ACQUIRED HYPOGONADOTROPIC HYPOGONADISM (AHH) IN THALASSAEMIA MAJOR PATIENTS: AN UNDERDIAGNOSED CONDITION?
Authors: De Sanctis Vincenzo 
Published: December 2015

IntroductionIn males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and a lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function and strength, a worsened sense of well being and degraded quality of life (QOL).Patients and methodsWe studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean ± SD: 34.3 ± 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy.Fasting venous blood samples were collected two weeks after  transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol,  luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*.   Bone mineral density was measured at the lumbar spine (L1-L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine.ResultsThe mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 IU/L  and 1.2 ± 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH proved azoospermia in 3 and  oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml was significantly higher in AHH patients compared to controls (45.4 % versus 8.3%, p: 0.043). Heart iron concentrations (T2* values) were significantly lower inAHH patients compared to controls (p: 0.004). Magnetic resonance imaging in the 3 azoospermic patients revealed volume loss and reduction of pituitary signal intensity.  Using DXA, 63.6 % (7/11) of patients with AHH were osteoporotic and 36.3 % (4/11) were osteopenic.  ConclusionsIn our thalassemic patients iron overload and chronic liver disease appear to play a role in the development of AHH.  Treatment of AHH in TM patients is an important and vibrant field for improving their health and QOL. Early identification and management of AHH is very crucial to avoid long-term morbidity, including sexual dysfunction and infertility. Therapy aims to restore serum testosterone to the mid–normal range. Many exciting opportunities remain for further research and therapeutic development.Key words:Acquired hypogonadotropic hypogonadism, thalassemia, iron overload, liver disease.IntroductionIn males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and a lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function and strength, a worsened sense of well being and degraded quality of life (QOL).Patients and methodsWe studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean ± SD: 34.3 ± 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy.Fasting venous blood samples were collected two weeks after  transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol,  luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*.   Bone mineral density was measured at the lumbar spine (L1-L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine.ResultsThe mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 IU/L  and 1.2 ± 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH proved azoospermia in 3 and  oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml was significantly higher in AHH patients compared to controls (45.4 % versus 8.3%, p: 0.043). Heart iron concentrations (T2* values) were significantly lower inAHH patients compared to controls (p: 0.004). Magnetic resonance imaging in the 3 azoospermic patients revealed volume loss and reduction of pituitary signal intensity.  Using DXA, 63.6 % (7/11) of patients with AHH were osteoporotic and 36.3 % (4/11) were osteopenic.  ConclusionsIn our thalassemic patients iron overload and chronic liver disease appear to play a role in the development of AHH.  Treatment of AHH in TM patients is an important and vibrant field for improving their health and QOL. Early identification and management of AHH is very crucial to avoid long-term morbidity, including sexual dysfunction and infertility. Therapy aims to restore serum testosterone to the mid–normal range. Many exciting opportunities remain for further research and therapeutic development.Key words:Acquired hypogonadotropic hypogonadism, thalassemia, iron overload, liver disease.