**3. Hypogonadism and puberty in thalassaemia**

Sexual immaturity is a profound complication of severe thalassaemia [35]. Disruption of the hypothalamic–pituitary-gonadal axis (HPG) may result in infertility [36]. While hypogonadism can occur as a result of primary or secondary hypogonadism or as a combination of both, multiple studies have shown

gonadotropin failure (hypogonadotropic hypogonadism) is the commonest complication [36, 37]. Primary gonadal failure is caused by iron deposition on gonadal tissue [37]. Secondary hypogonadism occurs as a result of pituitary gland gonadotrophic cell iron deposition, as evidenced by GnRH stimulation which demonstrates inadequate FSH and LH response [38–40]. Failure of pubertal onset has a very high incidence rate, with studies varying between 50–100% [9]. In female patients, delayed puberty is defined as a lack of breast development in girls by age 13 and in male patients, by a lack of testicular development by age 14 [30].

Delayed puberty in patients with beta thalassaemia major occurs as a result of multiple factors. Evidence suggests that the accumulation of excess iron from multiple transfusions leads to tissue damage in multiple organs (e.g. the liver, heart, endocrine organs), and the presence of free radicals leads to oxidative stress [41]. Delays in sexual maturation has been shown to be a result of impaired synthesis of leptin caused by the deposition of iron on adipose tissue [42]. Adipose cells response to the expression of the *ob* gene to produce leptin which functions as an indicator to instigate puberty. Despite chelation therapy, iron accumulation continues to occur in the pituitary, hypothalamus and gonads [43]. The lack of response to gonadotropin releasing hormone in patients with low gonadotropin levels is synonymous with hypothalamic and pituitary damage [44].

While MRI assessment of the pituitary gland for iron accumulation has been studied with promising results, it is currently not part of routine assessment [45]. In terms of growth velocity, patients with thalassaemia were found to have distinctly lower or completely absent annual growth rates [46]. Short stature was found in up to 20% of such patients [14] and the lack of pubertal growth spurt in puberty, whether spontaneous or induced, ultimately adversely affected the attainment of a normal final height [18]. Impairment of truncal growth [47] is also compounded by disproportionate body ratios and variation in spinal growth. As a result, failure of pubertal growth spurt, delayed or absence of sexual development and infertility are common sequelae among patients with beta thalassaemia major [36].

Hypogonadism as an endocrine complication in patients with thalassaemia major has been reported in multiple studies [36]. A high incidence of hypogonadotropic hypogonadism has been found by Chern et al. in their study population [48]. A 45% prevalence was found in male patients and 39% in female patients, with an overall prevalence of 72%. Of note were significant delays or cessation in development of secondary sexual characteristics and the menstrual cycle. These findings were reiterated in a cross-sectional study set up in Hong Kong, in which 75% of female patients and 62% of male patients were found to have diminished gonadal function [13]. In a study conducted of by Saffari et al., hypogonadism was found to be the most common endocrine complication. From a study population of 77 patients, 36 (46.8%) patients were found to have hypogonadism, 28 (36.4%) had delayed puberty and in 8 (10.4%) patients there was absence of pubertal progression [49]. In this study, it was also noted that there was 'significant correlation between bone mineral density and pubertal status (p = 0.001). This study demonstrates the effects of hypogonadism not only on the reproductive system, but also on bone mineral density as well [49].

Failure of puberty was reported by Moayeri et al. in 69% of patients with thalassaemia with suppressed FSH and LH levels (73.2% in male patients and 64.8% in female patients) [50]. Similar findings were reported in a separate Italian multicentre study, which described hypogonadism 47% of female patients and 51% of male patients. Hagag et al. demonstrated that in males testosterone levels and testicular volume were significantly lower in thalassaemic patients with iron overload [51]. A similar study conducted by Hagag et al. in female patients, they showed that FSH, LH and oestrogen levels were significantly lower in thalassaemic patients with iron overload [52].

**65**

2.8 kg/m2

in this population [30].

*Investigation and Management of Endocrinopathies in Thalassaemia Major*

achieved by women who receive adequate chelation therapy.

Pubertal failure has also been described in 73% of male and 42% of female patients under the age of 21 years old by Soliman et al. [23]. Similar findings were noted by Borgna-Pignatti and colleagues with 67% of males and 38% of females experiencing puberty failure [24]. Remarkably, successful conception may still be

Bone growth, growth velocity and puberty may be assisted by administration of chelation therapy before the commencement of sexual maturation and the use of

Effective management of patients suffering from homozygous beta thalassaemia has led to improved life expectancy and hence manifestations of haemosiderosis related complications, notably, disturbances of the exocrine and endocrine function of the pancreas [53]. The prevalence of glucose intolerance and diabetes mellitus (DM) in patients with homozygous beta thalassaemia has been found to be variable. A retrospective analysis of 92 patients performed by Ang et al. showed that diabetes mellitus was one of the most common endocrinopathies with 41% of the study population affected [54] while a study conducted by Kanbour et al. reported a prevalence of 16.7% for impaired fasting glucose and 12.5% for diabetes mellitus [55]. Recently, a meta-analysis conducted by He et al. which included 44 studies with 16,605 cases showed that diabetes mellitus was present in 6.54%, impaired fasting glucose (IGF) in 17.21% and impaired glucose tolerance (IGT) in 12.46% [56]. While the prevalence of glucose intolerance and diabetes mellitus is undoubtedly high, many risk factors have also been identified. There was evidence of

increased risk of diabetes mellitus with co-infection with hepatitis C [55–57], longer duration of disease [57–59] and with increased pancreatic iron deposition [58, 60]. Li et al. have found that in addition, patients with diabetes mellitus were characterised by higher ferritin levels, smaller pancreas volume, lower cardiac T2 magnetic resonance signal (MRI) than patients without diabetes, and higher prevalence of hypogonadism. Interestingly, patients with diabetes were found to be young (median age was 22 years [range of 10 to 34 years]) and non-obese (BMI of 20.1 ±

) [58]. This may explain why the classical association between diabetes

and increased prevalence of arteriosclerotic cardiovascular disease is not a feature

rioxamine therapy and high hepatic iron concentration.

Poor compliance with desferrioxamine therapy (p < 0.05), older age commencing intensive chelation therapy, liver cirrhosis and severe fibrosis were found to be risk factors for glucose intolerance and diabetes mellitus. Risk factors for impaired glucose tolerance (IGT) also included male sex [61], poor compliance with desfer-

Current UK guidelines recommend annual monitoring for impaired glucose tolerance and diabetes from the onset of puberty, or from the age of 10 years if

Current Standards for the Clinical Care of Children and Adults with Thalassaemia UK Guidelines recommend that assessment of gonadal function should be done annually throughout adulthood [30]. In men, this would include an annual morning testosterone level alongside LH/FSH and SHBG if testosterone levels are low. In women, no testing is required in the presence of a normal menstrual history. However, in the presence of menstrual disturbances, further testing (LH/FSH and oestradiol) is recommended [30]. Deficiency should be replaced with oestrogen/testosterone while bearing in mind that under-replacement contributes to a low bone mineral density. Management is best achieved through a joint multidisciplinary consultation between the endocrinologist and thalassaemia team [30].

*DOI: http://dx.doi.org/10.5772/intechopen.93861*

low dose sex steroids in adolescence [9].

**4. Glucose intolerance and diabetes mellitus**

*Investigation and Management of Endocrinopathies in Thalassaemia Major DOI: http://dx.doi.org/10.5772/intechopen.93861*

*Human Blood Group Systems and Haemoglobinopathies*

hypothalamic and pituitary damage [44].

bone mineral density as well [49].

gonadotropin failure (hypogonadotropic hypogonadism) is the commonest complication [36, 37]. Primary gonadal failure is caused by iron deposition on gonadal tissue [37]. Secondary hypogonadism occurs as a result of pituitary gland gonadotrophic cell iron deposition, as evidenced by GnRH stimulation which demonstrates inadequate FSH and LH response [38–40]. Failure of pubertal onset has a very high incidence rate, with studies varying between 50–100% [9]. In female patients, delayed puberty is defined as a lack of breast development in girls by age 13 and in

Delayed puberty in patients with beta thalassaemia major occurs as a result of multiple factors. Evidence suggests that the accumulation of excess iron from multiple transfusions leads to tissue damage in multiple organs (e.g. the liver, heart, endocrine organs), and the presence of free radicals leads to oxidative stress [41]. Delays in sexual maturation has been shown to be a result of impaired synthesis of leptin caused by the deposition of iron on adipose tissue [42]. Adipose cells response to the expression of the *ob* gene to produce leptin which functions as an indicator to instigate puberty. Despite chelation therapy, iron accumulation continues to occur in the pituitary, hypothalamus and gonads [43]. The lack of response to gonadotropin releasing hormone in patients with low gonadotropin levels is synonymous with

While MRI assessment of the pituitary gland for iron accumulation has been studied with promising results, it is currently not part of routine assessment [45]. In terms of growth velocity, patients with thalassaemia were found to have distinctly lower or completely absent annual growth rates [46]. Short stature was found in up to 20% of such patients [14] and the lack of pubertal growth spurt in puberty, whether spontaneous or induced, ultimately adversely affected the attainment of a normal final height [18]. Impairment of truncal growth [47] is also compounded by disproportionate body ratios and variation in spinal growth. As a result, failure of pubertal growth spurt, delayed or absence of sexual development and infertility are

Hypogonadism as an endocrine complication in patients with thalassaemia major has been reported in multiple studies [36]. A high incidence of hypogonadotropic hypogonadism has been found by Chern et al. in their study population [48]. A 45% prevalence was found in male patients and 39% in female patients, with an overall prevalence of 72%. Of note were significant delays or cessation in development of secondary sexual characteristics and the menstrual cycle. These findings were reiterated in a cross-sectional study set up in Hong Kong, in which 75% of female patients and 62% of male patients were found to have diminished gonadal function [13]. In a study conducted of by Saffari et al., hypogonadism was found to be the most common endocrine complication. From a study population of 77 patients, 36 (46.8%) patients were found to have hypogonadism, 28 (36.4%) had delayed puberty and in 8 (10.4%) patients there was absence of pubertal progression [49]. In this study, it was also noted that there was 'significant correlation between bone mineral density and pubertal status (p = 0.001). This study demonstrates the effects of hypogonadism not only on the reproductive system, but also on

Failure of puberty was reported by Moayeri et al. in 69% of patients with thalassaemia with suppressed FSH and LH levels (73.2% in male patients and 64.8% in female patients) [50]. Similar findings were reported in a separate Italian multicentre study, which described hypogonadism 47% of female patients and 51% of male patients. Hagag et al. demonstrated that in males testosterone levels and testicular volume were significantly lower in thalassaemic patients with iron overload [51]. A similar study conducted by Hagag et al. in female patients, they showed that FSH, LH and oestrogen

levels were significantly lower in thalassaemic patients with iron overload [52].

common sequelae among patients with beta thalassaemia major [36].

male patients, by a lack of testicular development by age 14 [30].

**64**

Pubertal failure has also been described in 73% of male and 42% of female patients under the age of 21 years old by Soliman et al. [23]. Similar findings were noted by Borgna-Pignatti and colleagues with 67% of males and 38% of females experiencing puberty failure [24]. Remarkably, successful conception may still be achieved by women who receive adequate chelation therapy.

Bone growth, growth velocity and puberty may be assisted by administration of chelation therapy before the commencement of sexual maturation and the use of low dose sex steroids in adolescence [9].

Current Standards for the Clinical Care of Children and Adults with Thalassaemia UK Guidelines recommend that assessment of gonadal function should be done annually throughout adulthood [30]. In men, this would include an annual morning testosterone level alongside LH/FSH and SHBG if testosterone levels are low. In women, no testing is required in the presence of a normal menstrual history. However, in the presence of menstrual disturbances, further testing (LH/FSH and oestradiol) is recommended [30]. Deficiency should be replaced with oestrogen/testosterone while bearing in mind that under-replacement contributes to a low bone mineral density. Management is best achieved through a joint multidisciplinary consultation between the endocrinologist and thalassaemia team [30].
