Endocrine complications due to haemosiderosis are present in a significant number of patients with beta-thalassemia major (BTM) worldwide and often become barriers in their desire for parenthood. Thus, although spontaneous fertility can occur, the majority of females with BTM is infertile due to hypogonadotropic hypogonadism (HH) and need assisted reproductive techniques. Infertility in these women seems to be attributed to iron deposition and iron-induced oxidative stress (OS) in various endocrine organs, such as hypothalamus, pituitary, and female reproductive system, but also through the iron effect on other organs, such as liver and pancreas, contributing to the impaired metabolism of hormones and serum antioxidants. Nevertheless, the gonadal function of these patients is usually intact and fertility is usually retrievable. Meanwhile, a significant prooxidants/antioxidants imbalance with subsequent increased (OS) exists in patients with BTM, which is mainly caused by tissue injury due to overproduction of free radicals by secondary iron overload, but also due to alteration in serum trace elements and antioxidant enzymes. Not only using the appropriate antioxidants, essential trace elements, and minerals, but also regulating the advanced glycation end products, could probably reduce the extent of oxidative damage and related complications and retrieve BTM women’s infertility. 1. Introduction In beta-thalassemia major (BTM), iron overload is the joint outcome of multiple blood transfusions and an inappropriately increased iron absorption associated with ineffective erythropoiesis [1]. The outpouring of catabolic iron that exceeds the iron-carrying capacity of transferrin results in the emergence of nontransferrin-bound iron (NTBI), which catalyzes the formation of free radicals, resulting in oxidative stress (OS) and damage to mitochondria, lysosomes, lipid membranes, proteins, and DNA [1]. Thus, thalassemics are in a state of enhanced OS [2]. Meanwhile, recent advances in the management of BTM have significantly improved life expectancy and quality of life of BTM patients, with a consequent increase in their reproductive potential and desire to have children [3]. However, endocrine complications due to haemosiderosis are still present in a significant number of patients worldwide and often become a barrier in their desire for parenthood [4]. Female patients with BTM usually suffer from hypogonadotropic hypogonadism (HH) associated with amenorrhea, anovulation, and infertility, attributed to the iron effect on the pituitary gland as well as on the
References
[1]
C. Hershko, “Pathogenesis and management of iron toxicity in thalassemia,” Annals of the New York Academy of Sciences, vol. 1202, pp. 1–9, 2010.
[2]
F. Waseem, K. A. Khemomal, and R. Sajid, “Antioxidant status in beta thalassemia major: a single-center study,” Indian Journal of Pathology and Microbiology, vol. 54, no. 4, pp. 761–763, 2011.
[3]
R. Origa, A. Piga, G. Quarta et al., “Pregnancy and β-thalassemia: an Italian multicenter experience,” Haematologica, vol. 95, no. 3, pp. 376–381, 2010.
[4]
N. Skordis, L. Petrikkos, M. Toumba et al., “Update on fertility in thalassaemia major,” Pediatric Endocrinology Reviews, vol. 2, supplement 2, pp. 296–302, 2004.
[5]
M. Toumba, A. Sergis, C. Kanaris, and N. Skordis, “Endocrine complications in patients with thalassaemia major,” Pediatric Endocrinology Reviews, vol. 5, no. 2, pp. 642–648, 2007.
[6]
E. A. Rachmilewitz, O. Weizer-Stern, K. Adamsky et al., “Role of iron in inducing oxidative stress in thalassemia: can it be prevented by inhibition of absorption and by antioxidants?” Annals of the New York Academy of Sciences, vol. 1054, pp. 118–123, 2005.
[7]
S. Ansari, A. Azarkeivan, and A. Tabaroki, “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,” Pediatric Hematology-Oncology, vol. 23, no. 1, pp. 33–37, 2006.
[8]
M. R. Safarinejad, “Reproductive hormones and hypothalamic-pituitary-ovarian axis in female patients with homozygous β-thalassemia major,” Journal of Pediatric Hematology/Oncology, vol. 32, no. 4, pp. 259–266, 2010.
[9]
S. T. Singer, E. P. Vichinsky, G. Gildengorin, J. van Disseldorp, M. Rosen, and M. I. Cedars, “Reproductive capacity in iron overloaded women with thalassemia major,” Blood, vol. 118, no. 10, pp. 2878–2881, 2011.
[10]
G. Vizziello, D. Carone, E. Caroppo, A. Vitti, A. Pasquadibisceglie, and G. D'amato, “Ovulation induction with gonadotropin in patients with thalassemia pretreated with pulsatile GnRH: outcome,” Minerva Ginecologica, vol. 56, no. 5, pp. 485–487, 2004.
[11]
N. Skordis, S. Christou, M. Koliou, N. Pavlides, and M. Angastiniotis, “Fertility in female patients with thalassemia,” Journal of Pediatric Endocrinology and Metabolism, vol. 11, supplement 3, pp. 935–943, 1998.
[12]
L. Danesi, M. Scacchi, A. M. Miragoli et al., “Induction of follicle maturation and ovulation by gonadotropin administration in women with β-thalassemia,” European Journal of Endocrinology, vol. 131, no. 6, pp. 602–606, 1994.
[13]
R. Bajoria and R. Chatterjee, “Current perspectives of fertility and pregnancy in thalassemia,” Hemoglobin, vol. 33, supplement 1, pp. S131–S135, 2009.
[14]
R. Bajoria and R. Chatterjee, “Hypogonadotrophic hypogonadism and diminished gonadal reserve accounts for dysfunctional gametogenesis in thalassaemia patients with iron overload presenting with infertility,” Hemoglobin, vol. 35, no. 5-6, pp. 636–642, 2011.
[15]
M. Karagiorga-Lagana, “Fertility in thalassemia: the Greek experience,” Journal of Pediatric Endocrinology and Metabolism, vol. 11, supplement 3, pp. 945–951, 1998.
[16]
S. M. Tuck, “Fertility and pregnancy in thalassemia major,” Annals of the New York Academy of Sciences, vol. 1054, pp. 300–307, 2005.
[17]
D. Surbek, A. Koller, and N. Pavic, “Successful twin pregnancy in homozygous β-thalassemia after ovulation induction with growth hormone and gonadotropins,” Fertility and Sterility, vol. 65, no. 3, pp. 670–672, 1996.
[18]
K. Yamaguchi, M. Mandai, S. Toyokuni et al., “Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress,” Clinical Cancer Research, vol. 14, no. 1, pp. 32–40, 2008.
[19]
M. C. Kew, “Hepatic iron overload and hepatocellular carcinoma,” Cancer Letters, vol. 286, no. 1, pp. 38–43, 2009.
[20]
A. Agarwal, S. Gupta, and R. K. Sharma, “Role of oxidative stress in female reproduction,” Reproductive Biology and Endocrinology, vol. 3, article 28, 2005.
[21]
A. C. Chan, C. K. Chow, and D. Chiu, “Interaction of antioxidants and their implication in genetic anemia,” Proceedings of the Society for Experimental Biology and Medicine, vol. 222, no. 3, pp. 274–282, 1999.
[22]
A. Agarwal, A. Aponte-Mellado, B. J. Premkumar, A. Shaman, and S. Gupta, “The effects of oxidative stress on female reproduction: a review,” Reproductive Biology and Endocrinology, vol. 10, article 49, 2012.
[23]
M. Giergiel, M. Lopucki, N. Stachowicz, and M. Kankofer, “The influence of age and gender on antioxidant enzyme activities in humans and laboratory animals,” Aging Clinical and Experimental Research, vol. 24, pp. 551–559, 2012.
[24]
Q. Shazia, Z. H. Mohammad, T. Rahman, and H. U. Shekhar, “Correlation of oxidative stress with serum trace element levels and antioxidant enzyme status in Beta thalassemia major patients: a review of the literature,” Anemia, vol. 2012, Article ID 270923, 7 pages, 2012.
[25]
M. Y. Abdalla, M. Fawzi, S. R. Al-Maloul, N. El-Banna, R. F. Tayyem, and I. M. Ahmad, “Increased oxidative stress and iron overload in Jordanian β-thalassemic children,” Hemoglobin, vol. 35, no. 1, pp. 67–79, 2011.
[26]
R. A. Ghone, K. M. Kumbar, A. N. Suryakar, R. V. Katkam, and N. G. Joshi, “Oxidative stress and disturbance in antioxidant balance in beta thalassemia major,” Indian Journal of Clinical Biochemistry, vol. 23, no. 4, pp. 337–340, 2008.
[27]
M. A. Livrea, L. Tesoriere, A. M. Pintaudi et al., “Oxidative stress and antioxidant status in β-thalassemia major: iron overload and depletion of lipid-soluble antioxidants,” Blood, vol. 88, no. 9, pp. 3608–3614, 1996.
[28]
S.-S. Chiou, T.-T. Chang, S.-P. Tsai et al., “Lipid peroxidation and antioxidative status in β-thalassemia major patients with or without hepatitis C virus infection,” Clinical Chemistry and Laboratory Medicine, vol. 44, no. 10, pp. 1226–1233, 2006.
[29]
A. Agarwal and S. S. Allamaneni, “Role of free radicals in female reproductive diseases and assisted reproduction,” Reproductive BioMedicine Online, vol. 9, no. 3, pp. 338–347, 2004.
[30]
E. H. Ruder, T. J. Hartman, J. Blumberg, and M. B. Goldman, “Oxidative stress and antioxidants: exposure and impact on female fertility,” Human Reproduction Update, vol. 14, no. 4, pp. 345–357, 2008.
[31]
A. Agarwal, S. Gupta, L. Sekhon, and R. Shah, “Redox considerations in female reproductive function and assisted reproduction: from molecular mechanisms to health implications,” Antioxidants & Redox Signaling, vol. 10, no. 8, pp. 1375–1403, 2008.
[32]
P. J. Devine, S. D. Perreault, and U. Luderer, “Roles of reactive oxygen species and antioxidants in ovarian toxicity,” Biology of Reproduction, vol. 86, no. 2, article 27, 2012.
[33]
K. H. Al-Gubory, C. Garrel, P. Faure, and N. Sugino, “Roles of antioxidant enzymes in corpus luteum rescue from reactive oxygen species-induced oxidative stress,” Reproductive Biomedicine Online, vol. 25, no. 6, pp. 551–560, 2012.
[34]
A. Agarwal, A. Aponte-Mellado, B. J. Premkumar, A. Shaman, and S. Gupta, “The effects of oxidative stress on female reproduction: a review,” Reproductive Biology and Endocrinology, vol. 10, article 49, 2012.
[35]
S. Defrere, R. Gonzalez-Ramos, J.-C. Lousse et al., “Insights into iron and nuclear factor-kappa B (NF-κB) involvement in chronic inflammatory processes in peritoneal endometriosis,” Histology and Histopathology, vol. 26, no. 8, pp. 1083–1092, 2011.
[36]
A. van Langendonckt, F. Casanas-Roux, and J. Donnez, “Oxidative stress and peritoneal endometriosis,” Fertility and Sterility, vol. 77, no. 5, pp. 861–870, 2002.
[37]
M. Appasamy, E. Jauniaux, P. Serhal, A. Al-Qahtani, N. P. Groome, and S. Muttukrishna, “Evaluation of the relationship between follicular fluid oxidative stress, ovarian hormones, and response to gonadotropin stimulation,” Fertility and Sterility, vol. 89, no. 4, pp. 912–921, 2008.
[38]
Y. Asano, “Age-related accumulation of non-heme ferric and ferrous iron in mouse ovarian stroma visualized by sensitive non-heme iron histochemistry,” The Journal of Histochemistry & Cytochemistry, vol. 60, no. 3, pp. 229–242, 2012.
[39]
M. K. Al-Azemi, A. E. Omu, T. Fatinikun, N. Mannazhath, and S. Abraham, “Factors contributing to gender differences in serum retinol and α-tocopherol in infertile couples,” Reproductive BioMedicine Online, vol. 19, no. 4, pp. 583–590, 2009.
[40]
M. K. Kim, J. W. Lee, K. H. Baek, et al., “Endocrinopathies in transfusion-associated iron overload,” Clinical Endocrinology, vol. 78, no. 2, pp. 271–277, 2013.
[41]
L. M. Hempenius, P. S. van Dam, J. J. Marx, and H. P. Koppeschaar, “Mineralocorticoid status and endocrine dysfunction in severe hemochromatosis,” Journal of Endocrinological Investigation, vol. 22, no. 5, pp. 369–376, 1999.
[42]
J. M. Vasquez and R. B. Greenblatt, “Pituitary responsiveness to luteinizing-hormone-releasing hormone in different reproductive disorders. a review,” Journal of Reproductive Medicine for the Obstetrician and Gynecologist, vol. 30, no. 8, pp. 591–600, 1985.
[43]
I. Paris, M. Hermans, and M. Buysschaert, “Endocrine complications of genetic hemochromatosis,” Acta Clinica Belgica, vol. 54, no. 6, pp. 334–345, 1999.
[44]
W. Stremmel, C. Niederau, M. Berger, H.-K. Kley, H.-L. Kruskemper, and G. Strohmeyer, “Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic hemochromatosis,” Annals of the New York Academy of Sciences, vol. 526, pp. 209–223, 1988.
[45]
W. R. Meyer, K. A. Hutchinson-Williams, E. E. Jones, and A. H. Decherney, “Secondary hypogonadism in hemochromatosis,” Fertility and Sterility, vol. 54, no. 4, pp. 740–742, 1990.
[46]
L. J. Siemons and C. H. Mahler, “Hypogonadotropic hypogonadism in hemochromatosis: recovery of reproductive function after iron depletion,” The Journal of Clinical Endocrinology and Metabolism, vol. 65, no. 3, pp. 585–587, 1987.
[47]
J. H. McDermott and C. H. Walsh, “Hypogonadism in hereditary hemochromatosis,” The Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 4, pp. 2451–2455, 2005.
[48]
G. Kontogeorgos, S. Handy, K. Kovacs, E. Horvath, and B. W. Scheithauer, “The anterior pituitary in hemochromatosis,” Endocrine Pathology, vol. 7, no. 2, pp. 159–164, 1996.
[49]
A. Piperno, M. R. Rivolta, R. D'alba et al., “Preclinical hypogonadism in genetic hemochromatosis in the early stage of the disease: evidence of hypothalamic dysfunction,” Journal of Endocrinological Investigation, vol. 15, no. 6, pp. 423–428, 1992.
[50]
K. Siminoski, M. D'costa, and P. G. Walfish, “Hypogonadotropic hypogonadism in idiopathic hemochromatosis: evidence for combined hypothalamic and pituitary involvement,” Journal of Endocrinological Investigation, vol. 13, no. 10, pp. 849–853, 1990.
[51]
K. E. Oerter, G. A. Kamp, P. J. Munson, A. W. Nienhuis, F. G. Cassorla, and P. K. Manasco, “Multiple hormone deficiencies in children with hemochromatosis,” The Journal of Clinical Endocrinology and Metabolism, vol. 76, no. 2, pp. 357–361, 1993.
[52]
L. J. Noetzli, A. Panigrahy, S. D. Mittelman et al., “Pituitary iron and volume predict hypogonadism in transfusional iron overload,” American Journal of Hematology, vol. 87, no. 2, pp. 167–171, 2012.
[53]
R. Chatterjee and M. Katz, “Reversible hypogonadotrophic hypogonadism in sexually infantile male thalassaemic patients with transfusional iron overload,” Clinical Endocrinology, vol. 53, no. 1, pp. 33–42, 2000.
[54]
M. Berkovitch, T. Bistritzer, S. D. Milone, K. Perlman, W. Kucharczyk, and N. F. Olivieri, “Iron deposition in the anterior pituitary in homozygous beta-thalassemia: MRI evaluation and correlation with gonadal function,” Journal of Pediatric Endocrinology & Metabolism, vol. 13, no. 2, pp. 179–184, 2000.
[55]
S. Arguelles, M. Cano, A. Machado, and A. Ayala, “Effect of aging and oxidative stress on elongation factor-2 in hypothalamus and hypophysis,” Mechanisms of Ageing and Development, vol. 132, no. 1-2, pp. 55–64, 2011.
[56]
D. Gonzalez-Duarte, A. Madrazo-Atutxa, A. Soto-Moreno, and A. Leal-Cerro, “Measurement of oxidative stress and endothelial dysfunction in patients with hypopituitarism and severe deficiency adult growth hormone deficiency,” Pituitary, vol. 15, no. 4, pp. 589–597, 2012.
[57]
A. Birkenfeld, A. W. Goldfarb, E. A. Rachmilewitz, J. G. Schenker, and E. Okon, “Endometrial glandular haemosiderosis in homozygous beta-thalassaemia,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 31, no. 2, pp. 173–178, 1989.
[58]
S. T. Singer, N. Sweeters, O. Vega, A. Higa, E. Vichinsky, and M. Cedars, “Fertility potential in thalassemia major women: current findings and future diagnostic tools,” Annals of the New York Academy of Sciences, vol. 1202, pp. 226–230, 2010.
[59]
T. Dissayabutra, P. Tosukhowong, and P. Seksan, “The benefits of vitamin C and vitamin E in children with beta-thalassemia with high oxidative stress,” Journal of the Medical Association of Thailand, vol. 88, supplement 4, pp. S317–321, 2005.
[60]
C. Weeraphan, C. Srisomsap, D. Chokchaichamnankit, et al., “Role of curcuminoids in ameliorating oxidative modification in beta-thalassemia/Hb E plasma proteome,” The Journal of Nutritional Biochemistry, vol. 24, no. 3, pp. 578–585, 2012.
[61]
E. Vichinsky, “Emerging “A” therapies in hemoglobinopathies: agonists, antagonists, antioxidants, and arginine,” Hematology American Society Hematology Education Program, vol. 2012, no. 1, pp. 271–275, 2012.
[62]
C. Mora-Esteves and D. Shin, “Nutrient supplementation: improving male fertility fourfold,” Seminars in Reproductive Medicine, vol. 31, no. 4, pp. 293–300, 2013.
[63]
G. J. Kontoghiorghes, A. Efstathiou, M. Kleanthous, Y. Michaelides, and A. Kolnagou, “Risk/benefit assessment, advantages over other drugs and targeting methods in the use of deferiprone as a pharmaceutical antioxidant in iron loading and non iron loading conditions,” Hemoglobin, vol. 33, no. 5, pp. 386–397, 2009.
[64]
U. R. Kuppusamy and J. A. Tan, “Chelation therapy with desferrioxamine does not normalize ferritin level but attenuates oxidative damage and improves total antioxidant level in Malaysian Chinese beta-thalassaemia major patients,” The West Indian Medical Journal, vol. 60, no. 1, pp. 3–8, 2011.
[65]
P. B. Walter, E. A. Macklin, J. Porter et al., “Inflammation and oxidant-stress in β-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial,” Haematologica, vol. 93, no. 6, pp. 817–825, 2008.
[66]
V. Fenkci, S. Fenkci, M. Yilmazer, and M. Serteser, “Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease,” Fertility and Sterility, vol. 80, no. 1, pp. 123–127, 2003.
[67]
C. Tatone, M. C. Carbone, S. Falone et al., “Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modifications in human granulosa cells,” Molecular Human Reproduction, vol. 12, no. 11, pp. 655–660, 2006.
[68]
F. Gonzalez, N. S. Rote, J. Minium, and J. P. Kirwan, “Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome,” The Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 1, pp. 336–340, 2006.
[69]
G. Basta, G. Lazzerini, M. Massaro et al., “Advanced glycation end products activate endothelium through signal-transduction receptor RAGE a mechanism for amplification of inflammatory responses,” Circulation, vol. 105, no. 7, pp. 816–822, 2002.
[70]
E. Devangelio, F. Santilli, G. Formoso et al., “Soluble RAGE in type 2 diabetes: association with oxidative stress,” Free Radical Biology and Medicine, vol. 43, no. 4, pp. 511–518, 2007.
[71]
G. Basta, A. M. Schmidt, and R. de Caterina, “Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes,” Cardiovascular Research, vol. 63, no. 4, pp. 582–592, 2004.
[72]
R. Meerwaldt, T. Links, C. Zeebregts, R. Tio, J.-L. Hillebrands, and A. Smit, “The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes,” Cardiovascular Diabetology, vol. 7, article 29, 2008.
[73]
H. Unoki and S. Yamagishi, “Advanced glycation end products and insulin resistance,” Current Pharmaceutical Design, vol. 14, no. 10, pp. 987–989, 2008.
[74]
E. Diamanti-Kandarakis, C. Piperi, A. Kalofoutis, and G. Creatsas, “Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome,” Clinical Endocrinology, vol. 62, no. 1, pp. 37–43, 2005.
[75]
D. R. Mccance, D. G. Dyer, J. A. Dunn et al., “Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus,” Journal of Clinical Investigation, vol. 91, no. 6, pp. 2470–2478, 1993.
[76]
R. Singh, A. Barden, T. Mori, and L. Beilin, “Advanced glycation end-products: a review,” Diabetologia, vol. 44, no. 2, pp. 129–146, 2001.
[77]
E. Diamanti-Kandarakis, A. Piouka, S. Livadas et al., “Anti-mullerian hormone is associated with advanced glycosylated end products in lean women with polycystic ovary syndrome,” European Journal of Endocrinology, vol. 160, no. 5, pp. 847–853, 2009.
[78]
R. Chatterjee and R. Bajoria, “New concept in natural history and management of diabetes mellitus in thalassemia major diabetes and thalassaemia,” Hemoglobin, vol. 33, supplement 1, pp. S127–S130, 2009.
[79]
G. Paolisso, M. R. Tagliamonte, M. R. Rizzo, and D. Giugliano, “Advancing age and insulin resistance: new facts about an ancient history,” European Journal of Clinical Investigation, vol. 29, no. 9, pp. 758–769, 1999.
[80]
N. Sattarahmady, H. Heli, and A. A. Moosavi-Movahedi, “Desferal as improving agent for hemoglobin fructation: structural and functional impacts,” The Protein Journal, vol. 31, no. 8, pp. 651–655, 2012.
[81]
E. Fibach and E. A. Rachmilewitz, “The role of antioxidants and iron chelators in the treatment of oxidative stress in thalassemia,” Annals of the New York Academy of Sciences, vol. 1202, pp. 10–16, 2010.
[82]
L. M. Compagno, “Caring for adults with thalassemia in a pediatric world,” Annals of the New York Academy of Sciences, vol. 1054, pp. 266–272, 2005.
