Clinical hypogonadism is common in thalassemia patients (83%) with detectable cardiac iron and is independently associated with pituitary iron deposition and gland shrinkage [36
]. The pituitary gland maintains its anatomical and functional connections with the brain, yet sits outside the blood–brain barrier. Iron deposition in the anterior pituitary continues to pose a serious problem in homozygous beta thalassemia patients, particularly in terms of gonadal function. Magnetic resonance imaging (MRI) measurements are able to estimate the amount of iron in the pituitary, which can then be correlated with gonadal function. The anterior pituitary gland is particularly sensitive to free radicals produced by oxidative stress, such that exposure to these radicals injures the gland. MRI has shown that even a modest increase in iron deposition in the anterior pituitary can lead to dysfunction, such as abnormalities in the hypothalamic–pituitary growth hormone axis and growth hormone neurosecretory dysfunction, and low insulin-like growth-factor-1 levels. Abnormalities in the hypothalamic–pituitary–gonad axis will induce lower follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion, low LH/FSH response, and low sex steroid secretion from the gonads, i.e., testosterone (reviewed [37
]). The spleen plays an important role in destroying abnormal red cells, sequesters 30–40% of the circulating platelet pool, and plays a role in the regulation of plasma volume. In thalassemic patients, the spleen may become enlarged, which can result in an increased propensity to recurrent infection, such that a splenectomy is required. Following splenectomy, the pituitary iron loading increases [38
]. In early studies of four thalassemia patients, (Hb-E thalassemia and thalassemia major), the pituitary iron content, as assessed by MRI, was increased in all four patients compared to controls [39
]. A subsequent MRI study of 84 patients with β-thalassemia established a correlation between pituitary iron overload, (evaluated by T2*) and both hepatic and cardiac iron load. In addition, pituitary MRI values correlated with serum ferritin and patient age, but not with height of the pituitary [38
]. A study of 30 children and young adult thalassemic patients (13 females and 17 male patients) confirmed iron accumulation in the liver, myocardium, and the pituitary, a linear regression between pituitary iron and age in patients > 14 y, while MRI values between the pituitary and liver, and liver and myocardia, were only moderately correlated, (r = 0.34 and 0.42, respectively). However, no correlation was evident between pituitary and myocardial MRI results, which were of interest, since it might be considered that NTBI would be taken up by both of these organs [40
]. It is clear that a therapeutic approach based on the use of iron chelators offers a solution to many of these dilemmas, associated with systemic iron overload, and their development has resulted in innumerable lives being saved, and, just as importantly, has led to an enormous improvement in the quality of life of thalassemia patients all over the world [5
]. Investigations have now been extended to monitor whether excessive amounts of iron in specific brain regions and the pituitary can be removed by iron chelators.