Hypogonadotropic Hypogonadism in Severeβ-Thalassemia: Effect of Chelation and Pulsatile Gonadotropin-Releasing Hormone Therapy

Abstract

We studied pituitary-gonadal function in 11 male and 5 female patients, aged 12-30 yr, with severe beta-thalassemia and chronic iron overload. All had normal basal serum cortisol, T4, and PRL concentrations and normal serum cortisol and GH responses to insulin-induced hypoglycemia and TSH responses to TRH. Of the 11 male patients (all over 17 yr of age), only 3 attained full pubertal development and 4 had subnormal serum LH and FSH responses to GnRH. As a group, their mean basal serum testosterone (T) level was low [11.7 +/- 4.9 (+/- SE) nmol/L; normal, 10-40 nmol/L], and 9 of the 11 male patients responded to hCG with a rise in serum T. Two of the 3 female patients over 17 yr of age were prepubertal with undetectable serum estradiol (E2) levels and absent serum LH and FSH responses to GnRH; the other female patient had regular menstrual cycles and normal serum E2 levels and LH and FSH responses to GnRH. Six of the prepubertal patients (4 males and 2 females, aged 17-30 yr) were studied serially for 3 yr after the start of chelation therapy. Despite a fall of median serum ferritin from 11,910 to 1,303 pmol/L, there was no progression of puberty, and their basal and GnRH-stimulated serum LH and FSH and serum T or E2 levels did not change. Three of these patients (1 male and 2 female) then received pulsatile sc GnRH therapy in addition to chelation therapy for 6 months with no improvement. We conclude that chronic iron overload in patients with severe thalassemia leads to variable degrees of hypogonadotropic hypogonadism, which do not respond to chelation therapy given late in the course of the disease. The hypogonadism in most patients was due to pituitary hyporesponsiveness to GnRH.

Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?

“…43 Chronic conditions such as diabetes mellitus, 20 hypothyroidism, 44 hemodialysis, 45,46 or epilepsy 47 may affect the central production of gonadotropins. Iron deposition in the pituitary may cause hypogonadotropic hypogonadism in beta-thalassemia, 48 the effect of which was found to be separate from the production of diabetes in these patients. Some central suppression of testosterone production was even found during fasting in younger men.…”

Pubertal evaluation of adolescent boys with β-thalassemia major and delayed puberty

“…De Sanctis et al (9) demonstrated that 30% of their patients had gonadal failure, and Wang et al (19) found defective response to hCG in 2 (25%) of their 11 patients in whom 8 patients had delayed puberty. In a study by Soliman et al (15), 48% of their adolescents with ␤-thalassemia demonstrated poor response to hCG, denoting gonadal dysfunction, and in the report of Li et al (20), 3 of their 10 ␤-thalassemic boys had gonadal impairment.…”

Testicular Dysfunction in Systemic Diseases

“…Testosterone replacement therapy is often necessary and effective both symptomatically (Kley et al 1992) and in restoring bone density loss due to androgen deficiency (Diamond et al 1991). Gonadotropin induction of spermatogenesis is particularly effective in genetic hemochromatosis as the onset of gonadotropin deficiency follows anormal puberty while pulsatile GnRH therapy is ineffective since gonadotrop in secretion cannot be induced (Wang et al 1989). Earlier diagnosis by genetic and family screening should prevent the development of overt clinical manifestations of iron overload from genetic hemochromatosis.…”

“…Puberty is delayed in regularly transfused children with ß-thalassemia (Wang et al 1989) and prepubertal onset of iron chelation therapy enhances pubertal maturation, presumably by preventing pituitary siderosis (Bronspiegel-Weintrob et al 1990). …”