Thalassaemia International Federation | A non-profit, non-governmental patient-driven organization, founded in 1986

Nicos Skordis, MD and Andreas Kyriakou, MD
Pediatric Endocrine Unit, Makarios Hospital, Nicosia, Cyprus

Introduction

Treatment of beta-thalassaemia major is based on regular blood transfusions to maintain the pre-transfusional Hb level above 9 gr/dl and appropriate chelation therapy to avoid the consequences of iron overload. The metabolically active iron catalyses the formation of free radicals, which damage membrane lipids leading to cell death and eventually organ failure. The endocrine glands are particularly vulnerable to the excess iron, so that the appearance of endocrine dysfunction in thalassaemia major (TM) is a common and disturbing complication, which requires prompt recognition and treatment. The contribution of the underlying molecular defect in TM to the development of endocrinopathies, and particularly hypogonatotrophic hypogonadism, is significant because the patients with the more severe defects have a greater rate of iron loading through higher red cell consumption (1).

The child with thalassaemia major has a particular growth pattern, which is relatively normal until age of 9–10 years; after this age a slowing down of growth velocity and a reduced or absent pubertal growth spurt are observed. The pathogenesis of growth failure is multifactorial (2), as shown below.

Chronic anemia, hypersplenism, chronic liver disease (HBV, HCV)
Zinc and folic acid deficiency, skeletal dysplasia
Desferrioxamine toxicity
Emotional disturbance
Endocrinopathies: hypothyroidism, delayed puberty, hypogonadism, dysfunction of the growth hormone (GH) – IGF 1 axis

Growth Hormone (GH)

Chronic anaemia is no longer a factor in well-treated children in developed countries. The response of growth hormone to stimulation tests has been found to be normal or reduced. The presence of neurosecretory dysfunction is supported by the impaired 24 hour GH secretion. Evidence for partial GH resistance is based on the fact that children with thalassaemia major have normal GH and GHBP, with low levels of IGF-1 and IGFBP-3, which are not always properly increased following GH stimulation. Moreover the therapeutic administration of GH did not fulfil all our expectations and often supraphysiological doses of GH are required to overcome this resistance and lead to an improvement in linear growth (3,4,5). The response to growth hormone treatment cannot be predicted based on known parameters such as growth velocity, age, height SDS, bone age SDS, IGF-1 levels and the type of abnormality in the GH-IGF-1 axis, suggesting that additional factors such as skeletal dysplasia and Desferrioxamine (DFX) toxicity are implicated in the child’s growth retardation.

Desferrioxamine (DFX) toxicity and body disproportion

Short stature with disproportionate body composition due to desferrioxamine toxicity has been observed. Desferrioxamine exhibits its toxic effect on growth by inhibiting DNA synthesis, fibroblast proliferation and collagen formation, causing flattening of the vertebral bodies (platyspondylosis) and eventually poor spine growth. Both sitting and standing heights are normal until the age of 6-9 years but gradually decreased in older ages with particular shortening of the sitting height as shown in figure 1(6). Body disproportion with short trunk has been reported in patients who have been poorly chelated during childhood and adolescence, so that other contributing factors like haemosiderosis and deficiency of trace elements should influence spine growth (3). Sex steroid replacement therapy cannot adversely affect body disproportion, as truncal shortening at final height is evident in patients with either spontaneous or induced puberty (7). Body disproportion therefore is independent of pubertal or prepubertal period of greater height gain.

Management

Can children with thalassaemia major attain normal stature and develop normally with early and reasonable Desferrioxamine treatment? Although iron chelation can decrease the frequency of endocrinopathies, early DFX treatment may result in growth impairment. On the other hand poor compliance with DFX may eventually lead to severe iron burden, gonadal dysfunction and eventually growth failure (8). The benefits of treatment should be weighted against the potential adverse effects and the caring physician should balance between the efficacy and the injudicious use of Desferrioxamine. An ideal therapeutic regimen, which will avoid the toxic effects of iron overload and that of continuous subcutaneous chelation therapy, has yet to be found. It is therefore recommended that growth in both standing and sitting position should be assessed at 6-month intervals in order to detect early growth failure. Long-term observations on the effect of therapy are needed before this mysterious puzzle is solved. Alternative oral chelation agents are often an option in cases of DFX toxicity, although some bone lesions remain irreversible.

Prevention of growth retardation is essential.
Monitoring growth in all children by using growth charts for both standing and sitting height is mandatory.
The mean hemoglobin levels must be kept near to 9 gr/dl.
Prompt initiation of iron chelation therapy prevents pituitary haemosiderosis, which is the main cause of growth hormone insufficiency.
Treatment with growth hormone is recommended when GH deficiency is established. In poor responders such treatment should be discontinued. Therapeutic response with GH administration in cases with GH deficiency, is often non satisfactory.
Growth acceleration is mostly promoted with sex steroids in children with pubertal delay.
Sexual complications present a significant issue in thalassaemics. These include: delayed puberty, arrested puberty and hypogonadism. Transfusional haemosiderosis in the pituitary gonadotroph cell causes gonadotrophin deficiency, which is the underlying abnormality. Histological examination of the gonads shows minimal siderosis, so that the ovarian and testicular function is well preserved.

Protocol for investigation of poor growth in thalassaemic children

Measure current height both standing and sitting and plot on the growth chart. Calculate the target height based on parental heights. Compare with previous measurement to estimate the growth velocity. Examine pubertal status. Note any physical disproportion. Review emotional and social status.
Assess bone maturation
Routine blood tests including liver function tests, ferritin, biochemical profile, and zinc
Urine analysis
Thyroid function tests (Free T4, TSH)
IFG-1 and IGFBP-3
Stimulation tests to assess GH secretion. At least two tests are required. Priming with sex steroids is necessary in boys older than 10 years with testosterone and in girls older than 9 years with Estrogens.
IGF-1 generation test in patients with low levels of IFG-1 and IFGBP-3 and normal GH secretion to exclude GH resistance.

Puberty

Puberty is the biological phenomenon, which results from the activation of the hypothalamic–pituitary–gonadal axis and is clinically manifested by the appearance of sexual characteristics. Delayed puberty is defined as the absence of any pubertal sign in girls (breast enlargement) and in boys (testicular enlargement) by the age of 13 and 14 years respectively. Delayed puberty in thalassaemia is almost always due to hypogonadotrophic hypogonadism, which still remains the most common endocrine and stressful complication in thalassaemia major (9) (figure 2). The association of hypogonadotrophic hypogonadism with the genotype has already been proven (1). An additional contributing factor, whose role is thought to be weak, is the impaired synthesis of leptin in thalassaemic patients which seems to be related to transferrin receptor levels (10).

Arrested puberty is defined as the absence of further pubertal progression –once puberty has started –for more than one year, where testicular volume in boys never exceeds 6 to 8 ml and breast size in girls remains unchanged. Failure of sexual development by the age of 15 to 16 years in both sexes is defined as hypogonadism. Secondary hypogonadism appears later in life, and is manifested in women as secondary amenorrhea and in men as decline in sexual drive and azzoospermia.

Adolescent girls with TM often present with primary amenorrhea and boys fail to become well virilized. The damage to the hypothalamus and pituitary is progressive, even when intensive chelating therapy is given and the appearance of hypogonadism in both sexes is often unavoidable. Most women with TM manifest secondary amenorrhea at some stage in their life and men develop hypogonadism in their 3rd decade after being normal for some years and even becoming fathers (11, 12, 13).

Protocol for investigation of pubertal disorder

The absence of any clinical pubertal signs in a boy (testicular enlargement) older that 14 years and in a girl (breast development) older than 13 years requires investigation.

Measure testosterone in the boy and oestradiol in the girl. DHEA-S in both sexes is often helpful
Perform the GnRH test to evaluate the pituitary capacity to secrete the gonadotropins FSH and LH, where the response in hypogonadism is low
Bone age is helpful for the treatment decision options

Therapeutic approach in delayed puberty should mimic biological and biochemical pubertal changes, aiming on promotion of linear growth as well (14,15,16,17).

Induction of puberty in boys can be achieved with testosterone depot IM 25-50mg monthly for 6 months and reassessment. Pubic hair will appear and penile size will increase. Increase in testicular volume indicates activation of the axis and release of gonadotrophins (FSH and LH), where no further treatment is needed except for close observation. In case where testicular size is unchanged, then treatment is continued for 6 months and subsequently the dose is increased to 100mg monthly for one year. Therapeutic schedule is determined by the growth potential, clinical response and emotional factors. For testicular enlargement, the therapeutic regime is altered to the combination of hCG and hMG, both of which mimic the pituitary gonadotrophins. The final adult dose is testosterone depot 50mg/weekly IM or alternatively transdermally in patches 5 mg/daily. The oral route (testosterone undeconate) should be avoided due to liver toxicity.

For induction of puberty in girls oral ethinylestradiol is preferred at the dose 100ng/kg/day for 6 months, where increase in breast size and growth acceleration is noted. This dose is continued for additional 6 months and increased to 200ng/kg/day for the subsequent year. Therapeutic schedule is determined by the same factors as in boys. The adult dose is 400ng/kg/day, where the uterine size is satisfactorily increased for the induction of menarche. Induction of puberty can be successfully achieved by the transdermal use of estrogens.

Menarche is achieved by the addition of Medroxyprogesterone 10 mg/day for 10 days when the size of the uterus exceeds 5cm. When menstrual bleeding occurs spontaneously during estrogen treatment, the regime should be adjusted. For maintenance of the menstrual cycle the use of estrogens (Conjugated Estrogens 0.625 ή 1.25 mg, Ethinyl Estradiol 20 μg) from day 1st to 25th and Progesterone from day 14th to 25th is required. The transdermal use of Estradiol and Norethisterone is advantageous due to decreased liver toxicity.

Prompt chelation therapy before pubertal age and before extremely high levels of ferritin are reached is the fundamental tool to help children with thalassaemia major to attain normal stature and sexual maturity and to improve their bone mass. Poor pubertal growth in adolescents with thalassaemia major does not solely depend on gonadal failure. No difference has been observed in pubertal growth and final height between treated hypogonadal patients compared to those with spontaneous puberty (18,19). Failure to progress normally through puberty is associated with failure of adequate bone mineralization and achievement of peak bone mass, which is a contributing factor to the ultimate bone disease in thalassaemia (20).

Figure 1: Standing height and sitting height is SDS in different age-groups ^6.

Figure 2. FSH (a) and LH levels (b) after GnRH stimulation in thalassaemic women with normal menstrual cycles, primary amenorrhea and secondary amenorrhea. X-axis: time in minutes. Y-axis: FSH and LH in miu/l ⁶

References:

1) Skordis N, Michaelidou M, Savva SC, Ioannou Y, Rousounides A, Kleanthous M, Skordos G, Christou S. The impact of Genotype on Endocrine complications in Thalassaemia major. Eur J Hematol 2006
2) Skordis N. The growing child with Thalassaemia. J Pediatr Endocrinol Metab 2006; 19: 467-9.
3) De Sanctis V. Growth and puberty and its management in Thalassaemia. Horm Res 2002; 58(S1): 72-79
4) Raiola G, Galati MC, De Sanctis V, Caruso-Nicoletti M, Pintor C, De Simone M, Arcuri VM, Anastasi S. Growth and puberty in Thalassaemia major. J Pediatr Endocrinol Metab 2003; 16: 259-266
5) De Sanctis V, Urso L. Clinical experience with Growth Hormone treatment in patients with beta-Thalassaemia major. Bio Drugs 1999; 11:79-85
6) Toumba M, Sergis A, Kanaris C, Skordis N. Endocrine complications in patients with Thalassaemia major. Pediatric Endocrine Reviews 2007;5:642-648
7) Filosa A, Di Maio S, Baron I, Esposito G, Galati MG. Final height and body disproportion in Thalassaemic boys and girls with spontaneous or induced puberty. Acta Paediatr 2000; 89:1295-1301
8) De Sanctis V, Roos M, Gasser T, Fortini M, Raiola G, Pintor C. Impact of long-term iron chelation therapy on growth and endocrine functions in Thalassaemia. J Pediatr Endocrinol Metab 2006
9) Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Multicentre study on prevalence of endocrine complications in Thalassaemia major. Clin Endocrinol 1995; 42: 581-586.
10) Dedousis GVZ, Kyrtsonis MC, Andrikopoulos NE, Voskaridou E, Loutradis A. Inverse correlation of plasma leptin and soluble transferrin receptor levels in β-thalassaemia patients. Ann Hematol 2002; 81: 543-547.
11) De Sanctis V, Vullo C, Katz M, Wonke B, Tanaw R, Bagni B. Gonadal function in patients with B–Thalassaemia Major. J Clin Pathol 1988; 41:133-137.
12) Skordis N, Gourni M, Kanaris C, Toumba M, Kleanthous M, Karatzia N, Pavlides N, Angastiniotis M. The impact of iron overload and genotype on gonadal function in women with Thalassaemia major. Ped Endocrinol Rev 2004; 2(S2): 292-295
13) Skordis N, Petrikkos L, Toumba M, Simamonian K, Hadjigavriel M, Sitarou M, Kolnakou A, Skordos G, Pangalou E, Christou S. Update on fertility in Thalassaemia major Pediatric Endocrine Reviews. 2004; (S2):296-302
14) Pozo J, Argente J. Ascertainment and treatment of delayed puberty Horm Res. 2003; 60 (S3):35-48
15) Mac Gillivray MH. Induction of puberty in Hypogonadal children. J Pediatr Endocrinol Metab 2004;17(S4):1277-1287
16) Caruso –Nicoletti M, De Sanctis V, Cavallo L, Raiola G, Ruggiero L,Skordis N, Wonke B. Manegement of puberty for optimal Auxological results. J Pediatr Endocrinol Metab 2001;14(S2):939-944
17) De Sanctis V, Vullo C, Katz M, Wonke B, Nannetti C, Bagni B. Induction of spermatogenesis in Thalassaemia. Fertility Sterility 1998; 50: 969-975.
18) Caruso-Nicoletti M, De Sanctis V, Raiola G, Skordis N, Manusco M, Coco M, Wonke B. No difference in pubertal growth and final height between treated Hypogonadal and non-Hypogonadal Thalassaemic patients. Horm Res 2004;62:17-22
19) Filosa A, Di Maio S, Lamba M, Baron I, Saviano A, Esposito G. Bone age progression during five years of substitutive therapy for the induction of puberty in Thalassaemic girls-effects on height and sitting height J Pediatr Endocrinol Metab 1999;12:525-530
20) Bielinski BK, Darbyshire PJ, Mathers L, Crabtree NJ, Kirk JM, Stirling HF, Shaw NJ. Impact of disordered puberty on bone density in beta-Thalassaemia major. Br J Haematol. 2003; 120:353-358

This page was last updated September 2010 by Dr Michael Angastiniotis, MD, DCH (Paediatrician)

Medical focus

Nicos Skordis, MD and Andreas Kyriakou, MD Pediatric Endocrine Unit, Makarios Hospital, Nicosia, Cyprus