Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: A pharmacogenetic study

Manuela Simoni, Daniele Santi, Luciano Negri, Ivan Hoffmann, Monica Muratori, Elisabetta Baldi, Marta Cambi, Marios Marcou, Thomas Greither, Enrica Baraldi, Simonetta Tagliavini, Daniela Carra, Francesco Lombardo, Loredana Gandini, Francesco Pallotti, Csilla Krausz, Giulia Rastrelli, Alberto Ferlin, Massimo Menegazzo, Elisa PignattiFrancesca Linari, Marco Marino, Renzo Benaglia, Paolo E. Levi-Setti, Hermann M. Behre

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Abstract

Study question: Does the spermDNAfragmentation index (DFI) improve depending on the FSH receptor (FSHR) genotype as assessed by the nonsynonymous polymorphisms rs6166 (p.N680S) after 3 months of recombinant FSH treatment in men with idiopathic infertility? summary answer: FSH treatment significantly improves sperm DFI only in idiopathic infertile men with the p.N680S homozygous N FSHR. what is known already: FSH, fundamental for spermatogenesis, is empirically used to treat male idiopathic infertility and several studies suggest that DFI could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is known that the FSHR single nucleotide polymorphism (SNP) rs6166 (p.N680S) influences ovarian response in women and testicular volume in men. study design, size and duration: Amulticenter, longitudinal, prospective, open-label, two-arm clinical trial was performed. Subjects enrolled were idiopathic infertile men who received 150 IU recombinant human FSH s.c. every other day for 12 weeks and were followed-up for a further 12 weeks after FSH withdrawal. Patients were evaluated at baseline, at the end of treatment and at the end of follow-up. participants/materials, setting, methods: Eighty-nine men with idiopathic infertility carrier of the FSHR p.N680S homozygousNor S genotype, FSH ≤ 8 IU/l and DFI >15%,were enrolled. A total of 66 patients had DFI analysis completed on at least two visits. DFI was evaluated in one laboratory by TUNEL/PI (propidium iodide) assay coupled to flow cytometry, resolving two different fractions of sperm, namely the 'brighter' and 'dimmer' sperm DFI fractions. main results and the roleof chance: Thirty-eightmen(57.6%)were carriers of the p.N680S homozygousNand 28 (42.4%) of the homozygous S FSHR. Sperm concentration/number was highly heterogeneous and both groups included men ranging from severe oligozoospermia to normozoospermia. Total DFI was significantly lower at the end of the study in homozygous carriers of the p.N680SNversus p.N680S S allele (P = 0.008). Total DFI decreased significantly from baseline to the end of the study (P = 0.021) only in carriers of the p.N680S homozygous N polymorphism, and this decrease involved the sperm population containing vital sperm (i.e. brighter sperm) (P = 0.008). The dimmer sperm DFI fraction, including only nonvital sperm, was significantly larger in p.N680S S homozygous patients than in homozygous N men (P = 0.018). Total DFIwas inversely related to total sperm number (P = 0.020) and progressive sperm motility (P = 0.014).Whenpatients were further stratified according to sperm concentration (normoozospermic versus oligozoospermic) or -211G>T polymorphism in the FSHB gene (rs10835638) (homozygous Gversus others), the significant improvement of sperm DFI in FSHR p.N680S homozygousNmen was independent of sperm concentration and associated with the homozygous FSHB -211G>T homozygous G genotype. limitations, reasons for caution: The statistical power of the study is 86.9% with alpha error 0.05. This is the first pharmacogenetic study suggesting that FSH treatment induces a significant improvement of total DFI in men carriers of the p.N680S homozygousNFSHR; however, the results need to be confirmed in larger studies using a personalized FSH dosage and treatment duration. wider implications of the findings: The evaluation of sperm DFI as a surrogate marker of sperm quality, and of the FSHR SNP rs6166 (p.N680S), might be useful to predict the response to FSH treatment in men with idiopathic infertility. study funding/competing interest(s): The study was supported by an unrestricted grant to M.S. and H.M.B. from Merck Serono that provided the drug used in the study. MS received additional grants from Merck Serono and IBSA as well as honoraria from Merck Serono. The remaining authors declare that no conflicts of interest are present. trial registration number: EudraCT number 2010-020240-35.

Original languageEnglish
Pages (from-to)1960-1969
Number of pages10
JournalHuman Reproduction
Volume31
Issue number9
DOIs
Publication statusPublished - 2016

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Human Follicle Stimulating Hormone
FSH Receptors
DNA Fragmentation
Spermatozoa
Therapeutics
Infertility
Sperm Count
Organized Financing
Genotype
Pharmacogenomic Testing
Single Nucleotide Polymorphism
Oligospermia
Conflict of Interest
Propidium
Sperm Motility
Male Infertility
In Situ Nick-End Labeling
Spermatogenesis

Keywords

  • FSH
  • FSH receptor
  • FSHB -211G/T
  • FSHR pN680S
  • Male infertility
  • Sperm DNA fragmentation index

ASJC Scopus subject areas

  • Reproductive Medicine
  • Rehabilitation
  • Obstetrics and Gynaecology

Cite this

Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S : A pharmacogenetic study. / Simoni, Manuela; Santi, Daniele; Negri, Luciano; Hoffmann, Ivan; Muratori, Monica; Baldi, Elisabetta; Cambi, Marta; Marcou, Marios; Greither, Thomas; Baraldi, Enrica; Tagliavini, Simonetta; Carra, Daniela; Lombardo, Francesco; Gandini, Loredana; Pallotti, Francesco; Krausz, Csilla; Rastrelli, Giulia; Ferlin, Alberto; Menegazzo, Massimo; Pignatti, Elisa; Linari, Francesca; Marino, Marco; Benaglia, Renzo; Levi-Setti, Paolo E.; Behre, Hermann M.

In: Human Reproduction, Vol. 31, No. 9, 2016, p. 1960-1969.

Research output: Contribution to journalArticle

Simoni, M, Santi, D, Negri, L, Hoffmann, I, Muratori, M, Baldi, E, Cambi, M, Marcou, M, Greither, T, Baraldi, E, Tagliavini, S, Carra, D, Lombardo, F, Gandini, L, Pallotti, F, Krausz, C, Rastrelli, G, Ferlin, A, Menegazzo, M, Pignatti, E, Linari, F, Marino, M, Benaglia, R, Levi-Setti, PE & Behre, HM 2016, 'Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: A pharmacogenetic study', Human Reproduction, vol. 31, no. 9, pp. 1960-1969. https://doi.org/10.1093/humrep/dew167
Simoni, Manuela ; Santi, Daniele ; Negri, Luciano ; Hoffmann, Ivan ; Muratori, Monica ; Baldi, Elisabetta ; Cambi, Marta ; Marcou, Marios ; Greither, Thomas ; Baraldi, Enrica ; Tagliavini, Simonetta ; Carra, Daniela ; Lombardo, Francesco ; Gandini, Loredana ; Pallotti, Francesco ; Krausz, Csilla ; Rastrelli, Giulia ; Ferlin, Alberto ; Menegazzo, Massimo ; Pignatti, Elisa ; Linari, Francesca ; Marino, Marco ; Benaglia, Renzo ; Levi-Setti, Paolo E. ; Behre, Hermann M. / Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S : A pharmacogenetic study. In: Human Reproduction. 2016 ; Vol. 31, No. 9. pp. 1960-1969.
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abstract = "Study question: Does the spermDNAfragmentation index (DFI) improve depending on the FSH receptor (FSHR) genotype as assessed by the nonsynonymous polymorphisms rs6166 (p.N680S) after 3 months of recombinant FSH treatment in men with idiopathic infertility? summary answer: FSH treatment significantly improves sperm DFI only in idiopathic infertile men with the p.N680S homozygous N FSHR. what is known already: FSH, fundamental for spermatogenesis, is empirically used to treat male idiopathic infertility and several studies suggest that DFI could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is known that the FSHR single nucleotide polymorphism (SNP) rs6166 (p.N680S) influences ovarian response in women and testicular volume in men. study design, size and duration: Amulticenter, longitudinal, prospective, open-label, two-arm clinical trial was performed. Subjects enrolled were idiopathic infertile men who received 150 IU recombinant human FSH s.c. every other day for 12 weeks and were followed-up for a further 12 weeks after FSH withdrawal. Patients were evaluated at baseline, at the end of treatment and at the end of follow-up. participants/materials, setting, methods: Eighty-nine men with idiopathic infertility carrier of the FSHR p.N680S homozygousNor S genotype, FSH ≤ 8 IU/l and DFI >15{\%},were enrolled. A total of 66 patients had DFI analysis completed on at least two visits. DFI was evaluated in one laboratory by TUNEL/PI (propidium iodide) assay coupled to flow cytometry, resolving two different fractions of sperm, namely the 'brighter' and 'dimmer' sperm DFI fractions. main results and the roleof chance: Thirty-eightmen(57.6{\%})were carriers of the p.N680S homozygousNand 28 (42.4{\%}) of the homozygous S FSHR. Sperm concentration/number was highly heterogeneous and both groups included men ranging from severe oligozoospermia to normozoospermia. Total DFI was significantly lower at the end of the study in homozygous carriers of the p.N680SNversus p.N680S S allele (P = 0.008). Total DFI decreased significantly from baseline to the end of the study (P = 0.021) only in carriers of the p.N680S homozygous N polymorphism, and this decrease involved the sperm population containing vital sperm (i.e. brighter sperm) (P = 0.008). The dimmer sperm DFI fraction, including only nonvital sperm, was significantly larger in p.N680S S homozygous patients than in homozygous N men (P = 0.018). Total DFIwas inversely related to total sperm number (P = 0.020) and progressive sperm motility (P = 0.014).Whenpatients were further stratified according to sperm concentration (normoozospermic versus oligozoospermic) or -211G>T polymorphism in the FSHB gene (rs10835638) (homozygous Gversus others), the significant improvement of sperm DFI in FSHR p.N680S homozygousNmen was independent of sperm concentration and associated with the homozygous FSHB -211G>T homozygous G genotype. limitations, reasons for caution: The statistical power of the study is 86.9{\%} with alpha error 0.05. This is the first pharmacogenetic study suggesting that FSH treatment induces a significant improvement of total DFI in men carriers of the p.N680S homozygousNFSHR; however, the results need to be confirmed in larger studies using a personalized FSH dosage and treatment duration. wider implications of the findings: The evaluation of sperm DFI as a surrogate marker of sperm quality, and of the FSHR SNP rs6166 (p.N680S), might be useful to predict the response to FSH treatment in men with idiopathic infertility. study funding/competing interest(s): The study was supported by an unrestricted grant to M.S. and H.M.B. from Merck Serono that provided the drug used in the study. MS received additional grants from Merck Serono and IBSA as well as honoraria from Merck Serono. The remaining authors declare that no conflicts of interest are present. trial registration number: EudraCT number 2010-020240-35.",
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author = "Manuela Simoni and Daniele Santi and Luciano Negri and Ivan Hoffmann and Monica Muratori and Elisabetta Baldi and Marta Cambi and Marios Marcou and Thomas Greither and Enrica Baraldi and Simonetta Tagliavini and Daniela Carra and Francesco Lombardo and Loredana Gandini and Francesco Pallotti and Csilla Krausz and Giulia Rastrelli and Alberto Ferlin and Massimo Menegazzo and Elisa Pignatti and Francesca Linari and Marco Marino and Renzo Benaglia and Levi-Setti, {Paolo E.} and Behre, {Hermann M.}",
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pages = "1960--1969",
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TY - JOUR

T1 - Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S

T2 - A pharmacogenetic study

AU - Simoni, Manuela

AU - Santi, Daniele

AU - Negri, Luciano

AU - Hoffmann, Ivan

AU - Muratori, Monica

AU - Baldi, Elisabetta

AU - Cambi, Marta

AU - Marcou, Marios

AU - Greither, Thomas

AU - Baraldi, Enrica

AU - Tagliavini, Simonetta

AU - Carra, Daniela

AU - Lombardo, Francesco

AU - Gandini, Loredana

AU - Pallotti, Francesco

AU - Krausz, Csilla

AU - Rastrelli, Giulia

AU - Ferlin, Alberto

AU - Menegazzo, Massimo

AU - Pignatti, Elisa

AU - Linari, Francesca

AU - Marino, Marco

AU - Benaglia, Renzo

AU - Levi-Setti, Paolo E.

AU - Behre, Hermann M.

PY - 2016

Y1 - 2016

N2 - Study question: Does the spermDNAfragmentation index (DFI) improve depending on the FSH receptor (FSHR) genotype as assessed by the nonsynonymous polymorphisms rs6166 (p.N680S) after 3 months of recombinant FSH treatment in men with idiopathic infertility? summary answer: FSH treatment significantly improves sperm DFI only in idiopathic infertile men with the p.N680S homozygous N FSHR. what is known already: FSH, fundamental for spermatogenesis, is empirically used to treat male idiopathic infertility and several studies suggest that DFI could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is known that the FSHR single nucleotide polymorphism (SNP) rs6166 (p.N680S) influences ovarian response in women and testicular volume in men. study design, size and duration: Amulticenter, longitudinal, prospective, open-label, two-arm clinical trial was performed. Subjects enrolled were idiopathic infertile men who received 150 IU recombinant human FSH s.c. every other day for 12 weeks and were followed-up for a further 12 weeks after FSH withdrawal. Patients were evaluated at baseline, at the end of treatment and at the end of follow-up. participants/materials, setting, methods: Eighty-nine men with idiopathic infertility carrier of the FSHR p.N680S homozygousNor S genotype, FSH ≤ 8 IU/l and DFI >15%,were enrolled. A total of 66 patients had DFI analysis completed on at least two visits. DFI was evaluated in one laboratory by TUNEL/PI (propidium iodide) assay coupled to flow cytometry, resolving two different fractions of sperm, namely the 'brighter' and 'dimmer' sperm DFI fractions. main results and the roleof chance: Thirty-eightmen(57.6%)were carriers of the p.N680S homozygousNand 28 (42.4%) of the homozygous S FSHR. Sperm concentration/number was highly heterogeneous and both groups included men ranging from severe oligozoospermia to normozoospermia. Total DFI was significantly lower at the end of the study in homozygous carriers of the p.N680SNversus p.N680S S allele (P = 0.008). Total DFI decreased significantly from baseline to the end of the study (P = 0.021) only in carriers of the p.N680S homozygous N polymorphism, and this decrease involved the sperm population containing vital sperm (i.e. brighter sperm) (P = 0.008). The dimmer sperm DFI fraction, including only nonvital sperm, was significantly larger in p.N680S S homozygous patients than in homozygous N men (P = 0.018). Total DFIwas inversely related to total sperm number (P = 0.020) and progressive sperm motility (P = 0.014).Whenpatients were further stratified according to sperm concentration (normoozospermic versus oligozoospermic) or -211G>T polymorphism in the FSHB gene (rs10835638) (homozygous Gversus others), the significant improvement of sperm DFI in FSHR p.N680S homozygousNmen was independent of sperm concentration and associated with the homozygous FSHB -211G>T homozygous G genotype. limitations, reasons for caution: The statistical power of the study is 86.9% with alpha error 0.05. This is the first pharmacogenetic study suggesting that FSH treatment induces a significant improvement of total DFI in men carriers of the p.N680S homozygousNFSHR; however, the results need to be confirmed in larger studies using a personalized FSH dosage and treatment duration. wider implications of the findings: The evaluation of sperm DFI as a surrogate marker of sperm quality, and of the FSHR SNP rs6166 (p.N680S), might be useful to predict the response to FSH treatment in men with idiopathic infertility. study funding/competing interest(s): The study was supported by an unrestricted grant to M.S. and H.M.B. from Merck Serono that provided the drug used in the study. MS received additional grants from Merck Serono and IBSA as well as honoraria from Merck Serono. The remaining authors declare that no conflicts of interest are present. trial registration number: EudraCT number 2010-020240-35.

AB - Study question: Does the spermDNAfragmentation index (DFI) improve depending on the FSH receptor (FSHR) genotype as assessed by the nonsynonymous polymorphisms rs6166 (p.N680S) after 3 months of recombinant FSH treatment in men with idiopathic infertility? summary answer: FSH treatment significantly improves sperm DFI only in idiopathic infertile men with the p.N680S homozygous N FSHR. what is known already: FSH, fundamental for spermatogenesis, is empirically used to treat male idiopathic infertility and several studies suggest that DFI could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is known that the FSHR single nucleotide polymorphism (SNP) rs6166 (p.N680S) influences ovarian response in women and testicular volume in men. study design, size and duration: Amulticenter, longitudinal, prospective, open-label, two-arm clinical trial was performed. Subjects enrolled were idiopathic infertile men who received 150 IU recombinant human FSH s.c. every other day for 12 weeks and were followed-up for a further 12 weeks after FSH withdrawal. Patients were evaluated at baseline, at the end of treatment and at the end of follow-up. participants/materials, setting, methods: Eighty-nine men with idiopathic infertility carrier of the FSHR p.N680S homozygousNor S genotype, FSH ≤ 8 IU/l and DFI >15%,were enrolled. A total of 66 patients had DFI analysis completed on at least two visits. DFI was evaluated in one laboratory by TUNEL/PI (propidium iodide) assay coupled to flow cytometry, resolving two different fractions of sperm, namely the 'brighter' and 'dimmer' sperm DFI fractions. main results and the roleof chance: Thirty-eightmen(57.6%)were carriers of the p.N680S homozygousNand 28 (42.4%) of the homozygous S FSHR. Sperm concentration/number was highly heterogeneous and both groups included men ranging from severe oligozoospermia to normozoospermia. Total DFI was significantly lower at the end of the study in homozygous carriers of the p.N680SNversus p.N680S S allele (P = 0.008). Total DFI decreased significantly from baseline to the end of the study (P = 0.021) only in carriers of the p.N680S homozygous N polymorphism, and this decrease involved the sperm population containing vital sperm (i.e. brighter sperm) (P = 0.008). The dimmer sperm DFI fraction, including only nonvital sperm, was significantly larger in p.N680S S homozygous patients than in homozygous N men (P = 0.018). Total DFIwas inversely related to total sperm number (P = 0.020) and progressive sperm motility (P = 0.014).Whenpatients were further stratified according to sperm concentration (normoozospermic versus oligozoospermic) or -211G>T polymorphism in the FSHB gene (rs10835638) (homozygous Gversus others), the significant improvement of sperm DFI in FSHR p.N680S homozygousNmen was independent of sperm concentration and associated with the homozygous FSHB -211G>T homozygous G genotype. limitations, reasons for caution: The statistical power of the study is 86.9% with alpha error 0.05. This is the first pharmacogenetic study suggesting that FSH treatment induces a significant improvement of total DFI in men carriers of the p.N680S homozygousNFSHR; however, the results need to be confirmed in larger studies using a personalized FSH dosage and treatment duration. wider implications of the findings: The evaluation of sperm DFI as a surrogate marker of sperm quality, and of the FSHR SNP rs6166 (p.N680S), might be useful to predict the response to FSH treatment in men with idiopathic infertility. study funding/competing interest(s): The study was supported by an unrestricted grant to M.S. and H.M.B. from Merck Serono that provided the drug used in the study. MS received additional grants from Merck Serono and IBSA as well as honoraria from Merck Serono. The remaining authors declare that no conflicts of interest are present. trial registration number: EudraCT number 2010-020240-35.

KW - FSH

KW - FSH receptor

KW - FSHB -211G/T

KW - FSHR pN680S

KW - Male infertility

KW - Sperm DNA fragmentation index

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JF - Human Reproduction

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