Medical director: Doc. Cinchini Elisabetta



  • Short stature
  • Delayed puberty
  • Hypogonadism


Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and close follow-up by specialists.The normal growth rate during childhood is reported in the figure.


Growth retardation occurs almost invariably in homozygous β-thalassemia.

Significant size retardation is observed in standing and sitting height (Figures), weight, biacromial (shoulder; figure), and bicristal (iliac crest) breadths.



After the age of 4 years the longitudinal growth patterns display rates consistently behind those of normal controls. The bone age is frequently delayed after the age of 6-7 years. Growth retardation becomes markedly severe with the failure of the pubertal growth spurt.


With the introduction of high transfusion regimes and efficient iron chelation, prepubertal linear growth has been improved markedly. However, abnormal growth is still observed in the majority of patients during late childhood and adolescence.The prevalence of short stature in subjects with TM is reported in the table.


The childhood phase of growth is growth hormone (GH) dependent. The pubertal phase depends on both GH and sex steroids secretion.

In addition, adequate nutrition and weight gain play an important role to mediate growth during all of its phases (Figure).


Hemosiderosis-induced damage of the endocrine glands is implicated to be one of the main causes for growth failure. However, other factors could considerably contribute in the aetiology of this growth delay including (a) chronic anemic hypoxia secondary to low hemoglobin  oncentration; (b) toxicity of desferrioxamine treatment; (c) increased energy expenditure due to high erythopoietic turnover and cardiac work; (d) nutritional deficiencies including calories, folic-acid, zinc, and vitamin A; (e) disturbed calcium homeostasis and bone disease and (f) pancreatic or hepatic dysfunction (Figure).


The classification of the GH-IGF disorders and the prevalence of growth hormone deficiency are given in the Tables.



Patients’ growth should be assessed every 6 months by accurate measurement of standing and sitting heights and weight. Annual growth velocity, body mass index and upper/lower segment ratio are calculated. Mid-parental height is recorded. Growth data are plotted on ethnically adjusted charts or internationally (WHO) adjusted charts.A protocol of investigation and treatment in patients with short stature (less than 3rd centile) and/or reduced growth velocity (less than 10th centile for the bone age) is presented in Table.


The diagnosis of growth hormone deficiency (GHD) is generally straightforward in children as growth retardation is present.However, in adults the diagnosis of GHD is often challenging. GHD in adults is a clinical syndrome associated with lack of positive well-being, depressed mood, feelings of social isolation, decreased energy, alterations in body composition with reduced bone and muscle mass, diminished exercise performance and cardiac capacity and altered lipid metabolism with increase in adiposity.Management consists of optimizing blood transfusion, improving nutrition with high caloric balanced diet and zinc, vitamin D, calcium and folic acid, supplementations. Optimizing iron chelation through the new oral chelators and intensive and combined chelation. Also, early diagnosis and treatment of endocrinopathies and induction of puberty at proper time are essentials. Lastly, psychological support is mandatory.

A flow chart for the assessment and treatment of growth retardation in thalassaemia is presented below.




There is a wide range in the timing, start and subsequent milestones of normal puberty. The change from prepuberty to full reproductive capacity may take as little as 18 months or as long as five years. Both boys and girls pass through identifiable stages of development of secondary sex characteristics (Tanner stages).Puberty starts with breast development in girls around the age of 11, and is associated with rapid growth, so no sign of this happening in a girl over 13 years warrants further investigationBoys’ first sign of puberty is testicular enlargement, normally around the age of 12. The peak of the growth spurt and other changes such as voice lowering, muscle bulking and facial hair growth usually do not appear for another 2-3 years (Figure).


Iron deposition on gonadotrophic cells leads to disruption of gonadotrophin production. In the majority of patients the function of gonads is normal; however, gonadal iron deposition may occurs (Figues). TM patients with a favorable genotype manifest less severe gonadal dysfunction, due to less iron loading.


TM patients with a favorable genotype manifest less severe gonadal dysfunction, due to less iron loading.Delayed puberty and hypogonadism are the most obvious clinical consequences of iron overload.Delayed puberty is defined as the complete lack of pubertal development in girls by the age of 13 years, and in boys by the age of 14 years (Figure).


Hypogonadism is defined in boys by the absence of testicular enlargement (less than 4 ml; Figure), and in girls by the absence of breast development by the age of 16 years.

Arrested puberty is a relatively common complication in moderately or grossly iron overloaded patients with TM. This is characterised by the lack of pubertal progression over a year or longer. In such cases, the yearly growth velocity is either markedly reduced or completely absent.Secondary hypogonadism appears later in life, and is manifested in women as secondary amenorrhea and in men as decline in sexual drive and azoospermia (Figure).


The diagnosis of hypogonadism requires careful clinical assessment and appropriate laboratory testing. Its management is more complex compared to other ‘classical’ causes of hypogonadism because of multiple associated disorders (cardiac, hepatic and endocrine) and other contributing factors basically iron overload and iron toxicity.


  • Tanner staging should be recorded every six months.
  • Girls without evidence of an advancing pubertal stage by 12-13 years and boys by 14 years require screening with LH/ FSH, and sex steroid.
  • If LH and FSH levels are low for the patient’s age, suspect hypogonadism.
  • GnRH stimulation may help to diagnose hypogonadotropic hypogonadism.
  • Testosterone level should be checked annually in boys, starting in the early adolescent years (at approximately 12 years old).
  • If testosterone level is low-ask for endocrine consultation and start monthly testosterone treatment.

Treatment of hypogonadism

Treatment depends on age, severity of iron overload, the coexistence of chronic liver disease, psychological factors as well as the degree of damage to the hypothalamo-pituitary-gonadal axis.For girls:• Ethinyl estradiol (2.5-5 μg daily) for 6 months and then hormonal assessment• If puberty does not occur, gradually increase dose to 5-10μg daily for 12 months• If breakthrough uterine bleeding does not occur, then low oestrogen-progesterone hormone replacement is recommendedFor boys:• Low dose IM depot-testosterone esters (25-50mg) monthly for 6 months followed by hormonal assessment• If no response 50mg per month is continued until growth rate wanes• The full virilising dose of depot testosterone is 75-100mg every 10 days, after growth is completed (the same effect is can be achieved with topical gel• If there is pubertal arrest, treatment is with testosterone esters or gelTreatment for these pubertal disorders is considered for each patient individually because of the complexity of the contributing factors.Induction of spermatogenesis and ovulation:Human chorionic gonadotropin (hCG), human menopausal gonadotropin (hMG), and intracytoplasmic sperm injection (ICSI) can be offered to males with spermatogenesis problems to assist in attaining pregnancy in the partner.In females with chronic anovulation, stimulation with gonadotropins can still increase estradiol and produce ova, but global assessment of the patient is necessary before induction of pregnancy.Optimal management of pregnant TM women requires a multidisciplinary approach with close maternal and fetal surveillance.  

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