Testosterone Serum Levels Are Related to Sperm DNA Fragmentation Index Reduction after FSH Administration in Males with Idiopathic Infertility

Purpose: Although a robust physiological rationale supports follicle stimulating hormone (FSH) use in male idiopathic infertility, useful biomarkers to evaluate its efficacy are not available. Thus, the primary aim of the study was to evaluate if testosterone serum levels are related to sperm DNA fragmentation (sDF) index change after FSH administration. The secondary aim was to confirm sDF index validity as a biomarker of FSH administration effectiveness in male idiopathic infertility. Methods: A retrospective, post-hoc re-analysis was performed on prospectively collected raw data of clinical trials in which idiopathic infertile men were treated with FSH and both testosterone serum levels and sDF were reported. Results: Three trials were included, accounting for 251 patients. The comprehensive analysis confirmed FSH’s beneficial effect on spermatogenesis detected in each trial. Indeed, an overall significant sDF decrease (p < 0.001) of 20.2% of baseline value was detected. Although sDF resulted to be unrelated to testosterone serum levels at baseline, a significant correlation was highlighted after three months of FSH treatment (p = 0.002). Moreover, testosterone serum levels and patients’ age significantly correlated with sDF (p = 0.006). Dividing the cohort into responders/not responders to FSH treatment according to sDF change, the FSH effectiveness in terms of sDF improvement was related to testosterone and male age (p = 0.003). Conclusion: Exogenous FSH administration in male idiopathic infertility is efficient in reducing sDF basal levels by about 20%. In terms of sDF reduction, 59.2% of the patients treated were FSH-responders. After three months of FSH administration, a significant inverse correlation between sDF and testosterone was detected, suggesting an association between the FSH-administration-related sDF improvement and testosterone serum levels increase. These observations lead to the hypothesis that FSH may promote communications or interactions between Sertoli cells and Leydig cells.

[1]  D. Santi,et al.  Real-world evidence analysis of the follicle-stimulating hormone use in male idiopathic infertility. , 2022, Best practice & research. Clinical obstetrics & gynaecology.

[2]  P. Patel,et al.  An update on male infertility and intratesticular testosterone—insight into novel serum biomarkers , 2022, International Journal of Impotence Research.

[3]  E. Baldi,et al.  Extended semen examinations in the sixth edition of the World Health Organization manual on semen analysis: contributing to the understanding of the function of the male reproductive system. , 2022, Fertility and sterility.

[4]  OUP accepted manuscript , 2022, Human Reproduction Update.

[5]  A. Agarwal,et al.  The Sixth Edition of the WHO Manual for Human Semen Analysis: A Critical Review and SWOT Analysis , 2021, Life.

[6]  O. Ishihara,et al.  International Committee for Monitoring Assisted Reproductive Technologies world report: assisted reproductive technology, 2014†. , 2021, Human reproduction.

[7]  A. Salonia,et al.  European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility. , 2021, European urology.

[8]  Abdullah M. Al Khayal,et al.  Empirical therapy for male factor infertility: Survey of the current practice , 2021, Urology annals.

[9]  J. Milic,et al.  Health status is related to testosterone, estrone and body fat: moving to functional hypogonadism in adult men with HIV. , 2020, European journal of endocrinology.

[10]  G. Wood,et al.  Bariatric Surgery Impact on Reproductive Hormones, Semen Analysis, and Sperm DNA Fragmentation in Men with Severe Obesity: Prospective Study , 2020, Obesity Surgery.

[11]  E. Baldi,et al.  DNA Fragmentation in Viable and Non-Viable Spermatozoa Discriminates Fertile and Subfertile Subjects with Similar Accuracy , 2020, Journal of clinical medicine.

[12]  H. Thaker,et al.  Empirical medical therapy for idiopathic male infertility , 2020, F&S reports.

[13]  D. Santi,et al.  Follicle-Stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles , 2020, Journal of clinical medicine.

[14]  R. Ramasamy,et al.  Serum 17-Hydroxyprogesterone is a Potential Biomarker for Evaluating Intratesticular Testosterone. , 2020, The Journal of urology.

[15]  K. C. K. Lloyd,et al.  DNA fragmentation index (DFI) as a measure of sperm quality and fertility in mice , 2020, Scientific Reports.

[16]  S. Esteves,et al.  An update on clinical and surgical interventions to reduce sperm DNA fragmentation in infertile men , 2020, Andrology.

[17]  D. Santi,et al.  FSH treatment of male idiopathic infertility: Time for a paradigm change , 2019, Andrology.

[18]  L. Cree,et al.  Incidence of high sperm DNA fragmentation in a targeted population of subfertile men , 2019, Systems biology in reproductive medicine.

[19]  A. Calogero,et al.  FSH dosage effect on conventional sperm parameters: a meta-analysis of randomized controlled studies , 2019, Asian journal of andrology.

[20]  M. Nasr-Esfahani,et al.  Zeta method: A noninvasive method based on membrane charge for selecting spermatozoa expressing high level of phospholipaseCζ , 2019, Andrologia.

[21]  A. Lenzi,et al.  Human sperm motility: a molecular study of mitochondrial DNA, mitochondrial transcription factor A gene and DNA fragmentation , 2019, Molecular Biology Reports.

[22]  R. Rey,et al.  Comparing the role of anti-Müllerian hormone as a marker of FSH action in male and female fertility , 2019, Expert review of endocrinology & metabolism.

[23]  R. Ramasamy,et al.  Can serum 17-hydroxyprogesterone and insulin-like factor 3 be used as a marker for evaluation of intratesticular testosterone? , 2019, Translational andrology and urology.

[24]  E. Baldi,et al.  Sperm DNA Fragmentation: Mechanisms of Origin. , 2019, Advances in experimental medicine and biology.

[25]  D. Santi,et al.  Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management - meta-analyses. , 2018, Reproductive biomedicine online.

[26]  S. Esposito,et al.  Inhibin B in healthy and cryptorchid boys , 2018, Italian Journal of Pediatrics.

[27]  V. de Leo,et al.  Recombinant FSH Improves Sperm DNA Damage in Male Infertility: A Phase II Clinical Trial , 2018, Front. Endocrinol..

[28]  D. Goulis,et al.  European Academy of Andrology guideline Management of oligo‐astheno‐teratozoospermia , 2018, Andrology.

[29]  A. Lenzi,et al.  The use of follicle stimulating hormone (FSH) for the treatment of the infertile man: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS) , 2018, Journal of Endocrinological Investigation.

[30]  E. Baldi,et al.  Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: a pharmacogenetic study. , 2016, Human reproduction.

[31]  A. Kopitar,et al.  Sperm DNA fragmentation and mitochondrial membrane potential combined are better for predicting natural conception than standard sperm parameters. , 2016, Fertility and sterility.

[32]  G. Belaaloui,et al.  Sperm DNA Fragmentation and Standard Semen Parameters in Algerian Infertile Male Partners , 2015, The world journal of men's health.

[33]  E. Baldi,et al.  Investigation on the Origin of Sperm DNA Fragmentation: Role of Apoptosis, Immaturity and Oxidative Stress , 2015, Molecular medicine.

[34]  Kristian Thorlund,et al.  Reanalyses of randomized clinical trial data. , 2014, JAMA.

[35]  A. Zini,et al.  Sperm deoxyribonucleic acid damage in normozoospermic men is related to age and sperm progressive motility. , 2014, Fertility and sterility.

[36]  Osamu Ishihara,et al.  International Committee for Monitoring Assisted Reproductive Technologies world report: Assisted Reproductive Technology 2006. , 2013, Human reproduction.

[37]  S. Greenland,et al.  The table 2 fallacy: presenting and interpreting confounder and modifier coefficients. , 2013, American journal of epidemiology.

[38]  A. Matsumoto,et al.  Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: a randomized, controlled trial. , 2013, Fertility and sterility.

[39]  N. Colacurci,et al.  Recombinant human FSH reduces sperm DNA fragmentation in men with idiopathic oligoasthenoteratozoospermia. , 2012, Journal of andrology.

[40]  Denny Sakkas,et al.  Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. , 2010, Fertility and sterility.

[41]  P. Cohen-Bacrie,et al.  Correlation between DNA damage and sperm parameters: a prospective study of 1,633 patients. , 2009, Fertility and sterility.

[42]  C. O’Flaherty,et al.  Characterization of sperm chromatin quality in testicular cancer and Hodgkin's lymphoma patients prior to chemotherapy. , 2008, Human reproduction.

[43]  A. Matsumoto,et al.  Serum 17-hydroxyprogesterone strongly correlates with intratesticular testosterone in gonadotropin-suppressed normal men receiving various dosages of human chorionic gonadotropin. , 2008, Fertility and sterility.

[44]  R. Sram,et al.  GSTM1 genotype influences the susceptibility of men to sperm DNA damage associated with exposure to air pollution. , 2007, Mutation research.

[45]  C. Farquhar,et al.  Gonadotrophins for idiopathic male factor subfertility. , 2007, The Cochrane database of systematic reviews.

[46]  H. Katayose,et al.  Successful pregnancy after ICSI with strontium oocyte activation in low rates of fertilization. , 2006, Reproductive biomedicine online.

[47]  Thomas T. F. Huang,et al.  An endogenous nuclease in hamster, mouse, and human spermatozoa cleaves DNA into loop-sized fragments. , 2005, Journal of andrology.

[48]  K. Chaudhury,et al.  Acrosin activity as a potential marker for sperm membrane characteristics in unexplained male infertility. , 2005, Fertility and sterility.

[49]  Jens Peter Bonde,et al.  Correlation between sperm motility and sperm chromatin structure assay parameters. , 2003, Fertility and sterility.

[50]  H. Baker,et al.  Frequency of defective sperm-zona pellucida interaction in severely teratozoospermic infertile men. , 2003, Human reproduction.

[51]  N. Tarozzi,et al.  Nature of DNA Damage in Ejaculated Human Spermatozoa and the Possible Involvement of Apoptosis1 , 2002, Biology of reproduction.

[52]  D. Evenson,et al.  Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. , 2002, Journal of andrology.

[53]  A. Agarwal,et al.  Characterization of subsets of human spermatozoa at different stages of maturation: implications in the diagnosis and treatment of male infertility. , 2001, Human reproduction.

[54]  E. Clegg,et al.  Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. , 1999, Human reproduction.

[55]  E. Nieschlag,et al.  An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. , 1996, The Journal of clinical endocrinology and metabolism.

[56]  F. Longo,et al.  Chromatin structure-function alterations during mammalian spermatogenesis: DNA nicking and repair in elongating spermatids. , 1993, European journal of histochemistry : EJH.