Pituitary iron and volume predict hypogonadism in transfusional iron overload

Abstract

Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy.

Guidelines for quantifying iron overload

“…40 Hypogonadism rates are lower in cohorts having better access to iron chelation, particularly oral chelators, but secondary hypogonadism and impaired fertility remain a major issue. Preclinical pituitary iron deposition can be detected using R2 techniques, 41 whereas severe iron deposition is associated with decreased response to gonatropin-releasing hormone challenge and clinical hypogonadism. 41 Shrinkage of the pituitary gland is associated with more significant, irreversible loss of gonadotrophic production 41 ; Figure 5 summarizes the relationship.…”

Pubertal induction in hypogonadism: Current approaches including use of gonadotrophins

“…Infiltration of the gonad or hypothalamic pituitary area with iron may occur with chronic diseases that require multiple blood transfusions [Thalassaemia major, Blackfan Diamond syndrome] or where the disease itself causes iron deposition ]haemochromatosis [42] Similar problems occur with galactosaemia, with progressive ovarian failure resulting from accumulation of galactose products, with consequent gonadal fibrosis [43].…”

Iron and copper in male reproduction: a double-edged sword

“…Hypogonadism and abnormal spermatogenesis have been identified as primary causes of sexual dysfunction seen in β-thalassemia patients [100,102]. The hypogonadism-like symptoms are related to either anemia [103] or iron accumulation in the pituitary gland [104]. Treating infertile male patients with β-thalassemia with growth hormone and gonadotropins improved semen parameters [105].…”