Gonadal Dysfunction in Thalassemia

Gonadal Dysfunction in Thalassemia

Homozygous β-thalassemia major is transfusion dependent autosomal recessive hemoglobinopathy in which there is disturbance of growth, delayed sexual maturation and impaired fertility affecting 80-90% of patients worldwide. This is largely attributed to transfusion iron overload. Anterior pituitary damage affecting gonadotrophins and growth hormone secretory dynamic is a well established cause of their pubertal failure (Chatterjee et al., 1993a; Low et al., 1997).

Women with thalassemia often present with primary amenorrhea, or may manifest secondary amenorrhea later in their lives. The incidence of primary amenorrhea in some reports is over 50% reaching that of 100% (Skordis et al., 2006).

However, these studies have not provided comprehensive information on the severity and reversibility of hypogonadism. This is primary due to the fact that they have relied on the traditional dynamic test of a bolus IV injection of GnRH to assess gonadotrophic hormones sufficiency, and this can not accurately determine the degree of gonadotrophin deficiency in hypogonadal patients. Gonadotrophin secretion fluctuates markedly in the same individual and varies considerably between individuals (Chatterjee et al., 2000).

In patients with transfusion-dependent β-thalassemia, delayed puberty and hypogonadism may result form iron deposition in the hypothalamic-pituitary cells, the gonads, or both (Soliman et al., 2000).

As thalassemics depend on repeated blood transfusion for their survival, the transfusional iron overload progressively damages their H-P axis in an irreversible way (Chatterjee et al., 1993b). There is a correlation between the degree of organ damage and the degree of iron overload in patients with β-thalassemia. Damage to the gonads form iron overload is an irreversible process, even if the iron level is corrected at a later stage (De Sanctis, 2002). Chelation therapy with desferrioxamine before the age of puberty has been helpful in attaining normal sexual maturation in children with transfusion dependent beta thalassemia major (Soliman et al., 1999). The ovaries are vulnerable to the toxic effect of excess iron even if it is not persistent. This reflects the importance of compliance with sustained usage of desferrioxamine to prevent fluctuation in the ferritin levels and irreversible damage to the ovaries. It has been suggested that once patients develop secondary amenorrhea, then the damage would have been severe and progressive despite intensive chelation therapy later (Al-Rimawi et al., 2005).

Other possible causes for delayed puberty and hypogonadism in beta-thalassemia major include liver disorders, chronic hypoxia, diabetes mellitus and zinc deficiency (Al-Remawi et al., 2005).

In thalassaemic patients with pubertal failure, iron overload is most important factor affecting the H.P axis in a dose dependent fashion. However metabolic factors including chronic ill health, chronic hypoxia, underweight and low body mass index may be confounding variables accounting for derangement of the H.P axis. The exact pathogenesis of the GnRH secretory insufficiency in these patients is still unclear. They may have a derangement in synthesis, secretion or delivery of GnRH or they may have a sub-optimal gonadotroph response to normal GnRH stimulation (Chatterjee et al., 2000).

Hypogonadotrophic hypogonadism in thalassemia is related not only to iron toxicity on gonadotroph cells but also to iron toxicity on the adipose tissue, thus changing the physiological role of leptin in sexual maturation and fertility. Leptin is a polypeptide hormone that is produced in fat cells due to expression of the ob gene. In girls leptin levels increase dramatically as puberty develops and stimulate the hypothalamic-pituitary-gonadal axis. There is evidence that this hormone acts as permissive signal allowing pubertal progression. The impaired synthesis of leptin in thalassemic patients seems to be related to transferrin levels, with toxic effect of iron on adipocytes (Skordis et al., 2006).

Jensen et al. (1997) first reported the incidence of endocrine dysfunction in relation to the detailed genotype of thalassemia in a retrospective study of 97 patients in whom a significant association was observed between the genotype and the development of hypogonadotrophic hypogonadism because of different transfusion requirements.

The genotype in women with TM could be a contributing factor for gonadal dysfunction. Women with no mitigating factor in their genotype tend to develop secondary amenorrhea more frequently although they have lower ferritin levels for along period of time. Moreover the mean duration of eumenorrhea in women with favorable genotype, who finally develop secondary amenorrhea is much longer (Skordis et al., 2006). Genetic differences are found to influence the susceptibility to hypogonadism in patients with TM, possibly as a result of differences in the amount of blood transfused and / or the vulnerability to free radical damage (Chern et al., 2003).