Role of hypogonadism in development of bone alterations in thalassemic patients

Beta thalassemia major (TM) is an important health concern in many countries, mostly in the Mediterranean area, in the Middle East, India, East Asia. In 1988 a report from the WHO documented that almost 50000 children per year were born with TM.

In the last decades, improved programs of transfusional and chelation therapy have permitted to TM patients to survive until their forties or fifties and to get a better quality of life. However, several complications progressively arise and in particular endocrine alterations are common with diabetes, hypothyroidism, hypoparathyroidism, and hypogonadism being well known complications of adult thalassemia major. More recently, in adult TM patients, bone mass deficiency has been recognised as a major problem that may cause pathologic fractures and limb deformities and greatly worsen the quality of life of these patients. The etiology of bone mass deficiency in thalassemia is still unclear and many factors have been suggested as possible causes, including IGF-I deficiency, low vitamin D levels, alterations of genes related to collagen synthesis, bone cortical thinning because of bone marrow expansion and altered levels of some oligoelements such as zinc and copper. However, a main role is probably played by hypogonadism that is a hallmark of adult TM patients. In this brief review, we will examine the characteristics of hypogonadism in TM patients and the possible link between hypogonadism and bone mass deficiency. Finally, we will discuss the role of the hormonal substitutive therapy in the prevention and treatment of bone mass deficiency in TM.

Prevalence and characteristics of gonadal failure in thalassemia major

Most TM patients present a delayed or absent puberty. In the patients who present puberty (at normal or late age), a gonadal failure often progressively occurs with appearance of menstrual disorders and anovulation in women and spermatic abnormalities and reduced sexual activity in males. While it was initially suggested that a primary gonadal deficiency (a hyperg- onadotropic hypogonadism) occurs in TM patients, it is now clear that in most patients the gonadal failure is a consequence of a pituitary damage and that a hypogonadotropic hypogo- nadism occurs. Primitive gonadal damage may also occur but appears generally later (sometimes also in patients with hypog- onadotropic hypogonadism). Therefore, in some adult TM patients (generally after the third decade) a mixed hypogonadism (central and gonadal) may be present. All studies have documented that the prevalence of hypogonadism in adult TM patients is very high. In an Italian multicentric study, failure of the puberty was observed in 51% of the male and in 47% of female subjects. Between the female patients who reached a normal menarche, 23% presented a secondary amenorrhea and 11.6% oligomenorrhea. In an Iranian study, puberty was delayed or absent in 72.6% of females and 80.8 % of the males and a disturbance of gonadal function was the most common endocrinopathy. Several years ago, we have shown that about 70% of adult TM patients (both males and females) present some degree of hy- pogonadism. More recently, studying 30 adult TM women (mean age 28.5 ± 1.3 years), we found that TM patients had lower serum levels of LH, FSH and estradiol (Figure 1) than controls of similar age. A 80% prevalence of hypogonadotropic hypogonadism was found and 20% of patients with hypogonadotropic hypogonadism presented also some evidence of primary gonadal failure. Going without your pills? Buy cheap sale cialis tablets

Figure 1 - Serum FSH, LH and estradiol in normal and in thalassemic adult patients.

A subset of adult TM patients present normal gonadal function. In our study, six adult TM women had normal ovulatory cycles with normal circulating levels of LH, FSH, estradiol and progesterone. Two of these TM patients previously had spontaneous successful pregnancies. Therefore, while most TM patients progressively develop a sexual hormone deficiency, some remain eugonadal. It is unclear what mechanism may determine these differences. In fact, while it is possible that differences in chelation or transfusional programs may explain it, we did not find any evidence of it and serum ferritin levels were not signifi-cantly different in eugonadal compared to hypogonadic adult TM women.