHR -29G > A.

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University University Hospital Motol Prague Czechia

Department of Biomedicine University of Aarhus Aarhus Denmark

Laboratory of Reproductive Biology The Juliane Marie Centre for Women Children and Reproduction University Hospital of Copenhagen Copenhagen Denmark

See more in PubMed

Kristensen SG, Ebbesen P, Andersen CY. Transcriptional profiling of five isolated size matched stages of human preantral follicles. Mol Cell Endocrinol (2015) 401:189–201. 10.1016/j.mce.2014.12.012 PubMed DOI

Oktay K, Briggs D, Gosden RG. Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab (1997) 82:3748–51. 10.1210/jcem.82.11.4346 PubMed DOI

Jeppesen JV, Kristensen SG, Nielsen ME, Humaidan P, Dal Canto M, Fadini R, et al. LH-receptor gene expression in human granulosa and cumulus cells from antral and preovulatory follicles. J Clin Endocrinol Metab (2012) 97:E1524–31. 10.1210/jc.2012-1427 PubMed DOI PMC

Escamilla-Hernandez R, Little-Ihrig L, Orwig KE, Yue J, Chandran U, Zeleznik AJ. Constitutively active protein kinase A qualitatively mimics the 294 effects of follicle-stimulating hormone on granulosa cell differentiation. Mol Endocrinol (2008) 22:1842–52. 10.1210/me.2008-0103 PubMed DOI PMC

Lavoie HA, King SR. Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B. Exp Biol Med (Maywood) (2009) 234:880–907. 10.3181/0903-MR-97 PubMed DOI

Menon KMJ, Menon B. Structure, function and regulation of gonadotropin receptors – a perspective. Mol Cell Endocrinol (2012) 356:88–97. 10.1016/j.mce.2012.01.021 PubMed DOI PMC

Priyanka S, Medhamurthy R. Characterization of cAMP/PKA/CREB signaling cascade in the bonnet monkey corpus luteum: expressions of inhibin-alpha and StAR during different functional status. Mol Hum Reprod (2007) 13:381–90. 10.1093/molehr/gam015 PubMed DOI

Casarini L, Pignatti E, Simoni M. Effects of polymorphisms in gonadotropin and gonadotropin receptor genes on reproductive function. Rev Endocr Metab Disord (2011) 12:303–21. 10.1007/s11154-011-9192-2 PubMed DOI

Desai SS, Achrekar SK, Pathak BR, Desai SK, Mangoli VS, Mangoli RV, et al. Follicle-stimulating hormone receptor polymorphism (G-29A) is associated with altered level of receptor expression in granulosa cells. J Clin Endocrinol Metab (2011) 96:2805–12. 10.1210/jc.2011-1064 PubMed DOI

Nakayama T, Kuroi N, Sano M, Tabara Y, Katsuya T, Ogihara T, et al. Mutation of the follicle stimulating hormone receptor gene 5’-untranslated region associated with female hypertension. Hypertension (2006) 48:512–8. 10.1161/01.HYP.0000233877.84343.d7 PubMed DOI

Perez Mayorga M, Gromoll J, Behre HM, Gassner C, Nieschlag E, Simoni M. Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab (2000) 85:3365–9. 10.1210/jcem.85.9.6789 PubMed DOI

Themmen APN, Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev (2000) 21:551–83. 10.1210/edrv.21.5.0409 PubMed DOI

Wunsch A, Ahda Y, Banaz-Yaşar F, Sonntag B, Nieschlag E, Simoni M, et al. Single-nucleotide polymorphisms in the promoter region influence the expression of the human follicle-stimulating hormone receptor. Fertil Steril (2005) 84:446–53. 10.1016/j.fertnstert.2005.02.031 PubMed DOI

Yan Y, Gong Z, Zhang L, Li Y, Li X, Zhu L, et al. Association of follicle-stimulating hormone receptor polymorphisms with ovarian response in Chinese women: a prospective clinical study. PLoS One (2013) 8:e78138. 10.1371/journal.pone.0078138 PubMed DOI PMC

Borgbo T, Jeppesen JV, Lindgren I, Lundberg Giwercman Y, Hansen LL, Yding Andersen C. Effect of the FSH receptor single nucleotide polymorphisms (FSHR 307/680) on the follicular fluid hormone profile and the granulosa cell gene expression in human small antral follicles. Mol Hum Reprod (2015) 21:255–61. 10.1093/molehr/gau106 PubMed DOI

Casarini L, Moriondo V, Marino M, Adversi F, Capodanno F, Grisolia C, et al. FSHR polymorphism p.N680S mediates different responses to FSH in vitro. Mol Cell Endocrinol (2014) 393:83–91. 10.1016/j.mce.2014.06.013 PubMed DOI

Greb RR, Behre HM, Simoni M. Pharmacogenetics in ovarian stimulation – current concepts and future options. Reprod Biomed Online (2005) 11:589–600. 10.1016/S1472-6483(10)61167-4 PubMed DOI

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

Jun JK, Yoon JS, Ku S-Y, Choi YM, Hwang KR, Park SY, et al. Follicle-stimulating hormone receptor gene polymorphism and ovarian responses to controlled ovarian hyperstimulation for IVF-ET. J Hum Genet (2006) 51:665–70. 10.1007/s10038-006-0005-5 PubMed DOI

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

de Castro F, Ruiz R, Montoro L, Pérez-Hernández D, Sánchez-Casas Padilla E, Real LM, et al. Role of follicle-stimulating hormone receptor Ser680Asn polymorphism in the efficacy of follicle-stimulating hormone. Fertil Steril (2003) 80:571–6. 10.1016/S0015-0282(03)00795-7 PubMed DOI

Klinkert ER, te Velde ER, Weima S, van Zandvoort PM, Hanssen RGJM, Nilsson PR, et al. FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF. Reprod Biomed Online (2006) 13:687–95. 10.1016/S1472-6483(10)60660-8 PubMed DOI

Loutradis D, Theofanakis C, Anagnostou E, Mavrogianni D, Partsinevelos GA. Genetic profile of SNP(s) and ovulation induction. Curr Pharm Biotechnol (2012) 13:417–25. 10.2174/138920112799361954 PubMed DOI

Lindgren I, Bååth M, Uvebrant K, Dejmek A, Kjaer L, Henic E, et al. Combined assessment of polymorphisms in the LHCGR and FSHR genes predict chance of pregnancy after in vitro fertilization. Hum Reprod (2016) 31(3):672–83. 10.1093/humrep/dev342 PubMed DOI

Andersen CY. Characteristics of human follicular fluid associated with successful conception after in vitro fertilization. J Clin Endocrinol Metab (1993) 77:1227–34. 10.1210/jcem.77.5.7521343 PubMed DOI

Andersen CY, Schmidt KT, Kristensen SG, Rosendahl M, Byskov AG, Ernst E. Concentrations of AMH and inhibin-B in relation to follicular diameter in normal human small antral follicles. Hum Reprod (2010) 25:1282–7. 10.1093/humrep/deq019 PubMed DOI

Jeppesen JV, Anderson RA, Kelsey TW, Christiansen SL, Kristensen SG, Jayaprakasan K, et al. Which follicles make the most anti-Mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol Hum Reprod (2013) 19:519–27. 10.1093/molehr/gat024 PubMed DOI

Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, et al. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril (2014) 101:105–11. 10.1016/j.fertnstert.2013.09.007 PubMed DOI

Borgbo T, Macek M, Chrudimska J, Jeppesen JV, Hansen LL, Andersen CY. Size matters: associations between the androgen receptor CAG repeat length and the intrafollicular hormone milieu. Mol Cell Endocrinol (2016) 419:12–7. 10.1016/j.mce.2015.09.015 PubMed DOI

Borgbo T, Sommer Kristensen L, Lindgren I, Yding Andersen C, Hansen LL, Kristensen LS. Genotyping common FSHR polymorphisms based on competitive amplification of differentially melting amplicons (CADMA). J Assist Reprod Genet (2014) 31:1427–36. 10.1007/s10815-014-0329-6 PubMed DOI PMC

Simoni M, Casarini L. Mechanisms in endocrinology: genetics of FSH action: a 2014-and beyond view. Eur J Endocrinol (2014) 170:R91–107. 10.1530/EJE-13-0624 PubMed DOI

Smyth CD, Miró F, Whitelaw PF, Howles CM, Hillier SG. Ovarian thecal/interstitial androgen synthesis is enhanced by a follicle-stimulating hormone-stimulated paracrine mechanism. Endocrinology (1993) 133:1532–8. 10.1210/endo.133.4.8404591 PubMed DOI

Yding Andersen C, Rosendahl M, Byskov AG. Concentration of anti-Müllerian hormone and inhibin-B in relation to steroids and age in follicular fluid from small antral human follicles. J Clin Endocrinol Metab (2008) 93:2344–9. 10.1210/jc.2007-2342 PubMed DOI

Yding Andersen C. Inhibin-B secretion and FSH isoform distribution may play an integral part of follicular selection in the natural menstrual cycle. Mol Hum Reprod (2017) 23(1):16–24. 10.1093/molehr/gaw070 PubMed DOI

Timossi CM, Barrios-de-Tomasi J, González-Suárez R, Arranz MC, Padmanabhan V, Conn PM, et al. Differential effects of the charge variants of human follicle stimulating hormone. J Endocrinol (2000) 165:193–205. 10.1677/joe.0.1650193 PubMed DOI

Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab (1999) 84:2951–6. 10.1210/jcem.84.8.5929 PubMed DOI

Nielsen ME, Rasmussen IA, Kristensen SG, Christensen ST, Møllgård K, Wreford Andersen E, et al. In human granulosa cells from small antral follicles, androgen receptor mRNA and androgen levels in follicular fluid correlate with FSH receptor mRNA. Mol Hum Reprod (2011) 17:63–70. 10.1093/molehr/gaq073 PubMed DOI