Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 2  |  Page : 439-444

Risk factors for hypogonadism in multitransfused thalassemia major male patients


1 Department of Dermatology, Andrology and STIs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Dermatology, Andrology and STIs, Shebin El Kom Teaching Hospital, Menoufia, Egypt
3 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission24-Nov-2021
Date of Decision21-Jan-2022
Date of Acceptance30-Jan-2022
Date of Web Publication27-Jul-2022

Correspondence Address:
Rania E Elbana
Department of Dermatology, Andrology and STIs, Shebin El Kom Teaching Hospital, Menoufia, Shebeen El-Kom 32511
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_267_21

Rights and Permissions
  Abstract 


Background
Despite the continuous improvement in the treatment of patients with thalassemia, the disease is still associated with many complications.
Objectives
To identify the risk factors associated with hypogonadism in thalassemia major male patients.
Patients and methods
A case–control study included 20 male patients with a prior diagnosis of β-thalassemia major, and 20 age-matched and sex-matched persons as control, from the Hematology Unit, Pediatric and Medicine Department, Menoufia University. Only patients who provided written consent were included in the study. A complete physical and hormonal evaluation was performed on all patients, and data regarding treatment of the hematological disease were collected.
Results
In all, 20 male patients were included in the study (median age: 16 years, range 14–19 years). Of the study participants 80% (16 of 20) had early forms of hypogonadism (delayed or arrested puberty). Patients with hypogonadism had significantly lower average hemoglobin levels (P = 0.042), higher levels of serum ferritin (P = 0.003), and increased age at initiation of iron chelation (P = 0.030) versus patients without hypogonadism.
Conclusion
Our data show that hypogonadism is highly prevalent among male patients with β-thalassemia major, and its presence is associated with higher iron overload and lower hemoglobin values, and the late start of iron chelation therapy.

Keywords: hemoglobinopathy, hypogonadism, iron overload, thalassemia


How to cite this article:
Gaber MA, Elbana RE, Mahmoud AA. Risk factors for hypogonadism in multitransfused thalassemia major male patients. Menoufia Med J 2022;35:439-44

How to cite this URL:
Gaber MA, Elbana RE, Mahmoud AA. Risk factors for hypogonadism in multitransfused thalassemia major male patients. Menoufia Med J [serial online] 2022 [cited 2024 Mar 29];35:439-44. Available from: http://www.mmj.eg.net/text.asp?2022/35/2/439/352183




  Introduction Top


According to the Thalassemia International Federation, about 7% of the global population are carriers of a hemoglobin (Hb) disorder, and ~ 300 000 to 500 000 children are born every year with a severe hemoglobinopathy[1]. In Egypt, β-thalassemia is the most frequent hemoglobinopathy. The carrier rate of this disease varies between 5.3 and 9% and the gene frequency is 0.03%[2]. The disease hallmarks include imbalance in the α/β-globin chain ratio, ineffective erythropoiesis, chronic hemolytic anemia, compensatory hemopoietic expansion, hypercoagulability, and increased intestinal iron absorption[3]. The complications of iron overload, arising from blood transfusion, that represent the basis of disease management in patients with severe thalassemia might complicate the clinical phenotype[4]. The mechanisms leading to hypogonadism in thalassemia major patients are complex. Chronic anemia, iron overload, and chronic liver disease play major roles[5]. Other potential important factors are: (a) the cell surface transferrin receptors and the capacity of the cells to deploy defense mechanism against inorganic iron, (b) individual susceptibility to iron toxicity, (c) the development of organ damage due to severe iron overload in the years preceding iron chelation therapy, (d) the clinical phenotype and genotype of the disease, and (e) associated endocrine complications, such as diabetes[6]. Iron has a catalytic role that produces reactive oxidant species and free radicals, which leads to oxidative damage. Sensitivity of different organs to accumulate iron varies. Iron accumulates in tissues containing high levels of transferrin receptor such as the liver, heart, and endocrine glands[7]. The anterior pituitary gland is particularly sensitive to free radical oxidative stress that may impair gonadotropins and growth hormone secretion, so thalassemic patients with marked hemosiderosis are predisposed to develop hypogonadism and short stature[8]. Thus, the aim of this study was to identify the risk factors associated with hypogonadism in thalassemia major male patients.


  Patients and methods Top


A case–control study was carried out on 20 male patients with prior diagnosis of β-thalassemia major and 20 age-matched and sex-matched healthy persons from the Hematology Unit, Pediatric and Medicine Department, Menoufia University during the period from February to October 2021. Ethical consideration: the study was approved by the Ethics Committee of the Faculty of Medicine, Menoufia University; patients who agreed to participate gave their signed informed consent after explanation of the trial benefits and hazards. Patients were selected according to the inclusion and exclusion criteria as follows: Inclusion criteria: male patients aged more than 14 years, who are on regular blood transfusion and iron chelation. Exclusion criteria: patients who received hormonal treatment, patients with previously diagnosed pituitary diseases, hyperprolactinemia, or cryptorchidism. All prospective patients were evaluated for age, sex, weight, sexual maturation by Tanner scale based on the development of genitalia and pubic hair[9]. Blood samples were obtained in the morning after an overnight fast and before transfusion in all patients. Levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and total testosterone (TT) were measured. Delayed puberty is defined as the absence of any sign of pubertal development in boys aged 14 years. Arrested puberty is considered to be present if the patient has some clinical signs of sexual maturation, but no progression in pubertal development has been observed for 1 year. Hypogonadism after complete sexual maturation is diagnosed in patients with normal pubertal progression who have reached Tanner stage V (adult stage of sexual maturation) and present at the time of evaluation with testosterone deficiency syndrome or decreased body hair associated with low TT. Data regarding treatment of the hematological disease (age at start of transfusion treatment, age at start of chelation treatment, Hb levels, transfusion requirement, serum ferritin levels, history of splenectomy, deferoxamine dose) were obtained from medical records.

Statistical analysis

Results were tabulated and statistically analyzed using SPSS statistical package, version 23 (SPSS Inc. Released 2015. IBM SPSS statistics for Windows, version 23.0; IBM Corp., Armonk, New York, USA) and two types of statistics were done: descriptive statistics that includes description of data which was in the form of mean ± SD for quantitive data, and frequency and proportion for qualitative data and analytical statistics that includes standard Student's t test and χ2 test. P value less than 0.05 was considered statistically significant.


  Results Top


This study included 20 thalassemic male patients, and 20 healthy age-matched and sex-matched persons as control. The mean age was 16.8 ± 0.9 and 16.9 ± 0.9 among cases and controls, respectively. There were no statistically significant differences between the two studied groups regarding age, weight, height, or BMI (P > 0.05). Also, Hb, hematocrit (HCT), mean corpuscular volume (MCV), and mean cell hemoglobin (MCH) were significantly lower among cases than controls (P < 0.001), while serum urea, serum creatinine, alanine aminotransferase, and aspartate aminotransferase did not show any significant different between cases and control groups (P > 0.05) [Table 1].
Table 1: Demographic and laboratory data of the two studied groups

Click here to view


Also, LH, FSH, and TT were significantly lower among cases than controls (P < 0.001). However, serum ferritin level was significantly higher among cases than controls (P < 0.001) [Table 2].
Table 2: Luteinizing hormone, follicle-stimulating hormone, testosterone, and serum ferritin levels among the two studied groups

Click here to view


About 80% of the thalassemic patients had hypogonadism in the form of delayed (60%) and arrested (20%) puberty, while 20% had not. There were no statistically significant differences between thalassemia with and without hypogonadism groups regarding age, weight, height, BMI, blood transfusion, age of chelation, and dose of chelation Deferasirox (P > 0.05). However, age of transfusion was significantly lower among thalassemic patients with hypogonadism (1.2 ± 0.9) than those without hypogonadism (4.8 ± 1.5), with P = 0.030 [Table 3]. In our study, 14 patients had hypogonadism, seven patients had Tanner I, five patients had Tanner II, two patients had Tanner III, two patients had Tanner IV, and four patients had Tanner V. Tanner stages IV and V were considered normal, stage III arrested puberty, and stages I and II delayed puberties (data not shown in table).
Table 3: Comparison between thalassemic patients with hypogonadism and without regarding basic characteristics

Click here to view


Regarding iron chelation compliance, 16 thalassemic patients were with hypogonadism, six (37.5%) patients had no iron chelation compliance, and 10 (62.5%) patients had low and moderate grades (five patients for each), while four thalassemic patients without hypogonadism, two (50%) patients had moderate grade, and five (50%) patients had high grade of iron chelation compliance [Table 4].
Table 4: Compliance of iron chelation therapy among studied patients

Click here to view


Hb, HCT, LH, FSH, TT, MCV, and MCH levels were significantly lower among thalassemic patients with hypogonadism than those without hypogonadism (P < 0.05). However, platelet count and serum ferritin levels were significantly higher among thalassemic patients with hypogonadism than those without hypogonadism (P < 0.05). There were no statistically significant differences between thalassemia with and without hypogonadism groups regarding MCV, MCH, white blood cell, and splenectomy (P > 0.05) [Table 5].
Table 5: Comparison between thalassemic participants with hypogonadism and without regarding hematological data

Click here to view



  Discussion Top


Hypogonadism is the most frequently reported endocrine complication, affecting 70–80% of thalassemia major patients. Hypogonadism is likely to be caused by iron deposits in the gonads, pituitary gland, or both. However, hypogonadotropic hypogonadism resulting from iron deposition in the pituitary gonadotrope is more commonly found. Gonadal iron deposition in the ovaries or testes occurs less frequently, as the majority of amenorrheic women can still ovulate after hormonal treatment. Early identification and management of acquired hypogonadotropic hypogonadism (AHH) are very crucial to avoid long-term morbidity, including sexual dysfunction and underdiagnosed infertility condition[10]. Thus, the aim of this study was to identify the risk factors associated with hypogonadism in thalassemia major male patients. The present study showed that there were statistically significant differences between cases and controls regarding Hb, HCT, MCV, and MCH. This may be due to the genetic mutations in genes responsible for the synthesis of protein chains of Hb in thalassemia, which lead to disorder in the biosynthesis of the globin chains and loss of balance in the manufacture of Hb, and this may affect the number and shape and size of red blood cells during their formation stages in the bone marrow; as a result, the red blood cells are of small size and do not hold the same volume occupied by normal red blood cells[11]. These results showed agreement with the results of Hamed et al.[12], which showed significant lower mean pretransfusion levels in thalassemic patients than the mean Hb levels of study controls. Also, the Ezzat et al.[13] study concluded that β-thalassemia patients had reduced Hb levels (8.4 g/dl) when compared with control groups (11.3 g/dl). The Aboul-Enein et al.[14] study declared that β-thalassemia major patients had reduced Hb levels.

The present study found that LH, FSH, and TT were significantly lower among cases than controls. In agreement with our results, De Sanctis et al.[15] studied 11 adult men with thalassemia major, aged between 26 and 54 years (34.3 ± 8.8 years) with AHH, and 12 age-matched and sex-matched thalassemia major patients with normal pubertal development were used as a control group. The mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 and 1.2 ± 0.9 IU/l, respectively, and these values were significantly lower compared witho the control group. In agreement with our results, Al and Zuhairy[16] studied 50 children with β-thalassemia major patients, in the age range of 11 and 16 years and 50 age-matched and sex-matched healthy adolescents as the control group. Male patients have significant decreased serum FSH, LH, testosterone, and estradiol levels when compared with control. Also, Hamed et al.[12] found that LH, FSH, and TT were significantly different between thalassemia patients and controls.

The present study showed that the serum ferritin level was significantly higher among cases than controls. In agreement with our results, Gamberini et al.[17] found significantly higher mean serum ferritin levels and increased age at initiation of iron chelation treatment in hypogonadal patients, which support the idea of exposure to suboptimal chelation treatment. Also, the Susanah et al.[18] study showed that median serum ferritin level was significantly higher than those in controls. In males, AHH includes all disorders that damage or alter the function of gonadotropin-releasing hormone neurons and/or pituitary gonadotropic cells. The clinical characteristics of AHH are androgen deficiency and lack, delay, or halt of pubertal sexual maturation[1]. This study showed that 80% of thalassemic patients had hypogonadism, in the form of delayed (60%) and arrested (20%) puberty, while 20% had not. The low serum level of gonadotropins (FSH and LH) in patients with impaired puberty, indicating that hypogonadotropic hypogonadism, is responsible for this complication[10]. This result was comparable to a study by Safarinejad[19] who found that the prevalence of hypogonadotropic hypogonadism was 76.2%, and almost half of the thalassemic male patients had failure of pubertal development, but higher than the results of Hashemi et al.[20] who found that the prevalence of hypogonadism was 54.8%.

In the present study, age of transfusion was significantly lower among thalassemic patients with hypogonadism than those without hypogonadism, while there were no significant differences between thalassemia with and without hypogonadism groups regarding age, weight, height, BMI, blood transfusion, age of chelation, and dose of chelation. In agreement with our result, Sclafani et al.[21] demonstrated an association between hypogonadism and early-onset transfusion therapy. Also, AlAkhras et al.[22] found significant association between hypogonadism and earlier age of starting transfusion and frequency of blood transfusion. Contrarily, in their study Albu et al.[1] found thalassemia major patients with delayed puberty were significantly older (age 26 vs. 16.5 years), with increased age at initiation of iron chelation therapy.

There was significant difference between the eugonadal and hypogonadal thalassemic patients regarding HCT and Hb levels, suggesting that the persistently low Hb levels may be involved in the pathogenesis of gonadal failure independent of the other contributing factors. This was in line with the Shaheen[23] study, which revealed a significant relationship between hypogonadism and pretransfusion Hb. Other studies conducted in northern Egypt among 40 patients did not observe a relationship between Hb level and development of hypogonadism. These studies attributed the high rate of hypogonadism to factors other than chronic hypoxia, such as multi-endocrine dysfunction or iron accumulation[24]. Also, Shaheen[23] detected significant relationship between hypogonadism and BMI, pretransfusion Hb levels, and levels of serum ferritin. Also, blood transfusion rate per year, age of starting iron chelation therapy, and compliance to iron chelation therapy regimen were determined as risk factors for hypogonadism[23]. There is a relation between the degree of organ damage and the degree of iron overload in patients with β-thalassemia[25]. 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[26].

In the current study, platelet count and serum ferritin levels were significantly higher among thalassemic patients with hypogonadism than those without hypogonadism. These findings yield the importance of iron overload in the development of endocrine disorders. In agreement with our results, Shamshirsaz et al.[27] found significant difference in mean serum ferritin level between thalassemic patients with hypogonadism and those without endocrinopathies. Earlier studies have failed to show the effect of iron overload on sexual growth. There is also no direct relationship between the amount of iron accumulated and organ dysfunction[28] It is possible that endocrine glands are extremely sensitive to iron toxicity, and even small amounts of iron accumulated in the early years of life can cause irreversible damage[29]. Also, Albu et al.[1] found that patients with any form of hypogonadism had significantly higher age, significantly lower than average Hb levels, and higher than average serum ferritin levels compared with those without hypogonadism. In contrast, there are some other reports which have suggested no relation between the level of ferritin and some other endocrinopathies[30],[31].


  Conclusion Top


Hypogonadism is highly prevalent among male patients with β-thalassemia major, and its presence is associated with higher iron overload and lower Hb values, and the late start of iron chelation therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Albu A, Barbu C, Antonie L, Vladareanu F, Fica S. Risk factors associated with hypogonadism in β–thalassemia major patients: predictors for a frequent complication of a rare disease. Postgrad Med 2014; 126:121–127.  Back to cited text no. 1
    
2.
Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010; 115:4331–4336.  Back to cited text no. 2
    
3.
El-Beshlawy A, Manz C, Naja M, Eltagui M, Tarabishi C, Youssry I, et al. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ann Hematol 2008; 87:545–550.  Back to cited text no. 3
    
4.
Taher AT, Weatherall DJ, Cappellini MD. Thalassemia. Lancet 2018; 391:155–167.  Back to cited text no. 4
    
5.
Vichinsky E. Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. Ann N Y Acad Sci 2010; 1202:180–187.  Back to cited text no. 5
    
6.
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:2536–2559.  Back to cited text no. 6
    
7.
Waseem F, Khemomal KA, Sajid R. Antioxidant status in beta thalassemia major: a single-center study. Indian J Pathol Microbiol 2011; 54:761.  Back to cited text no. 7
    
8.
De Sanctis V. Growth and puberty and its management in thalassemia. Hormone Res Paediatr 2002; 58:72–79.  Back to cited text no. 8
    
9.
Mickey E, Brooke B R. “Tanner Stages”, StatPearls, StatPearls Publishing, 2019. PMID 29262142, retrieved 2019-08-01.  Back to cited text no. 9
    
10.
Srisukh S, Ongphiphadhanakul B, Bunnag P. Hypogonadism in thalassemia major patients. J Clin Transl Endocrinol 2016; 5:42–45.  Back to cited text no. 10
    
11.
Nienhuis AW, Nathan DG. Pathophysiology and clinical manifestations of the β-thalassemia's. Cold Spring Harb Perspect Med 2012; 2:a011726.  Back to cited text no. 11
    
12.
Hamed AT, Zughbur MR, Shaheen EA. Prevalence of hypogonadism in β-thalassemia major patients from Gaza Strip. Jordan J Pharm Sci 2021; 14:267–278.  Back to cited text no. 12
    
13.
Ezzat AM, Abdelmotaleb GS, Shaheen AM, Ismail YM, Diab AM. Peroxidative stress and antioxidant enzymes in children with β-thalassemia major. Med Res J 2016; 15:57–62.  Back to cited text no. 13
    
14.
Aboul-Enein A, Amal EB, Hamdy M, Shaheen I, El-Saadany Z, Samir A, et al. Peripheral expression of hepcidin gene in Egyptian β-thalassemia major. Gene 2015; 564:206–209.  Back to cited text no. 14
    
15.
De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Pepe A, Kattamis C, et al. Acquired hypogonadotropic hypogonadism in thalassemia major patients: an underdiagnosed condition. Mediterr J Hematol Infect Dis 2016; 8:e2016001.  Back to cited text no. 15
    
16.
Al TN, Zuhairy ZA. Evaluation of reproductive hormones in patients with β-thalassemia major in Misan Province, Iraq. Med Legal Update 2020; 20:274–279.  Back to cited text no. 16
    
17.
Gamberini MR, De Sanctis V, Gilli G. Hypogonadism, diabetes mellitus, hypothyroidism, hypoparathyroidism: incidence and prevalence related to iron overload and chelation therapy in patients with thalassemia major followed from 1980 to 2007 in the Ferrara Centre. Pediatr Endocrinol Rev 2008; 6:158–169.  Back to cited text no. 17
    
18.
Susanah S, Rakhmilla LE, Ghozali M, Trisaputra JO, Moestopo O, Sribudiani Y, et al. Iron status in newly diagnosed β-thalassemia major: high rate of iron status due to erythropoiesis drive. Biomed Res Int 2021; 2021:7.  Back to cited text no. 18
    
19.
Safarinejad MR. Evaluation of semen quality, endocrine profile and hypothalamus pituitary testis axis in male patients with homozygous β-thalassemia major. J Urol 2008; 179:2327–2332.  Back to cited text no. 19
    
20.
Hashemi A, Hashemian Z, Ordooei M, Amanat M, Purshamsi F, Ghasemi N, et al. Endocrine dysfunctions in iron overload in patients with major thalassemia. Iran J Ped Hematol Oncol 2012; 2:60–66.  Back to cited text no. 20
    
21.
Sclafani S, Calvaruso G, Agrigento V, Maggio A, Nigro VL, D'Alcamo E. Glutathione S transferase polymorphisms influence on iron overload in β-thalassemia patients. Thalassemia Rep 2013; 3:6–9.  Back to cited text no. 21
    
22.
AlAkhras A, Badr M, ElSafy U, Kohne E, Hassan T, Abdelrahman H, et al. Impact of genotype on endocrinal complications in βthalassemia patients. Biomed Rep 2016; 4:728–736.  Back to cited text no. 22
    
23.
Shaheen EA. Prevalence of hypogonadism in thalassemia major patients in Gaza strip [Doctoral dissertation]. Cairo, Egypt: Al-Azhar University of Gaza: 55–64.  Back to cited text no. 23
    
24.
Abdelrazik N, Ghanem H. Failure of puberty in Egyptian beta thalassemic patients: experience in north east region Dakahlia province. Hematology 2007; 12:449–456.  Back to cited text no. 24
    
25.
Soliman AT, Nasr I, Thabet A, Rizk MM, El Matary W. Human chorionic gonadotropin therapy in adolescent boys with constitutional delayed puberty vs those with β-thalassemia major. Metabolism 2005; 54:15–23.  Back to cited text no. 25
    
26.
Al-Rimawi HS, Jallad MF, Amarin ZO, Al Sakaan R. Pubertal evaluation of adolescent boys with β-thalassemia major and delayed puberty. Fertil Steril 2006; 86:886–890.  Back to cited text no. 26
    
27.
Shamshirsaz AA, Bekheirnia MR, Kamgar M, Pourzahedgilani N, Bouzari N, Habibzadeh M, et al. Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran. BMC Endocr Disord 2003; 3:1–6.  Back to cited text no. 27
    
28.
Borgna-Pignatti C, De Stefano P, Zonta L, Vullo C, De Sanctis V, Melevendi C, et al. Growth and sexual maturation in thalassemia major. J Pediatr 1985; 106:150–155.  Back to cited text no. 28
    
29.
Flynn DM, Hoffbrand AV, Politis D. Subcutaneous desferrioxamine: the effect of three years' treatment on liver, iron, serum ferritin, and comments on echocardiography. Birth Defects Orig Artic Ser 1982; 18:347–353.  Back to cited text no. 29
    
30.
Masala A, Meloni T, Gallisai D, Alagna S, Rovasio PP, Rassu S, et al. Endocrine functioning in multitransfused prepubertal patients with homozygous β-thalassemia. J Clin Endocrinol Metab 1984; 58:667–670.  Back to cited text no. 30
    
31.
Zervas A, Katopodi A, Protonotariou A, Livadas S, Karagiorga M, Politis C, et al. Assessment of thyroid function in two hundred patients with β-thalassemia major. Thyroid 2002; 12:151–154.  Back to cited text no. 31
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Patients and methods
Results
Discussion
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed716    
    Printed26    
    Emailed0    
    PDF Downloaded97    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]