Abstract
Better understanding of pathogenesis, diagnosis, prevention, and treatment of infertility problems in transfusion-dependent thalassemia (TDT) patients has taken priority in the recent years. Excess transfusional iron, if not effectively removed, imposes deleterious effects on the anterior pituitary and likely on the gonadal tissue as well, resulting in hypogonadotropic hypogonadism, amenorrhea, abnormal spermatogenesis, and a declining reproductive potential. Though spontaneous pregnancy can occur in some women with a low iron burden, many, in particular those 30–35 years and older, require ovulation induction and ART. Prepregnancy multidisciplinary counseling and close monitoring during gestation are required to avoid complications to both mother and fetus. In men, who often have a low sperm count and function, induction of spermatogenesis and micromanipulation along with IVF can be applied. Implementation of current methods for predicting reproductive status and for fertility preservation is needed for this patient population; these along with optimal iron chelation therapy could allow earlier intervention for fertility salvation.
Access this chapter
We’re sorry, something doesn't seem to be working properly.
Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.
Similar content being viewed by others
References
Casale M, et al. Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with beta-thalassemia major. Am J Hematol. 2014;89(12):1102–6.
Pennell DJ, et al. Continued improvement in myocardial T2* over two years of deferasirox therapy in beta-thalassemia major patients with cardiac iron overload. Haematologica. 2011;96(1):48–54.
Farmaki K, Tzoumari I, Pappa C. Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications. Blood Cells Mol Dis. 2011;47(1):33–40.
Berdoukas V, et al. Iron chelation in thalassemia: time to reconsider our comfort zones. Expert Rev Hematol. 2011;4(1):17–26.
De Sanctis V. Growth and puberty and its management in thalassaemia. Horm Res. 2002;58 Suppl 1:72–9.
De Sanctis V, et al. Growth and endocrine disorders in thalassemia: the international network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J Endocrinol Metab. 2013;17(1):8–18.
De Sanctis V, et al. Late-onset male hypogonadism and fertility potential in thalassemia major patients: two emerging issues. Mediterr J Hematol Infect Dis. 2015;7(1):e2015047.
Singer ST, et al. Reproductive capacity in iron overloaded women with thalassemia major. Blood. 2011;118(10):2878–81.
Gabutti V, Piga A. Results of long-term iron-chelating therapy. Acta Haematol. 1996;95(1):26–36.
Borgna-Pignatti C, et al. Survival and disease complications in thalassemia major. Ann N Y Acad Sci. 1998;850:227–31.
Chatterjee R, et al. Prospective study of the hypothalamic-pituitary axis in thalassaemic patients who developed secondary amenorrhoea. Clin Endocrinol (Oxf). 1993;39(3):287–96.
Allegra A, et al. Hypogonadism in beta-thalassemic adolescents: a characteristic pituitary-gonadal impairment. The ineffectiveness of long-term iron chelation therapy. Gynecol Endocrinol. 1990;4(3):181–91.
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. 1990;323(11):713–9.
Skordis N, et al. The impact of iron overload and genotype on gonadal function in women with thalassaemia major. Pediatr Endocrinol Rev. 2004;2 Suppl 2:292–5.
Borgna-Pignatti C, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187–93.
Al-Rimawi HS, et al. Hypothalamic-pituitary-gonadal function in adolescent females with beta-thalassemia major. Int J Gynaecol Obstet. 2005;90(1):44–7.
Papadimas J, et al. beta-thalassemia and gonadal axis: a cross-sectional, clinical study in a Greek population. Hormones (Athens). 2002;1(3):179–87.
Esposito BP, et al. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood. 2003;102(7):2670–7.
Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann N Y Acad Sci. 1998;850:191–201.
Livrea MA, et al. Oxidative stress and antioxidant status in beta-thalassemia major: iron overload and depletion of lipid-soluble antioxidants. Blood. 1996;88(9):3608–14.
Shazia Q, et al. Correlation of oxidative stress with serum trace element levels and antioxidant enzyme status in Beta thalassemia major patients: a review of the literature. Anemia. 2012;2012:270923.
Waseem F, Khemomal KA, Sajid R. Antioxidant status in beta thalassemia major: a single-center study. Indian J Pathol Microbiol. 2011;54(4):761–3.
Claster S, et al. Nutritional deficiencies in iron overloaded patients with hemoglobinopathies. Am J Hematol. 2009;84(6):344–8.
Vogiatzi MG, et al. Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Miner Res. 2009;24(3):543–57.
Chapman RW, et al. Effect of ascorbic acid deficiency on serum ferritin concentration in patients with beta-thalassaemia major and iron overload. J Clin Pathol. 1982;35(5):487–91.
Walter PB, et al. Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol. 2006;135(2):254–63.
Piga A, et al. High nontransferrin bound iron levels and heart disease in thalassemia major. Am J Hematol. 2009;84(1):29–33.
Desai N, et al. Physiologic and pathologic levels of reactive oxygen species in neat semen of infertile men. Fertil Steril. 2009;92(5):1626–31.
Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int. 2005;95(4):503–7.
Makker K, Agarwal A, Sharma R. Oxidative stress & male infertility. Indian J Med Res. 2009;129(4):357–67.
Appasamy M, et al. Evaluation of the relationship between follicular fluid oxidative stress, ovarian hormones, and response to gonadotropin stimulation. Fertil Steril. 2008;89(4):912–21.
Tarin JJ. Potential effects of age-associated oxidative stress on mammalian oocytes/embryos. Mol Hum Reprod. 1996;2(10):717–24.
Tatone C, et al. Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update. 2008;14(2):131–42.
Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005;3:28.
Agarwal A, et al. Effect of oxidative stress on male reproduction. World J Mens Health. 2014;32(1):1–17.
Zini A, San Gabriel M, Baazeem A. Antioxidants and sperm DNA damage: a clinical perspective. J Assist Reprod Genet. 2009;26(8):427–32.
Raijmakers MT, et al. Glutathione and glutathione S-transferases A1-1 and P1-1 in seminal plasma may play a role in protecting against oxidative damage to spermatozoa. Fertil Steril. 2003;79(1):169–72.
Atig F, et al. Impact of seminal trace element and glutathione levels on semen quality of Tunisian infertile men. BMC Urol. 2012;12:6.
Schulte RT, et al. Sperm DNA damage in male infertility: etiologies, assays, and outcomes. J Assist Reprod Genet. 2010;27(1):3–12.
Ebisch IM, et al. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update. 2007;13(2):163–74.
Kobori Y, et al. Antioxidant cosupplementation therapy with vitamin C, vitamin E, and coenzyme Q10 in patients with oligoasthenozoospermia. Arch Ital Urol Androl. 2014;86(1):1–4.
Agarwal A, Prabakaran SA. Mechanism, measurement, and prevention of oxidative stress in male reproductive physiology. Indian J Exp Biol. 2005;43(11):963–74.
Marzec-Wroblewska U, et al. Zinc and iron concentration and SOD activity in human semen and seminal plasma. Biol Trace Elem Res. 2011;143(1):167–77.
Reubinoff BE, et al. Increased levels of redox-active iron in follicular fluid: a possible cause of free radical-mediated infertility in beta-thalassemia major. Am J Obstet Gynecol. 1996;174(3):914–8.
Birkenfeld A, et al. Endometrial glandular haemosiderosis in homozygous beta-thalassaemia. Eur J Obstet Gynecol Reprod Biol. 1989;31(2):173–8.
Roussou P, et al. Beta-thalassemia major and female fertility: the role of iron and iron-induced oxidative stress. Anemia. 2013;2013:617204.
Carpino A, et al. Antioxidant capacity in seminal plasma of transfusion-dependent beta-thalassemic patients. Exp Clin Endocrinol Diabetes. 2004;112(3):131–4.
Perera D, et al. Sperm DNA damage in potentially fertile homozygous beta-thalassaemia patients with iron overload. Hum Reprod. 2002;17(7):1820–5.
De Sanctis V, et al. Spermatozoal DNA damage in patients with B thalassaemia syndromes. Pediatr Endocrinol Rev. 2008;6 Suppl 1:185–9.
De Sanctis V, et al. Spermatogenesis in young adult patients with beta-thalassaemia major long-term treated with desferrioxamine. Georgian Med News. 2008;156:74–7.
Singer ST, et al. Fertility in transfusion-dependent thalassemia men: effects of iron burden on the reproductive axis. Am J Hematol. 2015;90(9):E190–2.
Skandhan KP, Mazumdar BN, Sumangala B. Study into the iron content of seminal plasma in normal and infertile subjects. Urologia. 2012;79(1):54–7.
Meyer WR, et al. Secondary hypogonadism in hemochromatosis. Fertil Steril. 1990;54(4):740–2.
Olivieri NF, Brittenham GM. Management of the thalassemias. Cold Spring Harb Perspect Med. 2013;3(6):1–14.
Telfer PT, et al. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol. 2000;110(4):971–7.
Farmaki K, et al. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol. 2010;148(3):466–75.
Christoforidis A, et al. MRI for the determination of pituitary iron overload in children and young adults with beta-thalassaemia major. Eur J Radiol. 2006;62(1):138–42.
Christoforidis A, et al. Correlative study of iron accumulation in liver, myocardium, and pituitary assessed with MRI in young thalassemic patients. J Pediatr Hematol Oncol. 2006;28(5):311–5.
Argyropoulou MI, Kiortsis DN, Efremidis SC. MRI of the liver and the pituitary gland in patients with beta-thalassemia major: does hepatic siderosis predict pituitary iron deposition? Eur Radiol. 2003;13(1):12–6.
Lam WW, et al. One-stop measurement of iron deposition in the anterior pituitary, liver, and heart in thalassemia patients. J Magn Reson Imaging. 2008;28(1):29–33.
Noetzli LJ, et al. Pituitary iron and volume predict hypogonadism in transfusional iron overload. Am J Hematol. 2012;87(2):167–71.
Safarinejad MR. Evaluation of semen quality, endocrine profile and hypothalamus-pituitary-testis axis in male patients with homozygous beta-thalassemia major. J Urol. 2008;179(6):2327–32.
Chatterjee R, Katz M. Reversible hypogonadotropic hypogonadism in sexually infantile male thalassaemic patients with transfusional iron overload. Clin Endocrinol (Oxf). 2000;53(1):33–42.
Berkovitch M, et al. Iron deposition in the anterior pituitary in homozygous beta-thalassemia: MRI evaluation and correlation with gonadal function. J Pediatr Endocrinol Metab. 2000;13(2):179–84.
Borgna-Pignatti C, et al. Growth and sexual maturation in thalassemia major. J Pediatr. 1985;106(1):150–5.
De Sanctis V, et al. Hypothalamic-pituitary-gonadal axis in thalassemic patients with secondary amenorrhea. Obstet Gynecol. 1988;72(4):643–7.
Skordis N, et al. Update on fertility in thalassaemia major. Pediatr Endocrinol Rev. 2004;2 Suppl 2:296–302.
Tuck SM. Fertility and pregnancy in thalassemia major. Ann N Y Acad Sci. 2005;1054:300–7.
Skordis N, et al. Fertility in female patients with thalassemia. J Pediatr Endocrinol Metab. 1998;11 Suppl 3:935–43.
Cohen AR et al. Thalassemia. Am Soc Hematol Educ Book. 2004;2004:14–34.
Mancuso A, et al. Pregnancy in patients with beta-thalassaemia major: maternal and foetal outcome. Acta Haematol. 2008;119(1):15–7.
Reubinoff BE, et al. Defective oocytes as a possible cause of infertility in a beta-thalassaemia major patient. Hum Reprod. 1994;9(6):1143–5.
Bajoria R, Chatterjee R. Current perspectives of fertility and pregnancy in thalassemia. Hemoglobin. 2009;33 Suppl 1:S131–5.
De Sanctis V, et al. Gonadal function in patients with beta thalassaemia major. J Clin Pathol. 1988;41(2):133–7.
Scheffer GJ, et al. Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility. Fertil Steril. 1999;72(5):845–51.
Kwee J, et al. Evaluation of anti-Mullerian hormone as a test for the prediction of ovarian reserve. Fertil Steril. 2008;90(3):737–43.
Knauff EA, et al. Anti-Mullerian hormone, inhibin B, and antral follicle count in young women with ovarian failure. J Clin Endocrinol Metab. 2009;94(3):786–92.
Gracia CR, et al. Ovarian tissue cryopreservation for fertility preservation in cancer patients: successful establishment and feasibility of a multidisciplinary collaboration. J Assist Reprod Genet. 2012;29(6):495–502.
Senapati S, et al. Fertility preservation in patients with haematological disorders: a retrospective cohort study. Reprod Biomed Online. 2014;28(1):92–8.
Babayev SN, et al. Evaluation of ovarian and testicular tissue cryopreservation in children undergoing gonadotoxic therapies. J Assist Reprod Genet. 2013;30(1):3–9.
Revel A, et al. Micro-organ ovarian transplantation enables pregnancy: a case report. Hum Reprod. 2011;26(5):1097–103.
Karagiorga-Lagana M. Fertility in thalassemia: the Greek experience. J Pediatr Endocrinol Metab. 1998;11 Suppl 3:945–51.
Ansari S, Azarkeivan A, Tabaroki A. Pregnancy in patients treated for beta thalassemia major in two centers (Ali Asghar Children’s Hospital and Thalassemia Clinic): outcome for mothers and newborn infants. Pediatr Hematol Oncol. 2006;23(1):33–7.
Origa R, et al. Pregnancy and {beta}-thalassemia: an Italian multicenter experience. Haematologica. 2009;94:1777–8.
Farmaki K, et al. Rapid iron loading in a pregnant woman with transfusion-dependent thalassemia after brief cessation of iron chelation therapy. Eur J Haematol. 2008;81(2):157–9.
Skordis N, Porter J, Kalakoutis G. Fertility and pregnancy in Guidelines for the management of Transfusion Dependent Thalassaemia (TDT). TIF, 3rd edition. 2014;9:158–69.
Messina G, et al. Pregnant women affected by thalassemia major: a controlled study of traits and personality. J Res Med Sci. 2010;15(2):100–6.
Thompson AA, et al. Pregnancy outcomes in women with thalassemia in North America and the United Kingdom. Am J Hematol. 2013;88(9):771–3.
Perniola R, et al. High-risk pregnancy in beta-thalassemia major women. Report of three cases. Gynecol Obstet Invest. 2000;49(2):137–9.
Butwick A, Findley I, Wonke B. Management of pregnancy in a patient with beta thalassaemia major. Int J Obstet Anesth. 2005;14(4):351–4.
Singer ST, Vichinsky EP. Deferoxamine treatment during pregnancy: is it harmful? Am J Hematol. 1999;60(1):24–6.
Vaskaridou E, et al. Deferoxamine treatment during early pregnancy: absence of teratogenicity in two cases. Haematologica. 1993;78(3):183–4.
Vini D, Servos P, Drosou M. Normal pregnancy in a patient with beta-thalassaemia major receiving iron chelation therapy with deferasirox (Exjade(R)). Eur J Haematol. 2011;86(3):274–5.
Merchant R, et al. A successful twin pregnancy in a patient with HbE-β-thalassemia in western India. J Postgrad Med. 2015;61(3):203.
Aessopos A, et al. Pregnancy in patients with well-treated beta-thalassemia: outcome for mothers and newborn infants. Am J Obstet Gynecol. 1999;180(2 Pt 1):360–5.
Al-Riyami N, Al-Khaduri M, Daar S. Pregnancy outcomes in women with homozygous beta thalassaemia: a single-centre experience from Oman. Sultan Qaboos Univ Med J. 2014;14(3):e337–41.
Pafumi C, et al. The reproduction in women affected by cooley disease. Hematol Rep. 2011;3(1):e4.
Natali A, Turek PJ. An assessment of new sperm tests for male infertility. Urology. 2011;77(5):1027–34.
Bann CM, et al. Cancer survivors’ use of fertility preservation. J Womens Health (Larchmt). 2015;24:777–83.
Jensen CE, et al. Incidence of endocrine complications and clinical disease severity related to genotype analysis and iron overload in patients with beta-thalassaemia. Eur J Haematol. 1997;59(2):76–81.
Grunewald S, et al. Age-dependent inhibin B concentration in relation to FSH and semen sample qualities: a study in 2448 men. Reproduction. 2013;145(3):237–44.
Kumanov P, et al. Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility. Fertil Steril. 2006;86(2):332–8.
Bungum M, et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007;22(1):174–9.
Micinski P, et al. Total reactive antioxidant potential and DNA fragmentation index as fertility sperm parameters. Reprod Biol. 2011;11(2):135–44.
Erenpreiss J, et al. Sperm chromatin structure and male fertility: biological and clinical aspects. Asian J Androl. 2006;8(1):11–29.
Bajoria R, Chatterjee R. Hypogonadotropic hypogonadism and diminished gonadal reserve accounts for dysfunctional gametogenesis in thalassaemia patients with iron overload presenting with infertility. Hemoglobin. 2011;35(5–6):636–42.
Warne DW, et al. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril. 2009;92(2):594–604.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Singer, S.T. (2017). Fertility Issues in Transfusion-Dependent Thalassemia Patients: Pathophysiology, Assessment, and Management. In: Woodruff, T., Gosiengfiao, Y. (eds) Pediatric and Adolescent Oncofertility. Springer, Cham. https://doi.org/10.1007/978-3-319-32973-4_14
Download citation
DOI: https://doi.org/10.1007/978-3-319-32973-4_14
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-32971-0
Online ISBN: 978-3-319-32973-4
eBook Packages: MedicineMedicine (R0)