Pubertal evaluation of adolescent boys with -thalassemia major and delayed puberty

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1 Pubertal evaluation of adolescent boys with -thalassemia major and delayed puberty Hala Saleh Al-Rimawi, M.D., F.R.C.P., a Mohammad Fayez Jallad, M.D., M.R.C.O.G., b Zouhair Odeh Amarin, M.D., F.R.C.O.G., b and Rula Al Sakaan, M.D. a a Department of Pediatrics and b Department of Obstetrics and Gynecology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan Objective: To examine the hormonal status of the hypothalamic-pituitary-gonadal axis in adolescent males with -thalassemia major. Design: Controlled clinical study. Setting: Tertiary referral teaching hospital. Patient(s): Thirty-three adolescent males with -thalassemia major. Intervention(s): Basal LH, FSH, and T were examined. All individuals received 100 g GnRH analogue. Four hours later the hormone levels were retested. Patients with -thalassemia and low T levels received hcg. Main Outcome Measure(s): The preintervention and postintervention levels of FSH, LH, and T were examined. Result(s): Of the 33 -thalassemia major adolescents, 17 had delayed puberty. The difference in basal LH, FSH, and T levels between delayed and normal puberty -thalassemia groups were statistically significant. These levels were significantly lower compared with the constitutional delayed puberty group and become even more significant after GnRH analogue administration. The T levels in the -thalassemia group were significantly lower than in the control group. After hcg administration, the T levels remained significantly lower in the delayedpuberty -thalassemia compared to the normal-puberty -thalassemia group. Conclusion(s): Despite recent therapeutic advances in the management of -thalassemia major, the risk of secondary endocrine dysfunction remains high. Hypogonadism is one of the most frequent endocrine complications. (Fertil Steril 2006;86: by American Society for Reproductive Medicine.) Key Words: Thalassemia, adolescent males, hypogonadotropic hypogonadism, delayed puberty -Thalassemia major is a hereditary disorder of hemoglobin synthesis that results in severe anemia. Despite frequent blood transfusion and iron chelation, the risk of secondary endocrine dysfunction remains high. Hypogonadism is one of the most frequent endocrine complications, mostly due to gonadotropin deficiency secondary to siderosis of the pituitary gland (1). The aim of this study was to evaluate the pubertal development and function of the pituitary-testicular axis in adolescent males with -thalassemia. MATERIALS AND METHODS This prospective study was conducted between January 2001 and January 2003 at the Thalassemia Center of Princess Rahma Teaching Hospital in Irbid, Jordan. The study included 33 adolescent males with -thalassemia, whose ages ranged between 14 and 21 years, and 6 patients with constitutional delayed puberty. Another 10 healthy individuals with normal puberty were enrolled as a control group (Fig. 1). Their ages ranged between 12 and 20 years. None of the patients had received hormonal substitution therapy previously. Received November 23, 2005; revised and accepted February 18, Reprint requests: Zouhair Odeh Amarin, M.D., F.R.C.O.G., P. O. Box 1572, Amman 11953, Jordan (FAX: ; zoamarin@ hotmail.com). Puberty was evaluated in the -thalassemia patients, constitutional delayed puberty patients, and the control group according to Tanner s classification of pubic hair and testicular development (2). Testicular size 4 ml (long axis of 2.5 cm) was considered stage I (prepubertal genitalia), and size 25 ml ( 5 cm in length) was considered adult genitalia. Delayed puberty was defined as absence of secondary sexual characteristics with a testicular volume of 4 mlat the age of 14 years (3, 4). After overnight fasting, blood samples were collected from the -thalassemia patients, constitutional delayed puberty patients, and the control group for evaluation of their basal LH, FSH, and T. All individuals received a standard single dose, with no correction for weight, of 100 g GnRH analogue (GnRHa) (Decapeptyl; Ferring, Kiel, Germany) subcutaneously to stimulate pituitary release of gonadotropin. A second blood sample was collected 4 hours later to evaluate the response levels of the hormones after stimulation. Patients with -thalassemia and low T levels were given a daily dose of 2,500 U/m 2 hcg each day for 3 days by IM injection. Patients with constitutional delay or normal puberty were excluded. Blood samples were collected before and 1 week after to estimate testicular response. In addition, the -thalassemia and constitutional delayed puberty patients were evaluated for thyroid function, growth hormone, cortisol, zinc, ferritin, hepatitis screen, and liver function. 886 Fertility and Sterility Vol. 86, No. 4, October /06/$32.00 Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 FIGURE 1 Flow chart of the various study groups. Chemiluminescent immunoassay (Immuolyte 2000; Diagnostic Products, Los Angeles, CA) was used to measure the serum levels of LH, FSH, and T. The results for LH and FSH were expressed in miu/ml and for T in ng/dl. The values were presented as means SEM. Statistical analysis was performed using unpaired t test to compare the analyte concentration among groups. Mann- Whitney test was used to compare small size groups. P.05 was considered statistically significant. The study was supported by the Deanship of Research at Jordan University of Science and Technology and was approved by the University s Review Board. Parental or patient informed consent was obtained, as appropriate, before beginning the study. The results of basal hormonal levels of LH, FSH, and T were significantly lower in the -thalassemia group compared with the control group (Table 1). Despite a significant improvement after stimulation with GnRHa, the difference between the two groups remained statistically significant. When the -thalassemia delayed puberty and -thalassemia normal puberty groups were compared, the difference in the basal and post GnRHa administration levels of LH, FSH, and T were statistically significant (Table 2). The basal and post GnRHa administration values of LH and FSH in the -thalassemia normal puberty group were not statistically different from the values of the control group except for the post GnRHa administration FSH level. The basal levels of LH and FSH were significantly lower in the -thalassemia delayed puberty group compared with the constitutional delayed puberty group and became extremely significant after GnRHa administration (Table 3). The basal T levels were significantly lower in the -thalassemia delayed puberty group compared with both the -thalassemia normal puberty and the constitutional delayed puberty groups and became much lower after GnRHa administration. In addition, the levels in both the -thalassemia delayed puberty and -thalassemia normal puberty groups were found to be very significantly lower than the control group (Table 3). Furthermore, T levels in the -thalassemia delayed puberty group, after hcg administration, remained very significantly lower than the baseline levels of T in the -thalassemia normal puberty group (Table 4). RESULTS Of the 33 -thalassemia patients, 17 had delayed puberty with pubertal stage II and 16 had normal puberty. In the constitutional delayed puberty group, all patients were above 14 years of age and had a pubertal stage II. Two of the control group had pubertal stage II, four had pubertal stage III, and four had pubertal stage V. DISCUSSION Onset of puberty starts by the reactivation of endogenous GnRH secretion from the hypothalamus. The pulsatile release of pituitary gonadotropins stimulates gonadal release of T and subsequent secondary sexual characteristic development. The pulsatile LH secretion can be detected 1 2 years before the clinical signs of puberty (5, 6). This is TABLE 1 Basal LH, FSH, and T levels in patients with -thalassemia and control subjects. -Thalassemia group (n 33) Control group (n 10) Basal LH (miu/ml) LH after GnRH analogue (miu/ml) Basal FSH, miu/ml FSH after GnRH analogue (miu/ml) Basal T (ng/ml) T after GnRH analogue (ng/ml) Age (y) Fertility and Sterility 887

3 TABLE 2 Basal and post GnRHa administration levels of LH, FSH, and T in thalassemic males with normal and delayed puberty. Delayed puberty -thalassemic (n 17) Normal puberty -thalassemic (n 16) Basal LH (miu/ml) Peak LH (miu/ml) Basal FSH (miu/ml) Peak FSH (miu/ml) Basal T (ng/ml) Peak T (ng/ml) associated with an overnight increase in the T level for at least 1 year before puberty (7). The administration of GnRHa initially increases the pituitary gonadotropin secretion, which in turn increases sex steroid concentration. This flare-up of gonadotropins reaches its peak at 4 hours after GnRHa administration and is limited to about 10 days (8). In patients with transfusion-dependent -thalassemia, delayed puberty and hypogonadism may result from iron deposition in the hypothalamic-pituitary cells, the gonads, or both (9, 10). We evaluated the pubertal development in male adolescents with -thalassemia and investigated whether the cause of delayed puberty was due to hypothalamic-pituitary portion dysfunction or due to testicular damage. When the gonadotropin levels in the -thalassemia delayed puberty patients were compared with the constitutional delayed puberty group, there were no significant differences in the basal hormonal levels, but the response to GnRHa administration was extremely low in the -thalassemia delayed puberty group compared with the response in constitutional delayed puberty group (P.0001). On the other hand, no significant difference was noted between the basal and the peak levels of LH and FSH between the -thalassemia normal puberty group and the control group. This also indicated a defective gonadotropin reserve in the gonadotrope cells in the -thalassemia delayed puberty group compared with normal pituitary function in the constitutional delayed puberty group and the -thalassemia normal puberty group. Our findings are consistent with the report of Chatterjee and Katz (11), who found that naturally available LH and FSH in -thalassemic patients with failed puberty were concordant with our results after GnRHa stimulation. TABLE 3 Basal and post GnRHa administration levels of LH, FSH, and T in -thalassemic males with normal () and delayed () puberty and males with constitutional delayed puberty () and normal puberty (control). (n 16) Control (n 10) (n 17) (n 6) control Basal LH (miu/ml) LH after GnRH analogue (miu/ml) Basal FSH (miu/ml) FSH after GnRH analogue (miu/ml) Basal T (ng/ml) T after GnRH analogue (ng/ml) Al-Rimawi et al. Puberty of males with -thalassemia major Vol. 86, No. 4, October 2006

4 TABLE 4 Level of T before and after GnRH analogue stimulation and after hcg in male thalassemic males with normal and delayed puberty and males with constitutional delayed and normal (control) puberty. (n 16) Control (n 10) (n 17) (n 6) control Basal T (ng/ml) T after GnRH analogue (ng/ml) T after hcg (ng/ml in ) Abbreviations as in Table 3. For evaluation of testicular function, the basal and post GnRHa administration and post hcg administration levels of T showed that the mean levels in the -thalassemia delayed puberty group were extremely low compared with the -thalassemia normal puberty and constitutional delayed puberty groups. This indicated a defective Leydig cell function. When the basal T levels in the -thalassemia normal puberty group were compared with those in the control group, the results were not statistically different, but after GnRHa stimulation the T levels became significantly different between the groups. This suggests that the capacity of Leydig cells to secrete T was incomplete in the -thalassemia normal puberty group. It had been reported that the main factor for delayed or failed puberty in -thalassemic boys is the effect of iron overload on the pituitary gland and the gonads (10 12). The anterior pituitary is particularly sensitive to the toxic effect of free hydroxyl radicals, and exposure in early childhood leads to pituitary damage (12). Other investigators demonstrated through magnetic resonance imaging pituitary gland atrophy in -thalassemic patients with hemochromatosis (10) and the signal intensity reduction in the anterior lobe of the pituitary gland correlated with serum ferritin level and the severity of pituitary dysfunction (13). Furthermore, even a modest amount of iron deposition within the gland could interfere with its function (14). In this study the mean level of ferritin in patients with hypothalamic-pituitary portion dysfunction was significantly higher in patients with defective function than in patients with normal function. The difference was statistically very significant. The ferritin level in patients with abnormal T level was considerably high compared with patients with normal T level. There were no significant differences between patients with abnormal pituitary-gonadal function and those with normal function in mean levels of hemoglobin, liver disease, growth hormone, thyroid function, diabetes mellitus, zinc, and cortisol. This suggests that the main cause of pituitary and gonadal dysfunction in our patients is iron overload. On histologic examination of the testes, previous reports had demonstrated that most of the iron is deposited in the seminiferous tubules and interstitial tissue, with minimal deposition in Leydig cells, which suggests gonadal failure secondary to iron overload (12, 15). It has been demonstrated that damage to the gonads from iron overload is an irreversible process, even if the iron level is corrected at a later stage (12, 14, 16). There is a correlation between the degree of organ damage and the degree of iron overload in patients with -thalassemia (14 17). This affirms the importance of prevention of iron overload through the introduction of early and regular iron chelation therapy, before the onset of damage to the pituitary gland and the gonads. It also affirms the need for intensive chelation for -thalassemia normal puberty patients, especially those with partial response, with the aim of saving the residual functioning cells. The prevalence of delayed puberty in the adolescent boys in this study was 51.5%, which is consistent with the finding of others (18 20). Hypogonadotropic hypogonadism was found in 10 (30%) patients, and 14 (42.4%) patients had testicular dysfunction. Five of these (15%) had a good response to GnRHa and a weak response to hcg, indicating isolated testicular failure. However, in three of them the levels of LH and FSH after GnRHa were not elevated to levels expected in patients with isolated testicular failure (18), suggesting a combined defect in the pituitary. The prevalence, at 53%, of hypogonadotropic hypogonadism was significantly high in the -thalassemia delayed puberty group, compared with 6% in the -thalassemia normal puberty group (P.006). Further, the rate of testicular Fertility and Sterility 889

5 failure was significantly high, at 65%, in the -thalassemia delayed puberty group compared with 19% (P.01) in the -thalassemia normal puberty group. The figures in this study were higher than those of other investigators. De Sanctis et al. (9) demonstrated that 30% of their patients had gonadal failure, and Wang et al. (19) found defective response to hcg in 2 (25%) of their 11 patients in whom 8 patients had delayed puberty. In a study by Soliman et al. (15), 48% of their adolescents with -thalassemia demonstrated poor response to hcg, denoting gonadal dysfunction, and in the report of Li et al. (20), 3 of their 10 -thalassemic boys had gonadal impairment. The high rate of testicular failure in our patients could be related to a genetic difference which influences their iron load status and their testicular susceptibility to free radical damage. In summary, this study demonstrated that patients with -thalassemia and delayed puberty were at a high risk of testicular and pituitary failure. Such patients need hormonal replacement. Patients with normal puberty need regular evaluation of their gonadal function and regular monitoring of their iron status with intensive iron chelation. It is mandatory to carefully monitor the growth and pubertal development of these patients to detect abnormalities and to initiate appropriate treatment at an early stage. REFERENCES 1. Raiola G, Galati MC, De Sanctis V, Caruso Nicoletti M, Pintor C, et al. Growth and puberty in thalassaemia major. J Pediatr Endocrinol Metab 2003;16: Tanner JM, Whithehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and the stages of puberty. Arch Dis Child 1976;51: Italian Working Group on Endocrine Complications in Nonendocrine Diseases. Multicentre study on prevalence of endocrine complications in thalassaemia major. 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In: Becker KL, Bilezikian JP, Bremner WJ, Principles and practice of endocrinology and metabolism. 3rd ed. Lippincott Williams & Wilkins; 2001; Wang C, Tso SC, Todd R. Hypogonadotropic hypogonadism in severe beta-thalassemia: effect of chelation and pulsatile gonadotropin releasing hormone therapy. J Clin Endocrinol Metab 1989;68: Li CK, Chik KW, Wong GW, Cheng PS, Lee V, Shing MM. Growth and endocrine function following bone marrow transplantation for thalassemia major. Pediatr Hematol Oncol 2004;21: Al-Rimawi et al. Puberty of males with -thalassemia major Vol. 86, No. 4, October 2006