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Indian Pediatr 2021;58:635-638 |
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Pubertal Development
and its Determinants in Adolescents With Transfusion-Dependent
Thalassemia
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Preeti Singh, Sukla Samaddar, Nupur Parakh, Jagdish Chandra and Anju
Seth*
From Department of Pediatrics, Lady Hardinge Medical College and
Kalawati Saran Children’s Hospital, New Delhi.
Correspondence to: Dr Anju Seth, Director Professor, Department of
Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children’s
Hospital, New Delhi 110 001, India.
Email: [email protected]
Received: June 12, 2020;
Initial review: July 24, 2020;
Accepted: January 19, 2021.
Published online: March 26, 2021;
PII: S097475591600303
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Objective: To assess pubertal development
and its determinants in adolescents with transfusion-dependent
thalassemia (TDT). Methods: In this cross-sectional study from a
tertiary teaching hospital in Delhi, records of adolescents aged 17-19
years with TDT on regular transfusion at thalassemia day-care centre
were reviewed. Pubertal development and its determinants were assessed.
Results: Records of 58 (33 male) adolescents with TDT were
reviewed. Among them, 42 (72.4%) had normal/delayed onset with
spontaneous progression of puberty, while 16 (27.6%) had pubertal
arrest/failure and received hormonal replacement therapy (HRT). Short
stature was observed in all adolescents on HRT. Amongst other
endocrinopathies, only hypoparathyroidism was found to be significantly
higher in the HRT group. On multivariate analysis, serum ferritin
(OR-1.005, 95% CI 1.002, 1.009) was observed to be the only significant
determinant of pubertal arrest/failure. Conclusion: A significant
proportion of adolescents with TDT continue to have pubertal
arrest/failure. High systemic iron load is the key determinant for this.
Keywords: Delayed puberty, Growth failure,
Hypogonadotropic hypogonadism, Ferritin.
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W
ith the advent of
intensive transfusion and
robust chelation regimes, life expectancy
has increased significantly in patients
with transfusion-dependent thalassemia (TDT). Concurrently,
endocrine dysfunction has emerged as an important cause of
morbidity in adolescents and adults with TDT. Deranged pubertal
development is amongst the commonest endocrinopathies observed
in adolescents with thalassemia. Early recognition and timely
management of these adolescents can not only help in optimizing
growth and pubertal development but also improve their bone
mineral density, quality of life and preserve fertility
potential.
Children with TDT experience poor growth
predominantly during the peri-pubertal phase or puberty. This is
primarily due to transfusion associated iron overload affecting
the growth hormone-insulin like growth factor axis (GH-IGF axis)
and the hypothalamic-pituitary-gonadal (HPG) axis. Despite
regular transfusions and optimal chelation therapy, the
prevalence of pubertal disturbances in TDT still ranges between
30-70% [1-3]. In a previous study from our center, delayed
puberty and/or hypogonadism were reported in 54.1% of children
with TDT [4]. The key contributory factor is
transfusion-mediated hemosiderosis in HPG axis that leads to
hypogonadotropic hypogonadism (HH).
With improvement in the management of
children with TDT, the prevalence of growth failure and pubertal
disturbances have decreased. However, information on the
prevalence and manifestations of pubertal disturbances in
adolescents with TDT from India is scarce. We report the
spectrum of pubertal disturbances and their determinants in
adolescents with TDT.
METHODS
This cross-sectional study was conducted at
the thala-ssemia day-care centre and pediatric endocrine clinic
of a tertiary level teaching hospital in Delhi over a period of
3 months from June, 2019 to August, 2019. The records of all
adolescents with TDT in the age group 17 to 19 years attending
the center and on regular transfusion and chelation therapy (for
at least previous 7 years) were reviewed. Information on annual
transfusion requirement (ATR) and average ferritin (done at
least biannually) levels over last 7 years were recorded.
Anthropometric SD scores (SDS) were calculated according to age
and sex-specific norms using IAP 2015 growth reference charts
[5]. Mid-parental height (MPH) was calculated and the child’s
height within ±2SD of MPH was considered appropriate for the
genetic potential. Children with height for age below 2 SDS were
considered to have short stature. Pubertal development and
progression over the previous years as assessed by sexual
maturity rating (SMR) according to Tanner criteria was noted.
As a part of usual care protocol at our
center, children with TDT after 10 years age undergo regular
growth and pubertal assessment and an annual endocrine screen.
The latter consists of thyroid function tests, fasting plasma
glucose, oral glucose tolerance test (if indicated), serum
calcium, phosphate, alkaline phosphatase, 25-hydroxy vitamin D
and parathyroid hormone (if indicated by clinical or biochemical
features). Bone age, luteinizing hormone (LH), follicle
stimulating hormone (FSH), and sex steroids [estradiol (female)
and testosterone (male)] are assessed in adolescents with
delayed/arrested/failed puberty. Low FSH, LH and sex steroids
for age, sex and pubertal stage indicate hypogonadotropic
hypogona-dism. In those with equivocal results, gonadotropin-releasing
hormone (GnRH) analog stimulation test is performed to evaluate
the pitui-tary’s ability to synthesize and secrete gonadotropins.
In cases with arrested/delayed puberty, incremental age
appropriate hormone replacement therapy (HRT) is started as per
standard protocol. Screening for Hepatitis B, C, HIV and liver
function is done in all children annually. ECG, echocardiography
and MRI T2* imaging for cardiac and hepatic dysfunction is also
performed to look for trans-fusional iron overload. A baseline
DEXA (dual-energy X-ray absorptiometry) scan followed by
annual/biennial screening of bone mineral density (in case of
fragility fractures) is done on case to case basis.
Based on the onset and progression of
puberty, the children recruited in this study were categorized
into 4 groups: Group 1: Normal onset and progression of puberty,
Group 2: Delayed onset and spontaneous progression of puberty
after priming with low dose sex steroids for 3-6 months, Group
3: Normal/delayed onset with pubertal arrest, and Group 4: No
spontaneous onset of puberty – pubertal failure.
Delayed puberty was defined as absence of
gonadarche (testicular volume
<4 mL) in
males by 14 years and thelarche (appearance of breast bud) in
females by 13 years. The failure of pubertal progression from
one Tanner stage to the next over a period of 1 year was
considered as pubertal arrest. Failure to achieve menarche by 16
years was defined as primary amenorrhea while the absence of
menstrual cycles for >12 months after attaining menarche was
considered secondary amenorrhea.
The study was approved by the institutional
ethics committee and a written informed consent of the
parent/guardian of the participants was taken. Consent/assent of
the participants was also taken.
Statistical analysis: These were done
using SPSS version 20.0. Categorical variables were analyzed
using chi square test and continuous variables, using
indepen-dent t test. Multivariate logistic regression was
done to study factors determining pubertal failure and arrest.
RESULTS
The records of 58 adolescents with TDT were
reviewed (Table I). Thirty four (58.6%) children in group
1 and 8 (13.8%) in group 2 did not require HRT i.e., non HRT
group (n=42; 72.4%). Sixteen (27.6%) children [group 3; 7
(12.1%) and group 4; 9 (15.5%)] had pubertal arrest/failure and
received HRT. All girls in HRT group had primary amenorrhea,
except for one girl in group 3 with secondary amenorrhea.
All children in the HRT group had short stature while in the non
HRT group, 14/23 (60.9%) boys and 7/19 (43.8%) girls were short.
When compared with the respective MPH, two-third of children
fell short of their genetic potential in the HRT group. All
children with delayed, failed and arrested puberty had delayed
bone age i.e. < –2SD from chronological age.
Table I Anthropometric and Pubertal Characteristics of Children With Transfusion-Dependent Thalassemia
| Characteristics |
Males (n=33) |
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Females (n=25) |
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No HRT (n=23) |
HRT (n=10) |
No HRT (n=19) |
HRT (n=6) |
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Age pubertal onset, ya
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13.5 (1) |
16.5 (1) |
12 (1) |
15.5 (1) |
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Menarche, yb
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- |
- |
14.5 (1) |
17.5 (1) |
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Height z-scorec |
– 2.09 (0.90) |
– 3.29 (0.79) |
– 1.57 (1.52) |
– 4.25 (2.21) |
| Weight z-scored |
– 1.81 (0.74) |
– 2.76 (0.87) |
– 1.87 (0.78) |
– 2.70 (0.90) |
| BMI z-score |
– 1.06 (0.88) |
– 1.53 (0.85) |
– 0.51 (0.94) |
– 0.80 (0.81) |
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Final height - MPH, cme
|
– 6.9 (5.9) |
– 14.7 (8.6) |
– 4.1 (9.5) |
– 13.7 (6.5) |
| aP<0.001 for both
sexes; bP=0.002; cP<0.01 for both boys and girls; dP=0.003
for boys and 0.036 for girls; eP=0.005 for boys and 0.04
for girls. MPH: mid parental height; BMI: body mass
index; HRT: hormone replacement therapy. |
Table II Gonadotropin and Sex Hormone Profile on Gonadotropin Releasing Hormone (GnRH) Analog Stimulation Test in
Children With Transfusion-Dependent Thalassemia (N=24)
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Male, n=15
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Female, n=9 |
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Group 3 & 4, n=10 |
Group 2, n=5 |
Group 3 & 4, n=6 |
Group 2, n=3 |
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LH (mIU/mL)
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| Basal |
0.36 (0.19) |
0.80 (0.48) |
0.45 (0.02) |
0.90 (1.15) |
| Peak |
0.92 (0.45) |
2.50 (0.55) |
1.10 (0.13) |
2.22 (1.45) |
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FSH (mIU/mL)
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| Basal |
0.61(0.56) |
1.3 (1.12) |
0.85 (0.63) |
2.23 (1.89) |
| Peak |
0.94 (0.14) |
3.8 (1.55) |
1.5 (1.18) |
4.35 (2.65) |
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Estradiol (pg/mL)
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| Basal |
- |
- |
2.75 (0.65) |
9.80 (6.68) |
| Peak |
- |
- |
4.23 (1.13) |
26.33(8.55) |
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Total testosterone (ng/dL)
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- |
- |
| Basal |
2.24 (0.66) |
23.80 (5.77) |
- |
- |
| Peak |
3.51 (0.68) |
59.44 (6.50) |
- |
- |
| P<0.001 for all
comparisons between Group 2 and Group 3 and 4. GnRH
analog stimulation test was not performed in group 1
children who underwent spontaneous onset and progression
of puberty. |
Table III Clinical Characteristics and Co-morbidities in Children With Transfusion-Dependent Thalassemia
| Variables
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HRT, n=16 |
| Males, n (%) |
23 (54.8) |
10 (62.5) |
| Pretransfusion |
9.4 (0.4) |
9.3 (0.5) |
|
hemoglobin, mg/dL |
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| Annual transfusion |
135.6 (11.3) |
146.4 (17.2) |
|
requirement, mL/kgb |
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Serum ferritin, ng/mLc |
2752.4 (1082) |
5084.9 (1640.5) |
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SGOT, IU/Lc
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40.6 (15.7) |
73.4 (30.7) |
| SGPT, IU/L |
49.9 (30.2) |
107.2 (63.7) |
| Hypothyroidism, n (%)d |
5 (11.7) |
4 (25) |
| Hypoparathyroidism, n (%)b |
1 (2.3) |
4 (25) |
| Impaired glucose tolerance/ |
16 (38.1) |
8 (50) |
| Type I DM, n (%) |
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| HCV positive, n (%) |
4 (9.5) |
2 (12.5) |
| MRI T2* liver score, ms |
8.5 (7.2) |
9.3 (7.3) |
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MRI T2* cardiac score, msa
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19.4 (11.2) |
13.0 (5.6) |
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DEXA spine; SD scoresb
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–1.54 (1.64) |
–3.06 (1.50) |
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DEXA hip; SD scoresc
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–1.38 (1.11) |
–2.70 (0.96) |
| aP<0.05, bP<0.01, cP<0.001.
1 child in non-HRT group was hepatitis B positive, and 1
in HRT group was HIV-positive. SGOT: serum
glutamic-oxaloacetic transaminase; SGPT: serum glutamic
pyruvic transaminase; DM: diabetes mellitus; MRI:
magnetic resonance imaging; DEXA: dual energy x-ray
absorptiometry; HRT: hormone replacement therapy. dsub-clinical/avert. |
The baseline and stimulated GnRH levels of
LH, FSH, and estradiol (female) and testosterone (male) were
assessed for subjects in group 2,3 and 4 (Table II). Both
baseline and peak values of gonadotropins and sex steroids were
significantly lower in group 3 and 4 as compared to group 2. No
subject in this study had evidence of hypergonadotropic
hypogonadism. There was no significant difference in
endocrinopathies between HRT and non-HRT groups except for
hypoparathyroidism, which was significantly higher in the former
group (Table III). On multivariate analysis of factors
associated with failed/arrested puberty, the mean serum ferritin
(OR=1.005, 95% CI, 1.002, 1.009; P <0.05) remained the
only significant predictor while mean ATR, gender and other
co-morbidities like liver dysfunction, hypothy-roidism, type I
diabetes mellitus, hepatitis B/C failed to show any significant
association.
DISCUSSION
This study describes the spectrum of pubertal
disturbances in adolescents with TDT under regular follow-up.
While nearly 60% subjects had spontaneous onset and progre-ssion
of puberty, more than a quarter required HRT due to pubertal
arrest/failure. All adolescents requiring HRT had short stature.
Hypoparathyroidism and liver dysfunction were reported more in
the HRT group. High iron overload was the only significant
predictor of pubertal failure/arrest.
The main limitation of this study was that
the dynamics of the genotype-phenotype interaction in the
development of pubertal failure was not assessed.
bºbº
compared to bºb+
and b+b+
phenotypes have been shown to have increased need of blood
transfusions and thereby, higher iron overload and
endocrinopathies [6]. Further, the evaluation of growth axis and
its relative contribution to pubertal failure was not performed.
Growth failure is one of the most common
complications observed in children with TDT. This study found
short stature in all children on HRT. The pubertal
failure/arrest significantly contributed to the reduced final
heights in these children. This is in agreement with studies on
growth failure in children with TDT reported from India [7,8]
and globally [9].
Hypogonadism was found in 27.6% subjects
which is lower than that reported in a previous study from our
center [4] and literature published before 2005 [10]. The likely
cause for this observation is use of regular transfusions,
better chelation and monitoring in the current era. The
variability in worldwide prevalence of hypogonadism [1-3] may be
explained by discrepancy in definitions of pubertal failure,
differences in study cohort and their genetic variability. Also,
the design of this study would miss subjects who may develop
hypogonadism and secondary amenorrhea as an adult.
The mechanism of hypogonadotropic
hypogonadism is postulated to be pituitary iron deposition
resulting in volume loss and failure of HPG axis [11]. Priming
with low dose sex steroids improves the responsiveness of the
pituitary to gonadotropin releasing hormones. It is an effective
method of inducing physiological puberty, feasi-ble even in low
resource countries [12]. Therefore, it was used in adolescents
in group 2 to jump-start the puberty.
The prevalence of other endocrinopathies in
this study was consistent with the published literature [13].
Previous studies indicate male sex, high serum and tissue iron
overload, genotype-phenotype interaction, severe clinical
endocrinopathy as predictors of HH in children with TDT [14,15].
Our study showed no correlation with gender or endocrine
dysfunction, while high serum ferritin levels had a significant
association with pubertal failure/arrest. Further studies are
required to assess the genotype - phenotype correlation in TDT,
leading to a higher transfusion requirement and resultant
increased systemic iron load. This will help design strategies
to intensify chelation in subset of vulnerable children for the
prevention of endocrinopathies and other comorbidities.
Ethics Clearance: Institutional
Ethical Committee for Human Research, Lady Hardinge Medical
College and associated hospitals; No. LHMC/ECHR/2018/29, dated
10 May, 2018.
Contributors: PS: planning,
execution of the study, data analysis and writing the
manuscript; SS: data compilation, data analysis and writing the
manuscript; NP,JC: execution of the study and writing the
manuscript; AS: planning, execution of the study, data analysis
and writing the manuscript. All authors approved the final
version of manuscript.
Funding: None; Competing interests:
None stated.
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WHAT THIS STUDY ADDS?
• Despite regular transfusion and
intensive chelation, a significant proportion of
adolescents with transfusion-dependent thalassemia
continue to have pubertal arrest and failure.
• High systemic iron load is an important predictor
of pubertal disturbances in these children.
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REFERENCES
1. Toumba M, Sergis A, Kanaris C, Skordis N.
Endocrine complications in patients with thalassaemia major.
Pediatr Endocrinol Rev. 2007;5:642-8.
2. Raiola G, Galati MC, De Sanctis V. Growth
and puberty in thalassemia major. J Pediatr Endocrinol Metab.
2003;16: 259-66.
3. Delvecchio M, Cavallo L. Growth and
endocrine function in thalassemia major in childhood and
adolescence. J Endocrinol Invest. 2010;33:61-8.
4. Sharma R, Seth A, Chandra J, et al.
Endocrinopathies in adolescents with thalassaemia major
receiving oral iron chelation therapy. Paediatr Int Child
Health. 2016;36:22-7.
5. Indian Academy of Pediatrics Growth Charts
Committee, Khadilkar V, Yadav S, Agrawal KK, et al. Revised IAP
growth charts for height, weight and body mass index for 5- to
18-year-old Indian children. Indian Pediatr. 2015;52: 47-55.
6. Al-Akhras A, Badr M, El-Safy U, et al.
Impact of genotype on endocrinal complications in b-thalassemia
patients. Biomed Rep. 2016;4:728-36.
7. De Sanctis V, Soliman AT, Elsedfy H, et
al. Growth and endocrine disorders in thalassemia: The
international network on endocrine complications in thalassemia
(I-CET) position statement and guidelines. Indian J Endocrinol
Metab. 2013;17:8-18.
8. Pattanashetti MA, Pilli GS. Assessment of
growth parameters in transfusion dependent thalassemics at a
tertiary care hospital. Annals of Pathology and Laboratory
Medicine. 2018;5:316-21.
9. Soliman AT, El Zalabany MM, Amer M, Ansari
BM. Growth and pubertal development in transfusion- dependent
children and adolescents with thalassaemia major. Hemoglobin.
2009;33:16-20.
10. Chatterjee R, Bajoria R. Critical
appraisal of growth retardation and pubertal disturbances in
thalassemia. Ann N Y Acad Sci. 2010;1202:100-14.
11. Mousa AA, Ghonem M, Elhadidy el HM, et
al. Iron overload detection using pituitary and hepatic MRI in
thalassemic patients having short stature and hypogonadism.
Endocr Res. 2016;41:81-8.
12. Chatterjee R, Mukhopadhyay TN, Chandra S,
Bajoria R. Sex steroid priming for induction of puberty in
thalassemia patients with pulsatile reversible hypogonadotrophic
hypogonadism. Hemoglobin. 2011;35:659-64.
13. De Sanctis V, Eleftheriou A, Malaventura
C. Thalassaemia International Federation Study Group on Growth
and Endocrine complications in thalassaemia. Prevalence of
endocrine complications and short stature in patients with
thalassaemia major: A multicenter study by the Thalassaemia
International Federation (TIF). Pediatr Endocrinol Rev.
2004;2:249-55.
14. Albu A, Barbu CG, Antonie L, Vladareanu
F, Fica S. Risk factors associated with hypogonadism in â-thalassemia
major patients: Predictors for a frequent complication of a rare
disease. Postgrad Med. 2014;126:121-7.
15. Belhoul KM, Bakir ML, Saned M-S, Kadhim
AMA, Musallam KM, Taher AT. Serum ferritin levels and
endocrinopathy in medically treated patients with â thalassemia
major. Ann Hematol. 2012;91:1107-14.
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