Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The effect of red blood cell disorders on male fertility and reproductive health

Nature Reviews Urology (2024)Cite this article

Subjects

Abstract

Male infertility is defined as a failure to conceive after 12 months of unprotected intercourse owing to suspected male reproductive factors. Non-malignant red blood cell disorders are systemic conditions that have been associated with male infertility with varying severity and strength of evidence. Hereditary haemoglobinopathies and bone marrow failure syndromes have been associated with hypothalamic–pituitary–gonadal axis dysfunction, hypogonadism, and abnormal sperm parameters. Bone marrow transplantation is a potential cure for these conditions, but exposes patients to potentially gonadotoxic chemotherapy and/or radiation that could further impair fertility. Iron imbalance might also reduce male fertility. Thus, disorders of hereditary iron overload can cause iron deposition in tissues that might result in hypogonadism and impaired spermatogenesis, whereas severe iron deficiency can propagate anaemias that decrease gonadotropin release and sperm counts. Reproductive urologists should be included in the comprehensive care of patients with red blood cell disorders, especially when gonadotoxic treatments are being considered, to ensure fertility concerns are appropriately evaluated and managed.

Key points

  • Sickle cell disease is associated with semen parameter abnormalities in the majority of patients. This condition is commonly treated with hydroxyurea and bone marrow transplantation, which exposes patients to gonadotoxic agents (induction chemotherapy and/or radiation) that can temporarily or permanently impair spermatogenesis.

  • β-thalassaemia major results in ineffective haemoglobin synthesis that requires chronic red blood cell transfusions, which might result in iatrogenic iron accumulation, hypogonadism and/or aberrant spermatogenesis.

  • Hereditary haemochromatosis is associated with a state of iron excess from increased absorption of dietary iron, which might result in hypogonadism secondary to effects on the pituitary gland and testes.

  • Some bone marrow failure syndromes are associated with faulty DNA repair mechanisms that might also impair spermatogenesis.

  • The potential effects of red blood cell disorders on male reproduction should be considered, and reproductive urologists should be involved in the comprehensive care of these patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Physiology of iron absorption, usage and storage.
Fig. 2: Factors influencing hepcidin levels and subsequent effects on serum iron.

Similar content being viewed by others

References

  1. Zegers-Hochschild, F. et al. The international glossary on infertility and fertility care, 2017. Fertil. Steril. 108, 393–406 (2017).

    Article  PubMed  Google Scholar 

  2. Agarwal, A. et al. Male infertility. Lancet 397, 319–333 (2021).

    Article  PubMed  Google Scholar 

  3. Agarwal, A., Mulgund, A., Hamada, A. & Chyatte, M. R. A unique view on male infertility around the globe. Reprod. Biol. Endocrinol. 13, 37 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil. Steril. 103, e18–e25 (2015).

    Article  Google Scholar 

  5. Carlsen, E., Giwercman, A., Keiding, N. & Skakkebaek, N. E. Evidence for decreasing quality of semen during past 50 years. BMJ 305, 609–613 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mínguez-Alarcón, L. et al. Secular trends in semen parameters among men attending a fertility center between 2000 and 2017: identifying potential predictors. Environ. Int. 121, 1297–1303 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sengupta, P., Dutta, S. & Krajewska-Kulak, E. The disappearing sperms: analysis of reports published between 1980 and 2015. Am. J. Mens. Health 11, 1279–1304 (2017).

    Article  PubMed  Google Scholar 

  8. Abbaspour, N., Hurrell, R. & Kelishadi, R. Review on iron and its importance for human health. J. Res. Med. Sci. 19, 164–174 (2014).

    PubMed  PubMed Central  Google Scholar 

  9. Gulek, S., Anderson, G. J. & Collins, J. F. Mechanistic and regulatory aspects of intestinal iron absorption. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G397–G409 (2014).

    Article  Google Scholar 

  10. Sebastiani, G., Wilkinson, N. & Pantopoulos, K. Pharmacological targeting of the hepcidin/ferroportin axis. Front. Pharmacol. 7, 160 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ginzburg, Y. Z. Chapter two - hepcidin-ferroportin axis in health and disease. in: Litwack, G. (ed.) Vitamins and Hormones. 110, 17–45 (Academic Press, 2019).

  12. Nemeth, E. & Ganz, T. The role of hepcidin in iron metabolism. Acta Haematol. 122, 2284–2288 (2009).

    Article  Google Scholar 

  13. Wang, L. & Cherayil, B. J. Ironing out the wrinkles in host defense: interactions between iron homeostasis and innate immunity. J. Innate Immun. 1, 455–464 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Musci, G., Polticelli, F. & Bonaccorsi di Patti, M. C. Ceruloplasmin-ferroportin system of iron traffic in vertebrates. World J. Biol. Chem. 5, 204–215 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. Bartnikas, T. B. Known and potential roles of transferrin in iron biology. Biometals 25, 677–686 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sasaki, R., Masuda, S. & Nagao, M. Erythropoietin: multiple physiological functions and regulation of biosynthesis. Biosci. Biotechnol. Biochem. 64, 1775–1793 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Tremellen, K. Oxidative stress and male infertility–a clinical perspective. Hum. Reprod. Update 14, 243–258 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Farid, Y., Bowman, N. S. & Lecat, P. Biochemistry, hemoglobin synthesis. In: StatPearls. (StatPearls Publishing, 2022).

  19. Harewood, J. & Azevedo, A. M. Alpha thalassemia. In: StatPearls. (StatPearls Publishing, 2022).

  20. Forget, B. G. & Bunn, H. F. Classification of the disorders of hemoglobin. Cold Spring Harb. Perspect. Med. 3, a011684 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Therrell, B. L., Lloyd-Puryear, M. A., Eckman, J. R. & Mann, M. Y. Newborn screening for sickle cell diseases in the United States: a review of data spanning 2 decades. Semin. Perinatol. 39, 238–251 (2015).

    Article  PubMed  Google Scholar 

  22. Sedrak A & Kondamudi NP. Sickle Cell Disease. (StatPearls Publishing, 2022).

  23. Sundd, P., Gladwin, M. T. & Novelli, E. M. Pathophysiology of sickle cell disease. Annu. Rev. Pathol. 14, 263–292 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Rees, D. C., Williams, T. N. & Gladwin, M. T. Sickle-cell disease. Lancet 376, 2018–2031 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Yasara, N., Premawardhena, A. & Mettananda, S. A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic. Orphanet J. Rare Dis. 16, 114 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Taddesse, A. et al. Hypogonadism in patients with sickle cell disease: central or peripheral? Acta Haematol. 128, 65–68 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Fageera, W. et al. Placebo response and its determinants in children with ADHD across multiple observers and settings: a randomized clinical trial. Int. J. Methods Psychiatr. Res. 27, e1572 (2018).

    Article  PubMed  Google Scholar 

  28. Smith-Whitley, K. Reproductive issues in sickle cell disease. Blood 124, 3538–3543 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Berthaut, I. et al. Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males. Haematologica 93, 988–993 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Nahoum, C. R., Fontes, E. A. & Freire, F. R. Semen analysis in sickle cell disease. Andrologia 12, 542–545 (1980).

    Article  CAS  PubMed  Google Scholar 

  31. Shin, J.-H., Mori, C. & Shiota, K. Involvement of germ cell apoptosis in the induction of testicular toxicity following hydroxyurea treatment. Toxicol. Appl. Pharmacol. 155, 139–149 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Jones, K. M. et al. Adverse effects of a clinically relevant dose of hydroxyurea used for the treatment of sickle cell disease on male fertility endpoints. Int. J. Environ. Res. Public. Health 6, 1124–1144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sahoo, L. K. et al. Study of seminal fluid parameters and fertility of male sickle cell disease patients and potential impact of hydroxyurea treatment. J. Assoc. Physicians India 65, 22–25 (2017).

    PubMed  Google Scholar 

  34. Isabelle, B. et al. Adverse effect of hydroxyurea on spermatogenesis in patients with sickle cell anemia after 6 months of treatment. Blood 130, 2354–2356 (2017).

    Article  Google Scholar 

  35. Joseph, L. et al. Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease. Blood 137, 826–829 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. As, G. et al. Hydroxyurea does not affect the spermatogonial pool in prepubertal patients with sickle cell disease. Blood 137, 856–859 (2021).

    Article  Google Scholar 

  37. Fitzhugh, C. D. & Walters, M. C. The case for HLA-identical sibling hematopoietic stem cell transplantation in children with symptomatic sickle cell anemia. Blood Adv. 1, 2563–2567 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sargur Madabushi, S. et al. Development and characterization of a preclinical total marrow irradiation conditioning-based bone marrow transplant model for sickle cell disease. Front. Oncol. 12, 969429 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bhatia, M. et al. Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. Bone Marrow Transpl. 49, 913–920 (2014).

    Article  CAS  Google Scholar 

  40. Zhao, J. et al. Adolescent male fertility following reduced-intensity conditioning regimen for hematopoietic stem cell transplantation in non-malignant disorders. Pediatr. Transplant. 23, e13496 (2019).

    Article  PubMed  Google Scholar 

  41. Can, B. et al. Gonadal status and sexual function at long-term follow-up after allogeneic stem cell transplantation in adult patients with sickle cell disease. Exp. Clin. Transplant. https://doi.org/10.6002/ect.2021.0392 (2022).

  42. Abraham, A. A. & Tisdale, J. F. Gene therapy for sickle cell disease: moving from the bench to the bedside. Blood 138, 932–941 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kanter, J. et al. Biologic and clinical efficacy of lentiglobin for sickle cell disease. N. Engl. J. Med. 386, 617–628 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Musicki, B. & Burnett, A. L. Testosterone deficiency in sickle cell disease: recognition and remediation. Front. Endocrinol. 13, 892184 (2022).

    Article  Google Scholar 

  45. Araujo, A. B. et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab. 89, 5920–5926 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Leisegang, K., Roychoudhury, S., Slama, P. & Finelli, R. The mechanisms and management of age-related oxidative stress in male hypogonadism associated with non-communicable chronic disease. Antioxid. Basel Switz. 10, 1834 (2021).

    Article  CAS  Google Scholar 

  47. Roychoudhury, S. et al. Environmental factors-induced oxidative stress: hormonal and molecular pathway disruptions in hypogonadism and erectile dysfunction. Antioxidants 10, 837 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vona, R. et al. Sickle cell disease: role of oxidative stress and antioxidant therapy. Antioxid. Basel Switz. 10, 296 (2021).

    Article  CAS  Google Scholar 

  49. Levey, H. R., Segal, R. L. & Bivalacqua, T. J. Management of priapism: an update for clinicians. Ther. Adv. Urol. 6, 230–244 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Musicki, B. et al. Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis. Andrology 6, 184–191 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Lagoda, G., Sezen, S. F., Cabrini, M. R., Musicki, B. & Burnett, A. L. Molecular analysis of erection regulatory factors in sickle cell disease associated priapism in the human penis. J. Urol. 189, 762–768 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Dean, R. C. & Lue, T. F. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol. Clin. North. Am. 32, 379–395 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lin, C.-S., Chow, S., Lau, A., Tu, R. & Lue, T. F. Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters. Int. J. Impot. Res. 14, 15–24 (2002).

    Article  PubMed  Google Scholar 

  54. Goglia, L. et al. Endothelial regulation of eNOS, PAI-1 and t-PA by testosterone and dihydrotestosterone in vitro and in vivo. Mol. Hum. Reprod. 16, 761–769 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Crane, G. M. & Bennett, N. E. Priapism in sickle cell anemia: emerging mechanistic understanding and better preventative strategies. Anemia 2011, 297364 (2011).

    Article  PubMed  Google Scholar 

  56. Hou, L. T. & Burnett, A. L. Regimented phosphodiesterase type 5 inhibitor use reduces emergency department visits for recurrent ischemic priapism. J. Urol. 205, 545–553 (2021).

    Article  PubMed  Google Scholar 

  57. Nickel, R. S. et al. Fertility after curative therapy for sickle cell disease: a comprehensive review to guide care. J. Clin. Med. 11, 2318 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Committee Opinion No. 691. Carrier screening for genetic conditions. Obstet. Gynecol. 129, e41–e55 (2017).

    Article  Google Scholar 

  59. Leichtmann-Bardoogo, Y. et al. Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload. Am. J. Physiol. Endocrinol. Metab. 302, E1519–E1530 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Jabado, N., Canonne-Hergaux, F., Gruenheid, S., Picard, V. & Gros, P. Iron transporter Nramp2/DMT-1 is associated with the membrane of phagosomes in macrophages and Sertoli cells. Blood 100, 2617–2622 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Zhang, F.-L. et al. Multi-omics analysis reveals that iron deficiency impairs spermatogenesis by gut-hormone synthesis axis. Ecotoxicol. Environ. Saf. 248, 114344 (2022).

    Article  CAS  PubMed  Google Scholar 

  62. Lucesoli, F., Caligiuri, M., Roberti, M. F., Perazzo, J. C. & Fraga, C. G. Dose-dependent increase of oxidative damage in the testes of rats subjected to acute iron overload. Arch. Biochem. Biophys. 372, 37–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Angastiniotis, M. & Lobitz, S. Thalassemias: an overview. Int. J. Neonatal Screen. 5, 16 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Bellis, G. & Parant, A. Beta-thalassemia in Mediterranean countries. Findings and outlook. Investig. Geográficas https://doi.org/10.14198/INGEO.19079 (2021).

  65. Bajwa, H. & Basit, H. Thalassemia. in: StatPearls. (StatPearls Publishing, 2022).

  66. Ali, S. et al. Current status of beta-thalassemia and its treatment strategies. Mol. Genet. Genom. Med. 9, e1788 (2021).

    Article  CAS  Google Scholar 

  67. Viprakasit, V. & Ekwattanakit, S. Clinical classification, screening and diagnosis for thalassemia. Hematol. Oncol. Clin. North. Am. 32, 193–211 (2018).

    Article  PubMed  Google Scholar 

  68. Lal, A. et al. The transfusion management of beta thalassemia in the United States. Transfusion 61, 3027–3039 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Taher, A. T. & Saliba, A. N. Iron overload in thalassemia: different organs at different rates. Hematol. Am. Soc. Hematol. Educ. Program. 2017, 265–271 (2017).

    Article  Google Scholar 

  70. De Sanctis, V. et al. Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment. Acta Bio-Med. Atenei Parm. 89, 6–15 (2018).

    Google Scholar 

  71. Stewart, J., Evan, G., Watson, J. & Sikora, K. Detection of the c-myc oncogene product in colonic polyps and carcinomas. Br. J. Cancer 53, 1–6 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. De Sanctis, V. et al. Gonadal dysfunction in adult male patients with thalassemia major: an update for clinicians caring for thalassemia. Expert. Rev. Hematol. 10, 1095–1106 (2017).

    Article  PubMed  Google Scholar 

  73. Skordis, N. & Kyriakou, A. The multifactorial origin of growth failure in thalassaemia. Pediatr. Endocrinol. Rev. PER 8, 271–277 (2011).

    PubMed  Google Scholar 

  74. Safarinejad, M. R. Evaluation of semen quality, endocrine profile and hypothalamus-pituitary-testis axis in male patients with homozygous β-thalassemia major. J. Urol. 179, 2327–2332 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Soliman, A., Yasin, M., El-Awwa, A., Osman, M. & de Sanctis, V. Acute effects of blood transfusion on pituitary gonadal axis and sperm parameters in adolescents and young men with thalassemia major: a pilot study. Fertil. Steril. 98, 638–643 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Singer, S. T. et al. Fertility in transfusion-dependent thalassemia men: effects of iron burden on the reproductive axis. Am. J. Hematol. 90, E190–E192 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Perera, D. et al. Sperm DNA damage in potentially fertile homozygous β-thalassaemia patients with iron overload. Hum. Reprod. 17, 1820–1825 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, M.-J. et al. Effect of iron overload on impaired fertility in male patients with transfusion-dependent beta-thalassemia. Pediatr. Res. 83, 655–661 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. ElAlfy, M. & Ragab, E. Alpha thalassemia: practice essentials, pathophysiology, etiology. Egypt. J. Haematol. 38, 149–154 (2013).

    Google Scholar 

  80. Shalitin, S. et al. Serum ferritin level as a predictor of impaired growth and puberty in thalassemia major patients. Eur. J. Haematol. 74, 93–100 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Multicentre study on prevalence of endocrine complications in thalassaemia major. Italian working group on endocrine complications in non-endocrine diseases. Clin. Endocrinol. 42, 581–586 (1995).

    Google Scholar 

  82. ElAlfy, M., Ragab, E., Abdel-Aziz, E., Massoud, W. & Elsedfy, H. Deferiprone and desferrioxamine combined chelation could improve puberty of adolescent males with β-thalassemia major with preserved pituitary and testicular function. Egypt. J. Haematol. 38, 149.

  83. Bronspiegel-Weintrob, N. et al. Effect of age at the start of iron chelation therapy on gonadal function in beta-thalassemia major. N. Engl. J. Med. 323, 713–719 (1990).

    Article  CAS  PubMed  Google Scholar 

  84. Arya, Y. & Sahi, P. K. Cell-based gene therapy for b-thalassemia. Indian. Pediatr. 60, 313–316 (2023).

    Article  PubMed  Google Scholar 

  85. Thompson, A. A. et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 378, 1479–1493 (2018).

    Article  CAS  PubMed  Google Scholar 

  86. Cavazzana-Calvo, M. et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 467, 318–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pipe, S. W. et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N. Engl. J. Med. 388, 706–718 (2023).

    Article  CAS  PubMed  Google Scholar 

  88. Huijben, M. et al. Clomiphene citrate for male infertility: a systematic review and meta-analysis. Andrology 11, 987–996 (2023).

    Article  CAS  PubMed  Google Scholar 

  89. Naelitz, B. D. et al. Testosterone and luteinizing hormone predict semen parameter improvement in infertile men treated with anastrozole. Fertil. Steril. 120, 746–754 (2023).

    Article  CAS  PubMed  Google Scholar 

  90. Nickel, R. S. et al. Optimising the screening for haemoglobinopathies in pregnancy planning. Hum. Fertil. Camb. Engl. 1–6 https://doi.org/10.1080/14647273.2023.2190041 (2023).

  91. Satirapod, C. et al. Clinical utility of combined preimplantation genetic testing methods in couples at risk of passing on beta thalassemia/hemoglobin E disease: a retrospective review from a single center. PLoS One 14, e0225457 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chaibunruang, A. et al. Molecular and hematological studies in a large cohort of α(0)-thalassemia in northeast Thailand: data from a single referral center. Blood Cells Mol. Dis. 51, 89–93 (2013).

    Article  PubMed  Google Scholar 

  93. Lal, A. & Vichinsky, E. The clinical phenotypes of alpha thalassemia. Hematol. Oncol. Clin. North. Am. 37, 327–339 (2023).

    Article  PubMed  Google Scholar 

  94. Golfeyz, S., Lewis, S. & Weisberg, I. S. Hemochromatosis: pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI. Expert. Rev. Gastroenterol. Hepatol. 12, 767–778 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Merryweather-Clarke, A. T., Pointon, J. J., Shearman, J. D. & Robson, K. J. Global prevalence of putative haemochromatosis mutations. J. Med. Genet. 34, 275–278 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pantopoulos, K. Inherited disorders of iron overload. Front. Nutr. 5, (2018).

  97. Buretić-Tomljanović, A. et al. The impact of hemochromatosis mutations and transferrin genotype on gonadotropin serum levels in infertile men. Fertil. Steril. 91, 1793–1800 (2009).

    Article  PubMed  Google Scholar 

  98. Gunel-Ozcan, A., Basar, M. M., Kısa, U. & Ankaralı, H. C. Hereditary haemochromatosis gene (HFE) H63D mutation shows an association with abnormal sperm motility. Mol. Biol. Rep. 36, 1709–1714 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Peterlin, B. et al. Analysis of the hemochromatosis mutations C282Y and H63D in infertile men. Fertil. Steril. 86, 1796–1798 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. El Osta, R., Grandpre, N., Monnin, N., Hubert, J. & Koscinski, I. Hypogonadotropic hypogonadism in men with hereditary hemochromatosis. Basic. Clin. Androl. 27, 13 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Tvrda, E., Peer, R., Sikka, S. C. & Agarwal, A. Iron and copper in male reproduction: a double-edged sword. J. Assist. Reprod. Genet. 32, 3–16 (2015).

    Article  PubMed  Google Scholar 

  102. McDermott, J. H. & Walsh, C. H. Hypogonadism in hereditary hemochromatosis. J. Clin. Endocrinol. Metab. 90, 2451–2455 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Oehninger, S., Pike, I. & Slotnick, N. Hemochromatosis and male infertility. Obstet. Gynecol. 92, 652–653 (1998).

    CAS  PubMed  Google Scholar 

  104. Angelopoulos, N. G., Goula, A., Dimitriou, E. & Tolis, G. Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis. Fertil. Steril. 84, 1744.e11–1744.e13 (2005).

    Article  Google Scholar 

  105. Ide, V., Vanderschueren, D. & Antonio, L. Treatment of men with central hypogonadism: alternatives for testosterone replacement therapy. Int. J. Mol. Sci. 22, 21 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Meerim, P. Overview of inherited bone marrow failure syndromes. Blood Res 57, 49–54 (2022).

    Article  Google Scholar 

  107. Alter, B. P. Inherited bone marrow failure syndromes: considerations pre- and posttransplant. Blood 130, 2257–2264 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gulbis, B. et al. Epidemiology of rare anaemias in Europe. Adv. Exp. Med. Biol. 686, 375–396 (2010).

    Article  PubMed  Google Scholar 

  109. Auerbach, A. D. Fanconi anemia and its diagnosis. Mutat. Res. 668, 4–10 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fiesco-Roa, M. O., Giri, N., McReynolds, L. J., Best, A. F. & Alter, B. P. Genotype-phenotype associations in Fanconi anemia: a literature review. Blood Rev. 37, 100589 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tsui, V. & Crismani, W. The Fanconi anemia pathway and fertility. Trends Genet 35, 199–214 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Liu, J. M., Auerbach, A. D. & Young, N. S. Fanconi anemia presenting unexpectedly in an adult kindred with no dysmorphic features. Am. J. Med. 91, 555–557 (1991).

    Article  CAS  PubMed  Google Scholar 

  113. Basbous, J. & Constantinou, A. A tumor suppressive DNA translocase named FANCM. Crit. Rev. Biochem. Mol. Biol. 54, 27–40 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Kasak, L. et al. Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia. Am. J. Hum. Genet. 103, 200–212 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yin, H. et al. A homozygous FANCM frameshift pathogenic variant causes male infertility. Genet. Med. 21, 62–70 (2019).

    Article  PubMed  Google Scholar 

  116. Luo, Y. et al. Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling. PLOS Genet. 10, e1004471 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Fu, C., Begum, K., Jordan, P. W., He, Y. & Overbeek, P. A. Dearth and delayed maturation of testicular germ cells in Fanconi anemia E mutant male mice. PLoS One 11, e0159800 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Wagner, J. E. et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 109, 2256–2262 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ginsberg, J. P. et al. Testicular tissue cryopreservation in prepubertal male children: an analysis of parental decision-making. Pediatr. Blood Cancer 61, 1673–1678 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Paustian, L. et al. Androgen therapy in Fanconi anemia: a retrospective analysis of 30 years in Germany. Pediatr. Hematol. Oncol. 33, 5–12 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Zhang, Q.-S. et al. Oxymetholone therapy of Fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. Stem Cell Rep. 4, 90–102 (2014).

    Article  Google Scholar 

  122. Ribeiro, L. L. et al. Excellent option therapy of BONE marrow failure in Fanconi anemia patients without full match donor. Blood 128, 5075 (2016).

    Article  Google Scholar 

  123. Verlinsky, Y., Rechitsky, S., Schoolcraft, W., Strom, C. & Kuliev, A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 285, 3130–3133 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Gluckman, E. et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N. Engl. J. Med. 321, 1174–1178 (1989).

    Article  CAS  PubMed  Google Scholar 

  125. Lipton, J. M. & Ellis, S. R. Diamond Blackfan anemia: diagnosis, treatment and molecular pathogenesis. Hematol. Oncol. Clin. North. Am. 23, 261–282 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Vlachos, A. et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br. J. Haematol. 142, 859–876 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Piantanida, N. et al. Deficiency of ribosomal protein S26, which is mutated in a subset of patients with Diamond Blackfan anemia, impairs erythroid differentiation. Front. Genet. 13, (2022).

  128. Ohene-Abuakwa, Y., Orfali, K. A., Marius, C. & Ball, S. E. Two-phase culture in Diamond Blackfan anemia: localization of erythroid defect. Blood 105, 838–846 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Da Costa, L. M., Marie, I. & Leblanc, T. M. Diamond-Blackfan anemia. Hematol. Am. Soc. Hematol. Educ. Program. 2021, 353–360 (2021).

    Article  Google Scholar 

  130. Narla, A., Vlachos, A. & Nathan, D. G. Diamond Blackfan anemia treatment: past, present, and future. Semin. Hematol. 48, 117–123 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Quarello, P., Ramenghi, U. & Fagioli, F. Diamond-Blackfan anaemia with iron overload: a serious issue. Br. J. Haematol. 199, 171–172 (2022).

    Article  PubMed  Google Scholar 

  132. Sánchez González, S. R. et al. Cortisol modulates Ca2+ signaling and acrosome reaction in human sperm. Andrology 11, 134–142 (2023).

    Article  PubMed  Google Scholar 

  133. El Osta, R. et al. Anabolic steroids abuse and male infertility. Basic. Clin. Androl. 26, 2 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  134. HAMPL, R. & STÁRKA, L. Glucocorticoids affect male testicular steroidogenesis. Physiol. Res. 69, S205–S210 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Whirledge, S. & Cidlowski, J. A. Glucocorticoids, stress, and fertility. Minerva Endocrinol. 35, 109–125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Chen, Y., Wang, Q., Wang, F.-F., Gao, H.-B. & Zhang, P. Stress induces glucocorticoid-mediated apoptosis of rat Leydig cells in vivo. Stress 15, 74–84 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Yazawa, H., Sasagawa, I. & Nakada, T. Apoptosis of testicular germ cells induced by exogenous glucocorticoid in rats. Hum. Reprod. 15, 1917–1920 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Remacha, A. et al. Guidelines on haemovigilance of post-transfusional iron overload. Blood Transfus. 11, 128–139 (2013).

    PubMed  PubMed Central  Google Scholar 

  139. Kuliev, A., Rechitsky, S., Tur-Kaspa, I. & Verlinsky, Y. Preimplantation genetics: improving access to stem cell therapy. Ann. N. Y. Acad. Sci. 1054, 223–227 (2005).

    Article  PubMed  Google Scholar 

  140. Wagner, J. E., Kahn, J. P., Wolf, S. M. & Lipton, J. M. Preimplantation testing to produce an HLA-matched donor infant. JAMA 292, 803–804 (2004).

    CAS  PubMed  Google Scholar 

  141. Attia, M., Kripalani, S., Darbari, I. & Nickel, R. S. Parents of children with sickle cell disease are interested in preimplantation genetic testing. J. Pediatr. 223, 178–182.e2 (2020).

    Article  PubMed  Google Scholar 

  142. Fishman, S. M., Christian, P. & West, K. P. The role of vitamins in the prevention and control of anaemia. Public. Health Nutr. 3, 125–150 (2000).

    Article  CAS  PubMed  Google Scholar 

  143. Koury, M. J. & Ponka, P. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu. Rev. Nutr. 24, 105–131 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Kim, N. H. et al. Should asymptomatic young men with iron deficiency anemia necessarily undergo endoscopy? Korean J. Intern. Med. 33, 1084–1092 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Killip, S., Bennett, J. M. & Chambers, M. D. Iron deficiency anemia. Am. Fam. Physician 75, 671–678 (2007).

    PubMed  Google Scholar 

  146. Zanella, A. et al. Sensitivity and predictive value of serum ferritin and free erythrocyte protoporphyrin for iron deficiency. J. Lab. Clin. Med. 113, 73–78 (1989).

    CAS  PubMed  Google Scholar 

  147. Wang, W., Knovich, M. A., Coffman, L. G., Torti, F. M. & Torti, S. V. Serum ferritin: past, present and future. Biochim. Biophys. Acta 1800, 760–769 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Johnson-Wimbley, T. D. & Graham, D. Y. Diagnosis and management of iron deficiency anemia in the 21st century. Ther. Adv. Gastroenterol. 4, 177–184 (2011).

    Article  Google Scholar 

  149. Reyes, J. G. et al. The hypoxic testicle: physiology and pathophysiology. Oxid. Med. Cell. Longev. 2012, 929285 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Li, Z. et al. Effects of environmental and pathological hypoxia on male fertility. Front. Cell Dev. Biol. 9, 725933 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Gosney, J. R. Effects of hypobaric hypoxia on the Leydig cell population of the testis of the rat. J. Endocrinol. 103, 59–62 (1984).

    Article  CAS  PubMed  Google Scholar 

  152. Saxena, D. K. Effect of hypoxia by intermittent altitude exposure on semen characteristics and testicular morphology of male rhesus monkeys. Int. J. Biometeorol. 38, 137–140 (1995).

    Article  CAS  PubMed  Google Scholar 

  153. Donayre, J., Guerra-García, R., Moncloa, F. & Sobrevilla, L. A. Endocrine studies at high altitude. IV. Changes in the semen of men. J. Reprod. Fertil. 16, 55–58 (1968).

    Article  CAS  PubMed  Google Scholar 

  154. Verratti, V. et al. Evidence that chronic hypoxia causes reversible impairment on male fertility. Asian J. Androl. 10, 602–606 (2008).

    Article  PubMed  Google Scholar 

  155. Soliman, A., Yassin, M. & De Sanctis, V. Intravenous iron replacement therapy in eugonadal males with iron-deficiency anemia: effects on pituitary gonadal axis and sperm parameters; a pilot study. Indian. J. Endocrinol. Metab. 18, 310–316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Mehta, S. et al. Assessment of pituitary gonadal axis and sperm parameters in anemic eugonadal males before and after correction of iron deficiency anemia. J. Assoc. Physicians India 66, 11–12 (2018).

    PubMed  Google Scholar 

  157. Nikolaev, A. A., Lutskiĭ, D. L., Nikolaeva, N. N. & Lozhkina, L. V. [Iron and nonheme iron protein metabolism in ejaculates with varying degrees of fertility]. Urol. Nefrol. 5, 27–31 (1998).

    Google Scholar 

  158. Tsao, C.-W., Liao, Y.-R., Chang, T.-C., Liew, Y.-F. & Liu, C.-Y. Effects of iron supplementation on testicular function and spermatogenesis of iron-deficient rats. Nutrients 14, 2063 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Schlegel, P. N. et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. J. Urol. 205, 36–43 (2021).

    Article  PubMed  Google Scholar 

  160. Short, M. W. & Domagalski, J. E. Iron deficiency anemia: evaluation and management. Am. Fam. Physician 87, 98–104 (2013).

    PubMed  Google Scholar 

  161. Venkatramanan, S., Armata, I. E., Strupp, B. J. & Finkelstein, J. L. Vitamin B-12 and cognition in children. Adv. Nutr. Bethesda Md. 7, 879–888 (2016).

    Article  CAS  Google Scholar 

  162. Melse-Boonstra, A. Bioavailability of micronutrients from nutrient-dense whole foods: zooming in on dairy, vegetables, and fruits. Front. Nutr. 7, 101 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Diaz, K. et al. Prevalence of folic acid deficiency and cost effectiveness of folic acid testing: a single center experience. Blood 132, 4878 (2018).

    Article  Google Scholar 

  164. Shipton, M. J. & Thachil, J. Vitamin B12 deficiency — a 21st century perspective. Clin. Med. 15, 145–150 (2015).

    Article  Google Scholar 

  165. Stover, P. J. Physiology of folate and vitamin B12 in health and disease. Nutr. Rev. 62, S3–S12 (2004).

    Article  PubMed  Google Scholar 

  166. Nagao, T. & Hirokawa, M. Diagnosis and treatment of macrocytic anemias in adults. J. Gen. Fam. Med. 18, 200–204 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Baylin, S. B. et al. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum. Mol. Genet. 10, 687–692 (2001).

    Article  CAS  PubMed  Google Scholar 

  168. Steluti, J., Palchetti, C. Z., Miranda, A. M., Fisberg, R. M. & Marchioni, D. M. DNA methylation and one-carbon metabolism related nutrients and polymorphisms: analysis after mandatory flour fortification with folic acid. Br. J. Nutr. 123, 23–29 (2020).

    Article  CAS  PubMed  Google Scholar 

  169. Boxmeer, J. C. et al. Low folate in seminal plasma is associated with increased sperm DNA damage. Fertil. Steril. 92, 548–556 (2009).

    Article  CAS  PubMed  Google Scholar 

  170. Wang, W. et al. Studying the mechanism of sperm DNA damage caused by folate deficiency. J. Cell. Mol. Med. 26, 776–788 (2022).

    Article  CAS  PubMed  Google Scholar 

  171. Wong, W. Y. et al. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil. Steril. 77, 491–498 (2002).

    Article  PubMed  Google Scholar 

  172. Banihani, S. A. Vitamin B12 and semen quality. Biomolecules 7, 42 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Zhang, Y., Zhang, W., Dai, Y., Jiang, H. & Zhang, X. Serum folic acid and erectile dysfunction: a systematic review and meta-analysis. Sex. Med. 9, 100356 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Ekong, A., Berg, L., Amos, R. J. & Tsitsikas, D. A. Regular automated red cell exchange transfusion in the management of stuttering priapism complicating sickle cell disease. Br. J. Haematol. 180, 585–588 (2018).

    Article  PubMed  Google Scholar 

  175. Levey, H. R., Kutlu, O. & Bivalacqua, T. J. Medical management of ischemic stuttering priapism: a contemporary review of the literature. Asian J. Androl. 14, 156–163 (2012).

    Article  PubMed  Google Scholar 

  176. Bivalacqua, T. J. et al. The diagnosis and management of recurrent ischemic priapism, priapism in sickle cell patients, and non-ischemic priapism: an AUA/SMSNA guideline. J. Urol. 208, 43–52 (2022).

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Bryan D. Naelitz, Prajit S. Khooblall.

Authors and Affiliations

  1. Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Bryan D. Naelitz, Prajit S. Khooblall, Neel V. Parekh, Sarah C. Vij & Scott D. Lundy

  2. Department of Paediatric Hematology and Oncology, Cleveland Clinic Children’s Hospital, Cleveland Clinic, Cleveland, OH, 44195, USA

    Seth J. Rotz

Authors
  1. Bryan D. Naelitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prajit S. Khooblall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neel V. Parekh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah C. Vij
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seth J. Rotz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Scott D. Lundy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.D.N., P.S.K. and S.D.L. researched data for the article. N.V.P., S.C.V., S.J.R. and S.D.L. contributed substantially to discussion of the content. B.D.N., P.S.K., S.J.R. and S.D.L. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Bryan D. Naelitz.

Ethics declarations

Competing interests

N.V.P. is a speaker for Halozyme Therapeutics. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks R.S. Nickel and P. Schlegel for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Naelitz, B.D., Khooblall, P.S., Parekh, N.V. et al. The effect of red blood cell disorders on male fertility and reproductive health. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-023-00838-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41585-023-00838-8

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing