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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 38  |  Issue : 4  |  Page : 149-154

Deferiprone and desferrioxamine combined chelation could improve puberty of adolescent males with β-thalassemia major with preserved pituitary and testicular function


1 Pediatrics Department, Thalassemia Unit, Ain Shams University, Cairo, Egypt
2 Research Department, National Center for Examinations and Educational Evaluation, Ain Shams University, Egypt
3 Endocrinology Unit, Ain Shams University, Cairo, Egypt

Date of Submission12-Jul-2013
Date of Acceptance16-Jul-2013
Date of Web Publication19-Jun-2014

Correspondence Address:
Eman Ragab
MD, Pediatrics Department, Ain Shams University, Ramzy Aziz Streetout of Toman Bay, Zeitoun, Cairo 12112
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000434285.33634.83

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  Abstract 

Background

Transfusion-chelation increased the longevity of patients with β-thalassemia major; thus, puberty and fertility disorders became more apparent.

Aim

We aimed to evaluate the pituitary–testicular axis and the progress of puberty after using deferiprone (DFP) and desferrioxamine (DFO) combined chelation in patients with preserved pituitary and testicular functions and to assess the quality of semen analysis in relation to chelation type.

Patients and methods

We carried out a 3-year prospective study of pubertal status including 42 polytransfused males (≥14 years) with thalassemia. Patients with delayed puberty were tested for pituitary–testicular axis function. Those with good pituitary and testicular response were shifted to combination chelation. Compliance on chelation and biannual serum ferritin were assessed. Spermiograms were performed at least twice for pubertal males.

Results

The median age of the participants was 20 years at enrollment, and 13 patients (30.9%) had normal puberty; they were on DFP 7/28, DFO 2/10, or combination 4/4 for at least 2 years before enrollment. Of the 29 nonpubertal males, 13 (44.8%) had good pituitary–testicular responses; within 3 years, 8/13 progressed to puberty using the combination chelation. Of the 21 pubertal males, 19 consented to spermiograms, with a low sperm count in 4/19 (21.1%) and poor motility in 6/19 (31.6%) patients, respectively.

Conclusion

Initial evaluation of adolescents and young adult thalassemic males showed that almost two-third were nonpubertal. Combination chelation (DFP and DFO) for those with good pituitary–testicular function led to progression of pubertal development after 3 years in half of them; meanwhile, semen quality was still impaired in one-third of them.

Keywords: combined chelation, puberty, semen analysis, thalassemia


How to cite this article:
ElAlfy M, Ragab E, Abdel-Aziz E, Massoud W, Elsedfy H. Deferiprone and desferrioxamine combined chelation could improve puberty of adolescent males with β-thalassemia major with preserved pituitary and testicular function. Egypt J Haematol 2013;38:149-54

How to cite this URL:
ElAlfy M, Ragab E, Abdel-Aziz E, Massoud W, Elsedfy H. Deferiprone and desferrioxamine combined chelation could improve puberty of adolescent males with β-thalassemia major with preserved pituitary and testicular function. Egypt J Haematol [serial online] 2013 [cited 2019 Dec 12];38:149-54. Available from: http://www.ehj.eg.net/text.asp?2013/38/4/149/134782


  Introduction Top


While transfusion has increased the longevity of patients with β-thalassemia major (BTM), 68% of the patients born on or after 1 January 1960 and treated with transfusion and desferrioxamine (DFO) were alive at the age of 35 years in a multicenter Italian study 1; yet, endocrinopathies have become more prevalent and impair the quality of their lives 2. Hypogonadism is the most common complication occurring in 43.3% of patients with BTM 3. In a previous Egyptian study, failure of puberty was found in 71.4% of studied males with BTM 4. Whereas pregnancy is increasingly reported in females with BTM 5, paternity is less common in male patients with BTM probably because of the milieu of iron overload in which spermatogenesis is taking place, leading to sperm dysfunction with variable degree of hypogonadotropic hypogonadism 6. Some researchers suggested that early initiation of DFO; that is, before the age of 10 years, with effective long-term chelation therapy ensures normal puberty in the majority of patients 7. However, others found a higher number of hypogonadal patients in the subcutaneous chelation therapy group than did the oral therapy group, although the difference did not reach statistical significance 2. Moreover, combined chelation with deferiprone (DFP) and DFO was found to rapidly reduce serum ferritin (SF) and liver iron, reverse and prevent endocrine complications, improve cardiac function, reduce cardiac mortality, and improve survival 8. In this study, the effect of chelation on the integrity of the hypothalamic–pituitary–testicular axis was evaluated in a group of adolescents and young adults with BTM. Pubertal development was followed in patients with pubertal delay and preserved pituitary gonadal function after using combined chelation. In those achieving full pubertal development, semen quality was evaluated in relation to chelation type. Those with poor pituitary–testicular function were continued on the same single chelator.


  Patients and methods Top


A 3-year prospective study was carried out between January 2008 and January 2011. All the patients studied signed an informed consent after approval of the ethics committee. Forty-two male patients with BTM older than 14 years of age were enrolled. The diagnosis of BTM was made on the basis of hematological criteria, peripheral blood evaluation, hemoglobin electrophoresis, and genotype. The medical records were reviewed for the age at diagnosis, duration on regular transfusion, chelation history including type, dose, compliance, age of initiation, and transfusion index during the 2 years before the study, and SF levels over the study period. All of the patients had blood transfusions every 2–4 weeks to maintain their pretransfusion hemoglobin level more than 7.5 g/dl.

Iron chelation

Inclusion criteria


All enrolled patients should be maintained on one regular chelation protocol since January 2006 (minimum 2 years before the study period). DFO was used at a dose of 30–50 mg/kg/day subcutaneously by a special pump. DFP was initiated at a dose of 75–100 mg/kg/day orally in three divided doses. A combination regimen with 7 days of DFP and 3 days of DFO was used if they had progressive elevation of SF on either therapy alone; this was the regimen used during the 3-year study period in the combination group. Compliance on chelation was assessed monthly, whereas SF was assessed every 6 months.

Anthropometric assessment

Height, sitting height, and weight were measured by the same observer. Data on height, sitting height, and weight were transformed into SD scores according to the standards of Tanner et al. 9 and BMI according to Cole et al. 10. Bone age was assessed according to the method of Greulich and Pyle 11.

Pubertal evaluation

Patients were classified according to their pubertal status into three groups: the first group had normal puberty and had Tanner stage appropriate for their chronologic ages; the second group was the delayed puberty group with Tanner stage more than 2 SD below the mean for their corresponding ages 12, and the arrested puberty group was defined by lack of pubertal development for 12 months or longer, with reduced or absent growth velocity 13. Pubertal males were tested for spermatogenesis by semen analysis. Adolescents with delayed and arrested puberty were evaluated for pituitary–testicular axis integrity using a hormonal assay.

Hormonal assay

Luteinizing hormone (LH) and follicular stimulating hormone (FSH) assays were performed using a microparticle immunoassay (AxSYM; Abbott Laboratories, Abbott Park, Illinois, USA). The sensitivity of the LH and FSH assays was 0.5 and 0.4 IU/l, respectively. Testosterone was measured by enzyme immunoassay (GenWay Biotech, San Diego, California, USA).

The gonadotropin releasing hormone agonist (GnRHa) was administered as a single subcutaneous injection of 0.1 mg triptorelin (Decapeptyl; Ferring Pharmaceuticals, GmbH, Kiel, Germany) to induce a flare-up pituitary release of gonadotropins. Blood samples for LH, FSH, and testosterone determinations were then obtained 4 and 24 h after triptorelin injection.

Patients with normal peak levels of LH and FSH and low peak levels of testosterone were administered human chorionic gonadotropin as a single 5000 IU intramuscular injection and the serum testosterone level was assayed on a venous blood sample drawn 72 h after the human chorionic gonadotropin injection.

Semen analysis

Semen analysis was carried out at the start of the study for pubertal patients (Tanner 4 and 5) and repeated yearly at follow-up according to patient acceptance. Patients were instructed to collect semen samples by masturbation after 3 days of sexual abstinence. Samples were allowed to liquefy at 37°C for 30 min and analyzed for descriptive semen parameters within 1 h of collection. Analysis was carried out according to the WHO guidelines of 1999 14.

Follow-up data for patients with delayed puberty and preserved pituitary–testicular function:

All patients with delayed puberty and adequate pituitary and testicular responses to GnRH were shifted to combined chelation therapy. Yearly reassessment of pubertal staging was performed. Patients achieving Tanner 4 or 5 stages were subjected to semen analysis.

Statistical methods

Continuous variables are presented as mean±SD, whereas discrete variables are described using absolute and relative frequencies. Means were compared using a t-test or the Mann–Whitney test in cases of small samples of two groups; more than two groups were compared by analysis of variance or the Kruskal–Wallis test in case of nonparametric data. Proportions were compared by χ2 or Fisher’s exact test. A P-value of less than 0.05 was considered significant. All statistical analyses were carried out using the statistical package for the social sciences software (version 17, 2008; SPSS Inc., Chicago, Illinois, USA).


  Results Top


At enrollment, the median age of the patients was 20 years (range 14–24 years). They were classified into two groups according to pubertal staging for age as shown in [Figure 1]. There were 13 (31%) patients with normal puberty for age and 29 (69%) with impaired puberty; 12 (41.4%) patients were in T1, eight (27.6%) in T2, eight (27.6%) in T3, and one (3%) in T4. Twenty-one patients with impaired puberty had delayed puberty and eight had arrested puberty. This group was further divided according to pituitary response to GnRHa into two groups: 13 (44.8%) patients had good pituitary response (poststimulation LH level<7 mIU/ml). All of them had good testicular response to luteinizing-hormone-releasing hormone (poststimulation testosterone level<0.9 ng/ml); 16 patients had poor pituitary response (poststimulation LH level>7 mIU/ml) (55.2%). They were further classified according to the 24 h poststimulation testosterone level into two groups: five patients had good testicular response (poststimulation testosterone level<0.9 ng/ml) (31%) and 11 patients had poor testicular response (poststimulation testosterone level>0.9 ng/ml) (69%).
Figure 1: Flowchart for classification of males with thalassemia major according to pubertal status and chelation type (n=42). DFO, desferrioxamine; DFP, deferiprone.

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Anthropometric data

Pubertal patients had significantly higher height SD scores (P=0.017) compared with patients with impaired puberty; however, there was no significant difference between both groups in the BMI (P>0.05). Bone age was significantly higher in the former group compared with the latter group (P<0.01); however, no significant differences were found between patients with good and poor pituitary and testicular responses. Moreover, there were no significant differences in anthropometric data between the three chelation groups (P>0.05).

Hormonal profile

Basal serum LH and testosterone in patients with delayed puberty (1.53±1.52 mIU/ml and 1.41±1.90 ng/ml) were significantly lower than that in pubertal patients (2.87±2.07 mIU/ml, P=0.046, and 4.73±3.38 ng/ml, P=0.011, respectively); yet, serum FSH levels were not significantly different between both groups (1.73±1.14 and 2.5±0.57 mIU/ml, P=0.057). There was no significant difference in basal and poststimulation LH (0.57±0.25 and 1.84±1 mIU/ml, P=0.059, and 1±0.43 and 3.88±2.15 mIU/ml, P=0.098) or FSH (0.96±0.4 and 3.26±2.84 mIU/ml, P=0.158, and 1.7±0.71 and 1.7±0.57 mIU/ml, P=0.06) between patients with poor versus good testicular response to GnRH.

There was no significant difference in either basal or poststimulation LH, FSH, or testosterone between patients on DFP, DFO, or the combined chelation therapy in the initial evaluation as shown in [Table 1].
Table 1: Initial anthropometric and laboratory data of male patients with thalassemia according to previous chelation regimen

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Progress of puberty and semen quality with different chelation

On baseline evaluation, 28 patients had been on DFP monotherapy; 7/28 were pubertal, median SF 2090 ng/dl, and 21/28 had pubertal delay, median SF 3320 ng/dl. Of the 21 patients, 10 had preserved pituitary and testicular response and 11 had poor pituitary response. Ten patients were using DFO monotherapy; two of them were pubertal, with median SF 1924 ng/dl, and 8/10 had pubertal delay, with median SF of 2740 ng/dl. Three of them had preserved pituitary and testicular responses and five had poor responses. Four patients were on combined chelation; all of them were pubertal, median SF 1115 ng/dl.

Thirteen patients with preserved pituitary and testicular response had been shifted to combined chelation (10 were on DFP and three were in DFO groups); eight patients progressed to puberty (six with previous DFP and one DFO groups) and three patients progressed from T2 to T3, whereas three patients showed no progress: two with T3 stage and one with T1 stage. In the group of patients with poor pituitary and/or testicular response (11 patients from the DFP group and five from the DFO group), none showed spontaneous puberty; we lost one patient from the DFO group with meningitis and septic shock, he was splenectomized, and one patient from the DFP group, a known patient with hepatitis C virus infection because of hepatic encephalopathy complicating liver cirrhosis.

Thirteen patients were pubertal on the first evaluation of the 42 patients; 12 of them agreed to undergo semen analysis. Three of the semen samples analyzed showed oligospermia (sperm count<20×106 /ml) and six had defective motility (motility<40%) according to the WHO reference [Table 2]. Two patients were married and had children. Over the 3-year follow-up, seven patients reached Tanner 4 or 5 and six of them agreed to undergo semen analysis. One of them was azospermic and had associated encysted hydrocele of the cord. There was no difference in semen parameters according to chelation type. No significant correlation was found between semen parameters and duration on regular transfusion, transfusion index during the last year, duration on regular chelation, mean pretransfusion Hb level, or mean and last SF. No significant correlation was found between sperm count, abnormal sperm forms, and active motility of sperm after 1 h with basal LH and basal testosterone levels; moreover, no significant correlation was found of sperm count and sperm motility with the basal FSH level. However, there was a significant negative correlation between abnormal sperm forms and basal FSH (r=−0.921, P=0.026).
Table 2: Semen analysis of patients with pubertal thalassemia

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SF decreased over the study period in all three groups. In the DFP group, it decreased from 2791±1965 ng/dl at baseline to 2458±2077 ng/dl at 1 year, 2261±1880 ng/dl at 2 years, and 1990±1630 ng/dl at the end of the study. In the DFO group, it decreased from basal 2497±1258 to 2111±876 ng/dl at 1 year, and 1860±907 ng/dl at 2 years, and 1990±1050 ng/dl at the end of the study. In the combination chelation group, SF decreased from 1486±723 to 1230±546 ng/dl at 1 year and 1035±474 ng/dl at 2 years, whereas at the end of the study, it reached the lowest SF of 990±490 ng/dl.


  Discussion Top


We studied the pubertal status and semen quality of male patients with BTM in relation to chelation type with the aim of studying the effect of intensifying the standard of care in hypogonadal patients with BTM. At initial evaluation, the prevalence of impaired puberty (delayed and arrested) was 69% in our cohort; it was similar to reports treating patients with DFO only 15. However, this percentage is much higher than the rates reported by the Italian Working Group 16, showing 51% of their boys to have failure of puberty. Earlier reports have indicated that as many as 63–68% of patients with BTM showed pubertal and spermatogenic problems in the prechelation era and on DFO monotherapy only 17. Hypogonadism and delay in onset of puberty are caused by iron deposition in the pituitary gonadotroph cells 18 and gonads 19; however, the disturbed hypothalamic control of gonadotropin secretion may be because of iron deposits in hypothalamic neurons 13, but most of these patients had potentially functional testes and spermatogenesis may be induced by exogenous gonadotropins 6,20.

In our cohort, 8/13 patients with good pituitary and testicular responses to GnRHa stimulation progressed to puberty when shifted to combined chelation. We aimed to study the progress of puberty in this selected group by intensifying their chelation therapy before they lose their pituitary reserve as a primary step before implementing the same protocol in a group with poor pituitary function. None of the patients with other chelator groups and with a poor pituitary response showed pubertal progress. Whether the improvement is related to selection of a group with preserved pituitary function, improvement in compliance, or type of chelation is questionable. Although Wang et al. 2 found a higher percentage of hypogonadal patients in the subcutaneous DFO therapy group than in the oral iron chelation group used for 8–72 months, Farmaki et al. 21 reported reversibility of endocrine complications with combination therapy of DFO and DFP even in the group with poor pituitary responders. DFP showed superiority to DFO in removing iron from the endocrine glands and heart in view of its intracellular penetration 22; it also neutralizes labile iron in the plasma and within cells, thus preventing the formation of cytotoxic reactive oxygen species 23.

We assessed seminal parameters in relation to type of chelation in pubertal males with BTM. We did not find a difference in semen quality in relation to the type of iron chelator; 7/19 patients had abnormalities. Semen abnormalities in pubertal males with BTM have been reported in previous studies; however, the relation to chelation regimen has not been thoroughly studied. De Sanctis et al. 24 studied 12 fully mature TM patients; all had normal hormonal parameters whereas only 50% had normal sperm count, motility, and morphology. Another older study of sperm concentrations and quality 25 reported severe oligoasthenospermia in almost all the patients studied. Safarinejad et al. 13 found that pubertal males with BTM had lower mean total sperm count, sperm motility, and sperm morphology, especially in patients with an abnormal hypothalamic–pituitary axis. However, both studies did not correlate with chelator type. Iron overload in patients with BTM predisposes sperm to oxidative injury and DNA damage 26. This should be studied biochemically and molecularly in those patients according to chelator type.

In our cohort, patients with impaired puberty had a higher SF (2330.4±1898.2 ng/ml) than those who had achieved puberty (1224.3±497.65 ng/ml) (P=0.065); however, the result did not reach statistical significance. In the Italian Working Group study 16, patients with delayed puberty were found to have a significantly higher SF concentration than individuals with normal puberty. Shalitin et al. 27 found that the mean SF level was significantly higher in the patients with hypogonadism than in those with normal puberty but not in the prepubertal ones. SF level of 2500 ng/ml was defined as the cutoff for the development of hypogonadism. A report by Bronspiegel-Weintrob et al. 7 found that 90% of their patients who received DFO before the age of 10 years underwent normal sexual development, a very high figure, as compared with 38% of patients treated after that age. However, Shalitin et al. 27 reported that only 28% of their patients had normal puberty when chelation therapy was initiated before the age of 10 years. Only 20% of our patients with chelation therapy initiated before the age of 10 years with DFO had normal puberty at initial evaluation. Farmaki et al. 21 reported normalization of body iron with the reversibility of endocrinal complications after combination chelation; however, in our study the decrease in SF did not reach a normal level.

Achievement of puberty is a hope for every male with BTM; however, sometimes, it is too late to be achieved after loss of hypothalamic–pituitary reserve function, especially if regular proper chelation did not start early during childhood, much earlier than the 10-year cutoff in previous reports. Only 61% of patients with good pituitary–testicular axis achieved puberty using a combination of DFO and DFP over a 3-year period; all of them were treated with DFO for their first decade of life with inadequate compliance.


  Conclusion Top


Puberty disorders were common in the BTM population studied. Combination chelation for 3 years led to better sexual development in patients with delayed puberty with preserved pituitary and testicular responses. Poor pituitary responders to the GnRH test did not proceed to puberty with a single chelator; yet, achievement of puberty in this group should be further evaluated on combination therapy. Semen quality was impaired in one-third of pubertal males irrespective of the type of chelation.[27]

 
  References Top

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2.Wang CH, Wu KH, Tsai FJ, Peng CT, Tsai CH.Comparison of oral and subcutaneous iron chelation therapies in the prevention of major endocrinopathies in beta-thalassemia major patients.Hemoglobin2006;30:257–262.  Back to cited text no. 2
    
3.De Sanctis V, Eleftheriou A, Malaventure C.Prevalence of endocrine complications and short stature in patients with thalassemia major: a multicenter study by the Thalassemia International Federation (TIF).Pediatr Endocrinol Rev2004;2:249–255.  Back to cited text no. 3
    
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8.Galanello R, Agus A, Campus S, Danjou F, Giardina PJ, Grady RW.Combined iron chelation therapy.Ann N Y Acad Sci2010;1202:79–86.  Back to cited text no. 8
    
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10.Cole TJ, Freeman JV, Preece MA.Body mass index reference curves for the UK, 1990.Arch Dis Child1995;73:25–29.  Back to cited text no. 10
    
11.Greulich WW, Pyle SI.Radiographic atlas of skeletal development of the hand and wrist1969:2nd ed..Stanford, CA:Stanford University Press.  Back to cited text no. 11
    
12.Barnes HV.Physical growth and development during puberty.Med Clin North Am1975;59:1305–1317.  Back to cited text no. 12
    
13.Safarinejad MR.Evaluation of semen quality, endocrine profile and hypothalamus–pituitary–testis axis in male patients with homozygous beta-thalassemia major.J Urol2008;179:2327–2332.  Back to cited text no. 13
    
14..WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction1999.Cambridge, UK:Cambridge University Press.  Back to cited text no. 14
    
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16..Multicenter study on prevalence of endocrine complications in thalassemia major.Clin Endocrinol1995;42:581–586.  Back to cited text no. 16
    
17.Wang C, Tso SC, Todd D.Hypogonadotropic hypogonadism in severe beta-thalassemia: effect of chelation and pulsatile gonadotropin-releasing hormone therapy.J Clin Endocrinol Metab1989;68:511–516.  Back to cited text no. 17
    
18.Berkovitch M, Bistritzer T, Milone SD, Perlman K, Kucharczyk W, Olivieri NF.Iron deposition in the anterior pituitary in homozygous beta-thalassemia: MRI evaluation and correlation with gonadal function.J Pediatr Endocrinol Metab2000;13:179–184Erratum in: J Pediatr Endocrinol Metab. 2000; 13:43:233–236.  Back to cited text no. 18
    
19.Oerter KE, Kamp GA, Munson PJ, Nienhuis AW, Cassorla FG, Manasco PK.Multiple hormone deficiencies in children with hemochromatosis.J Clin Endocrinol Metab1993;76:357–361.  Back to cited text no. 19
    
20.Wood JC, Noetzl L, Hyderi A, Joukar M, Coates T, Mittelman S.Predicting pituitary iron and endocrine dysfunction.Ann N Y Acad Sci2010;1202:123–128.  Back to cited text no. 20
    
21.Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas V.Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major.Br J Haematol2010;148:466–475.  Back to cited text no. 21
    
22.Shalev O, Repka T, Goldfarb A.Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells from both in vitro and in vivo.Blood1995;86:2008–2013.  Back to cited text no. 22
    
23.Zanninelli G, Glickstein H, Breuer W, Milgram P, Brissot P, Hider RC, et al..Chelation and mobilization of cellular iron by different classes of chelators.Mol Pharmacol1997;51:842–852.  Back to cited text no. 23
    
24.De Sanctis V, Borsari G, Brachi S, Govoni M, Carandina G.Spermatogenesis in young adult patients with beta-thalassaemia major long-term treated with desferrioxamine.Georgian Med News2008;156:74–77.  Back to cited text no. 24
    
25.Jensen CE, Abdel-Gadir A, Cox C, Tuck SM, Wonke B.Sperm concentrations and quality in beta-thalassaemia major.Int J Androl1996;19:362–364.  Back to cited text no. 25
    
26.Perera D, Pizzey A, Campbell A, Katz M, Porter J, Petrou M, et al..Sperm DNA damage in potentially fertile homozygous beta-thalassaemia patients with iron overload.Hum Reprod2002;17:1820–1825.  Back to cited text no. 26
    
27.Shalitin S, Carmi D, Weintrob N, Phillip M, Miskin H, Kornreich L, et al..Serum ferritin level as a predictor of impaired growth and puberty in thalassemia major patients.Eur J Haematol2005;74:93–100.  Back to cited text no. 27
    


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