Oligozoospermia: etiology, pathogenesis, and algorithm for differential diagnostics

Aim: to compare international and Russian epidemiological data on the causes of oligozoospermia and to develop differential diagnostics and patient management algorithm by taking into account endocrine, genetic and immunological factors.

Materials and Methods. A retrospective observational study included 210 men aged 25-45 years with confirmed oligozoospermia and infertility complaints. All patients underwent semen analysis according to the World Health Organization standards (2021), blood hormone testing (follicle-stimulating hormone, luteinizing hormone, total testosterone, prolactin, thyroid-stimulating hormone, estradiol, inhibin B, anti-Müllerian hormone, 17-hydroxyprogesterone), scrotal ultrasound, as well as genetic testing (karyotyping and Y-chromosome microdeletions). The data provided by international clinical guidelines, European Association of Urology (EAU, 2024), American Urological Association/American Society for Reproductive Medicine (AUA/ASRM, 2024), publications in Russian and English retrieved from PubMed/MEDLINE, Scopus and eLibrary databases were analyzed.

Results. A wide spectrum of causes of oligozoospermia was identified: endocrine disorders (hypo- and hypergonadotropic hypogonadism), Klinefelter syndrome, Y-chromosome microdeletions, varicocele, and obstructive forms. The pathophysiological mechanisms of hypogonadism, the clinical significance of Klinefelter syndrome, features of AZF deletions, and the role of varicocele as a potentially reversible cause of male infertility are discussed in detail.

Conclusion. Differential diagnosis of oligozoospermia requires a comprehensive, stepwise approach. Incorporating repeated semen analysis, hormonal profiling, ultrasound, and genetic testing into the diagnostic algorithm enables identification of reversible causes (varicocele, hypogonadotropic hypogonadism) as well as timely diagnostics of genetic forms (Klinefelter syndrome, Y-chromosome microdeletions). This ensures a personalized therapeutic strategy and improves the effectiveness of assisted reproductive technologies.

1. World Health Organization. WHO laboratory manual for the examination and processing of human semen. 6th ed. Geneva: WHO Press, 2021. 292 р. https://doi.org/10.1002/9781119037063.

2. EAU Guidelines. Edn. presented at the EAU Annual Congress, Madrid, 2025. http://uroweb.org/guidelines/compilations-of-all-guidelines/.

3. Brannigan R.E., Hermanson L., Kaczmarek J. et al. Updates to male infertility: AUA/ASRM Guideline. J Urol. 2024;212(6):789–99. https://doi.org/10.1097/JU.0000000000004180/

4. Salonia A., Bettocchi C., Boeri L. et al. European Association of Urology guidelines on sexual and reproductive health. Part II: male sexual dysfunction. Eur Urol. 2021;80(3):333–57. https://doi.org/10.1016/j.eururo.2021.06.014.

5. Huhtaniemi I., Tajar A., Lee D.K. et al. Hypogonadism in ageing men: European Male Aging Study. J Clin Endocrinol Metab. 2012;97(5):1508–16. https://doi.org/10.1210/jc.2011-2513.

6. Abdel-Meguid T.A., Al-Sayyad A., Tayib A., Farsi H.M. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol. 2011;59(3):455–61. https://doi.org/10.1016/j.eururo.2010.12.008.

7. Pitteloud N., Hayes F.J., Boepple P.A. et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in hCG-induced spermatogenesis in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002;87(1):55–62. https://doi.org/10.1210/jcem.87.1.8131.

8. Corona G., Goulis D.G., Huhtaniemi I. et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males. Andrology. 2020;8(4):970–87. https://doi.org/10.1111/andr.12770.

9. Kavoussi P.K., Hudson K., Machen G.L. et al. FSH levels and testicular volumes are associated with the severity of testicular histopathology in men with non-obstructive azoospermia. J Assist Reprod Genet. 2021;38(11):3015–8. https://doi.org/10.1007/s10815-021-02313-y.

10. Dohle G.R., Colpi G.M., Hargreave T.B. et al. EAU guidelines on male infertility. Eur Urol. 2005;48(5):703–11. https://doi.org/10.1016/j.eururo.2005.06.002.

11. Simoni M., Santi D. FSH treatment of male idiopathic infertility: Time for a paradigm change. Andrology. 2020;8(3):535–44. https://doi.org/10.1111/andr.12746.

12. Selice R., Garolla A., Pengo M. et al. The response to FSH treatment in oligozoospermic men depends on FSH receptor gene polymorphisms. Int J Androl. 2011;34(4):306–12. https://doi.org/10.1111/j.1365-2605.2010.01086.x.

13. Kliesch S., Behre H.M., Nieschlag E. Recombinant human follicle-stimulating hormone and human chorionic gonadotropin for induction of spermatogenesis in a hypogonadotropic male. Fertil Steril. 1995;63(6):1326–8. https://doi.org/10.1016/s0015-0282(16)57619-5.

14. Kohn T.P., Kohn J.R., Owen R.C., Coward R.M. The prevalence of Y-chromosome microdeletions in oligospermic men: a systematic review and meta-analysis of European and North American studies. Eur Urol. 2019;76(5):626–36. https://doi.org/10.1016/j.eururo.2019.07.033.

15. Krausz C., Casamonti E. Spermatogenic failure and the Y chromosome. Hum Genet. 2017;136(5):637–55. https://doi.org/10.1007/s00439-017-1793-8.

16. Speiser P.W., White P.C. Congenital adrenal hyperplasia. N Engl J Med. 2003;349(8):776–88. https://doi.org/10.1056/NEJMra021561.

17. Baazeem A., Belzile E., Ciampi A. et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol. 2011;60(4):796–808. https://doi.org/10.1016/j.eururo.2011.06.018.

18. Sharma R., Harlev A., Agarwal A., Esteves S.C. Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 World Health Organization laboratory methods for the examination of human semen. Eur Urol. 2016;70(4):635–645. https://doi.org/10.1016/j.eururo.2016.04.010.

19. Cannarella R., Shah R., Hamoda T.A.A. et al. Global andrology forum. Does varicocele repair improve conventional semen parameters? A meta-analytic study of before-after data. World J Mens Health. 2024;42(1):92–132. https://doi.org/10.5534/wjmh.230034.

20. Gillam M.P., Molitch M.E., Lombardi G., Colao A. Advances in the treatment of prolactinomas. Endocr Rev. 2006;27(5):485–534. https://doi.org/10.1210/er.2005-9998.

21. Melmed S., Casanueva F.F., Hoffman A.R. et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–88. https://doi.org/10.1210/jc.2010-1692.

22. Hoang V.T., Van H.A.T., Hoang T.H. et al. A review of classification, diagnosis, and management of hydrocele. J Ultrasound Med. 2024;43(3):599–607. https://doi.org/10.1002/jum.16380.

23. Haratian K., Faegh A., Mehrpoor G. et al. Potential causes and associated conditions with anti-sperm antibody production among infertile males: a systematic literature review. BMC Immunol. 2025;26(1):58. https://doi.org/10.1186/s12865-025-00740-5.

24. Kotov S.V., Korochkin N.D., Klimenko A.A. Recurrent varicocele. [Retsidivnoe varikotsele]. Vestnik urologii. 2021;9(2):132–41. https://doi.org/10.21886/2308-6424-2021-9-2-132-141. (In Russ.).

25. Rozhivanov R.V., Parfenova N.S., Kurbatov D.G. Treatment of oligozoospermia in men with infertility. [Lechenie oligospermii u muzhchin s besplodiem]. Problemy endokrinologii. 2010;56(1):31–4. https://doi.org/10.14341/probl201056131-34. (In Russ.).

26. Ivanov N.V., Amandullaev K.Z., Yusupova Sh.K. et al. Azoospermia: etiology, pathogenesis, prevalence of forms and algorithm for differential diagnostics. [Azoospermiya: etiologiya, patogenez, rasprostranennost' form i algoritm differencial'noj diagnostiki]. Obstetrics, Gynecology and Reproduction. 2025;19(6). (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2025.679.