Article

The Impact of Acquired Hypothyroidism on the Growth and

Metabolic Profiles of Pediatric Patients: A Retrospective
Monocentric Study
Elena Malavolta 1 , Ignazio Cammisa 1 , Giulia Rotunno 1 , Lucia Celeste Pane 1 , Federica Arzilli 1 ,
Giorgio Sodero 1,2,3, * , Donato Rigante 1,4 and Clelia Cipolla 1

1 Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli
IRCCS, 00168 Rome, Italy; ignazio.cammisa01@[Link] (I.C.); giulia.rotunno01@[Link] (G.R.);
luciaceleste.pane01@[Link] (L.C.P.); [Link]@[Link] (D.R.)
2 Pediatric Department, Perrino Hospital, 72100 Brindisi, Italy
3 Pediatric Endocrinology Unit, Perrino Hospital, 72100, Brindisi, Italy
4 Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore di Roma,
00168 Rome, Italy
* Correspondence: giorgio.sodero01@[Link]; Tel.: +39-06-30154390

Abstract: Background: Hypothyroidism is the most common thyroid dysfunction in child-

hood, resulting from the decreased biological activity of thyroid hormones in tissues. Pedi-
atric patients with hypothyroidism, when left untreated or when thyroid hormone levels
fail to normalize despite treatment, may exhibit various complications such as growth retar-
dation, obesity, and hypercholesterolemia. Aim: We conducted a monocentric retrospective
study to evaluate potential differences in obesity rates and auxological parameters between
healthy patients and children with hypothyroidism undergoing levothyroxine replacement
therapy. Additionally, we examined possible differences in lipid and glucose metabolism
between the two groups. Materials and Methods: We collected and analyzed data from
the electronic medical records of 108 patients who were regularly followed up for thyroid
dysfunction at the Pediatric Endocrinology Unit of the Fondazione Policlinico Universitario
Academic Editors: Nicola Improda A. Gemelli IRCCS from January 2016 to June 2024. We also included 104 healthy controls
and Pierluigi Marzuillo who underwent thyroid function testing during the same period, followed up in the same
Received: 9 January 2025 department for regular auxological check-ups. Results: Our findings revealed that patients
Revised: 6 February 2025 with acquired hypothyroidism had a lower height z-score compared to healthy controls
Accepted: 21 February 2025 (t(210) = −2.6; p = 0.01). Additionally, they exhibited higher blood glucose and triglyceride
Published: 24 February 2025
levels, although these values remained within the normal range. Conclusions: We highlight
Citation: Malavolta, E.; Cammisa, I.; the critical importance of the early diagnosis of hypothyroidism to initiate levothyroxine
Rotunno, G.; Pane, L.C.; Arzilli, F.;
replacement therapy promptly and mitigate the long-term effects of hypothyroidism on
Sodero, G.; Rigante, D.; Cipolla, C.
children’s growth.
The Impact of Acquired
Hypothyroidism on the Growth and
Metabolic Profiles of Pediatric
Keywords: hypothyroidism; levothyroxine; growth; pediatric endocrinology
Patients: A Retrospective Monocentric
Study. Children 2025, 12, 272. https://
[Link]/10.3390/children12030272

Copyright: © 2025 by the authors.

1. Introduction
Licensee MDPI, Basel, Switzerland. Thyroid hormones have important physiologic functions in nearly every organ system
This article is an open access article of the human body; the critical role of thyroid hormones in growth and in physical and
distributed under the terms and
neurologic development lends particular importance to the prompt diagnosis and proper
conditions of the Creative Commons
treatment of hypothyroidism in infants and children [1]. The most common symptoms
Attribution (CC BY) license
([Link] of hypothyroidism in children and adolescents include growth retardation, delayed psy-
licenses/by/4.0/).

Children 2025, 12, 272 [Link]

Children 2025, 12, 272 2 of 12

chomotor and cognitive development, excessive fatigue, weight gain, dry skin and brittle
hair, bradycardia, cold intolerance, and constipation.
The thyroid gland is composed of two lobes which are connected by the central
isthmus located in the lower portion of the neck. The gland develops from an endodermal
diverticular outgrowth of the primitive pharynx, and the thyroid diverticulum first forms at
the end of the fourth week of development as a solid, proliferating mass of endoderm that
migrates down through the developing neck via the thyroglossal duct toward its eventual
home. The only remaining aspect of the thyroid’s embryonal development is the foramen
cecum at the base of the developed tongue. The isolated thyroid gland develops two distinct
lobes connected by an isthmus of tissue by this time and continues to descend and reach its
final destination by the end of the seventh week of development. The primary secretory
product of the thyroid gland is inactive thyroxine, or T4, a prohormone of triiodothyronine,
or T3. T4 is converted to T3 peripherally by type 1 deiodinase in tissues with high blood
flow, such as the liver and kidneys [2].
These iodothyronines are composed of thyroglobulin and iodine. Thyroglobulin is
formed from amino acids in a basal to apical fashion within the thyroid cells. Thyroglobulin
is then secreted into the follicular lumen and is enzymatically combined with iodine to
form iodinated thyroglobulin. Endosomes containing this iodinated thyroglobulin then
fuse with lysosomes, which enzymatically release the thyroglobulin from the resultant
thyroid hormone [2].
Primary hypothyroidism is the most common thyroid dysfunction in childhood,
resulting from the decreased biological activity of thyroid hormones in tissues, and could
be caused by an organic or functional alteration in the thyroid gland, with an insufficient
production and/or secretion of thyroid hormones: thyroxine [fT4] and triiodothyronine
[fT3]. Less common causes of hypothyroidism may include conditions such as resistance
to thyroid hormone action (peripheral hypothyroidism) or the accelerated degradation of
thyroid hormones in peripheral tissues (consumption hypothyroidism) [3].
Hypothyroidism can be classified as either congenital or acquired. Congenital hy-
pothyroidism (CH) arises from defective thyroid hormone production present from birth.
Furthermore, there are three major types of hypothyroidism due to the location of the
defect. Hypothyroidism due to abnormalities in the thyroid gland itself is primary hy-
pothyroidism. Secondary hypothyroidism is caused by a deficiency in thyroid stimulating
hormone (TSH) released from the anterior pituitary, and tertiary hypothyroidism is caused
by a deficiency in thyrotropin-releasing hormone (TRH) released from the hypothalamus,
which reduces the amount of TSH released. Both secondary and tertiary hypothyroidism
are central hypothyroidism.
Most congenital hypothyroidism is sporadic and usually occurs due to thyroid gland
dysgenesis. In some cases, hypothyroidism is familial, resulting from inborn errors leading
to the altered synthesis of thyroid hormones. Familial hypothyroidism can be due to
a number of genes and can have either an autosomal recessive or autosomal dominant
pattern. The mutation of various genes can lead to hereditary congenital hypothyroidism,
for example, paired box gene 8 (PAX8) and thyroid stimulating hormone receptor (TSHR),
which are important in thyroid gland development; dual oxidase 2 (DUOX2), solute carrier
family 5 member 5 (SLC5A5), thyroglobulin (TG), and thyroid peroxidase (TPO), which
are involved in the synthesis of thyroid hormones; and thyroid stimulating hormone beta
(TSHB), which has a role in the stimulation of hormone production, and mutations in this
gene lead to central hypothyroidism [4].
Most infants with CH are identified by the newborn screening in the first weeks
after birth, so early thyroxine replacement therapy can prevent intellectual disability
in a child [5].
Children 2025, 12, 272 3 of 12

In general, acquired hypothyroidism is not associated with intellectual disability,

except in early-onset cases appearing in the first two to three years of life. Globally,
iodine deficiency is the primary cause of hypothyroidism in regions with insufficient
iodine intake. However, in industrialized countries, where iodine is abundant in the diet,
autoimmune disorders are the predominant causes [4]. Hashimoto’s thyroiditis, or chronic
lymphocytic thyroiditis [CLT], is the most common autoimmune disorder and the leading
cause of acquired hypothyroidism in both adults and children or adolescents [6,7]. Acquired
hypothyroidism frequently presents at between 9 and 11 years of age and is rarely seen
before 4 years of age. Approximately 80% of children and adolescents are asymptomatic at
the time of diagnosis. Children with moderate-to-severe hypothyroidism, in both congenital
and acquired forms, often require medical attention to assess poor growth, constipation,
lethargy, and/or dry skin [8,9]. The distinctive characteristic of hypothyroidism during
childhood and adolescence, especially if acquired and with a belated diagnosis that does
not allow the adequate and rapid treatment of the thyroid hormone deficiency, is its
profound impact on skeletal growth, maturation, and pubertal development, with potential
repercussions on the final adult height [10–12]. Hypothyroidism can lead to weight gain;
therefore, it may have an important role in the development of obesity. Childhood obesity
may be the most serious health issue in developing countries [13].
Since thyroid hormones regulate the basal metabolic rate and thermogenesis, lipid
and glucose metabolism, and food intake and fat oxidation, involving metabolic pathways
relevant to resting energy expenditure (REE), it is not surprising that patients with thyroid
disease may show changes in their body weight and body composition, thermogenesis,
and REE apart from physical activity [14]. Hypothyroidism is usually associated with
weight gain or decreased thermogenesis and has been shown to correlate with a higher
body mass index [BMI] and higher prevalence of obesity [15]. Moreover, hypothyroidism
is a leading cause of hypercholesterolemia, characterized by elevated levels of low-density
lipoprotein cholesterol [LDL-C] and caused by a decreased catabolism of LDL because of
a reduction in the number of LDL receptors on liver cell surfaces mediated by T3, and
hypertriglyceridemia, caused by a reduced removal rate of triglycerides from plasma due
to the decreased activity of hepatic triglyceride lipase [16]. Obese children are at a high risk
of developing additional disorders, such as diabetes mellitus, dyslipidemia, hypertension,
and cardiovascular disease, or being diagnosed as having metabolic syndrome. In addition,
it has been estimated that children who are obese during childhood are more likely to
become obese adults [13–17].
Furthermore, obesity itself is associated with subclinical hypothyroidism. Indeed,
slight hyperthyrotropinemia and a moderate increase in free T3 (fT3) are the most common
hormonal abnormalities found in obese children: they correlate positively with BMI and
the degree of obesity [18,19], while no difference has been found for fT4. Higher TSH
levels were explained by the role of leptin which is predominantly released by adipocytes
and stimulates the secretion of thyrotropin-releasing hormone [TRH] and TSH by the
hypothalamic–pituitary axis [20,21]. At the same time, leptin influences the responsiveness
of the thyroid gland to TSH and the activity of deiodinases, as shown by the increase in
total T3 and free T3 [fT3]. The high conversion rate of T4 to T3 is interpreted as a defense
mechanism, to counteract the accumulation of fat by increasing the energy expenditure,
basal metabolic rate, and total energy expenditure [17,22,23]. Consistent with this interpre-
tation, some studies have reported that weight loss causes a significant decrease in serum
fT3 and TSH [24–28].
To address current gaps in the literature, we conducted a monocentric retrospective
study to evaluate potential differences in obesity rates and auxological parameters between
healthy patients and children with hypothyroidism undergoing levothyroxine replacement
Children 2025, 12, 272 4 of 12

therapy. We aimed to investigate whether children with hypothyroidism undergoing

adequate levothyroxine replacement therapy can achieve a risk of obesity and auxological
alterations comparable to those of the general population.

2. Materials and Methods

2.1. Study Characteristics
We conducted a single-center observational retrospective study investigating the
metabolic and anthropometric differences between patients with acquired hypothyroidism
and healthy controls; all parents of the recruited patients were informed about the purpose
of this study and signed an informed consent form to authorize access to their children’s
medical records and allow their personal data to be processed. None of the parents refused
to participate in our study. According to the General Authorization to Process Personal Data
for Scientific Research Purposes [Authorization No. 9/2014], ethics committee approval is
not required for retrospective studies that use identification codes preventing the tracing of
patients’ data.

2.2. Patients’ Selection

We collected and analyzed auxological and metabolic data from the electronic med-
ical records of patients regularly followed up for thyroid dysfunction at the Pediatric
Endocrinology Unit of the Fondazione Policlinico Universitario A. Gemelli IRCCS from
January 2016 to June 2024. We also included age-matched healthy controls who underwent
thyroid function testing during the same period, followed up in the same department for
regular auxological check-ups. We also analyzed the same parameters in a control group
consisting of healthy patients with no endocrine disorders, who were regularly monitored
at the pediatric endocrinology clinic for routine auxological evaluations.

2.3. Inclusion Criteria for Study Group

The inclusion criteria were as follows:
- Age under 20 years;
- Coded diagnosis of acquired hypothyroidism undergoing levothyroxine repla-
cement therapy;
- Patients who at diagnosis had altered TSH and FT4 values, defined by the following
cut-off points: TSH > 3.50 µUI/mL and fT4 < 8.5 pg/mL;
- Good adherence to levothyroxine therapy (as reported by the patient and/or par-
ents and confirmed through analysis of the thyroid hormone profile) and duration
>6 months;
- Absence of other medical conditions and/or pharmacological treatments that could
potentially affect the hypothalamic–pituitary axis.

2.4. Exclusion Criteria for Study Group

The exclusion criteria were as follows:
- Presence of genetic disorders or being small for gestational age;
- Patients born small for gestational age;
- Patients affected by congenital hypothyroidism;
- Patients affected by cancer.

2.5. Data Extraction and Interpretation

Data about laboratory and anthropometric parameters listed in [Table 1] were collected
in an electronic database for the subsequent statistical analysis.
Children 2025, 12, 272 5 of 12

Table 1. Laboratory and anthropometric parameters of our population of children with acquired
hypothyroidism on thyroid hormone replacement therapy.

No. of Subjects Mean (Max–Min)

TSH (microUI/mL) 212 3.26 (19.66–0)
fT3 (ng/L) 197 3.97 (12–0.15)
fT4 (ng/dL) 207 5.24 (18.7–5.51)
Glucose (mg/dL) 125 79.94 (123–37)
Triglycerides (mg/dL) 104 87.65 (490–33)
Total cholesterol (mg/dL) 109 160.47 (293–95)
HDL cholesterol (mg/dL) 96 51.51 (103–28)
LDL cholesterol (mg/dL) 97 91.75 (168–40)
Age (years) 212 9.78 (21–1)
Weight z-score 212 0.3 (3.43–−6.34)
BMI z-score 212 0.53 (3–−3.8)
Height z-score 212 −0.28 (3.12–−4.93)

Height was measured by a single endocrinologist using a stadiometer, with the subject
having bare feet, looking straight ahead, and standing with their back against the wall.
Weight was measured using an electronic scale, and BMI was calculated as weight in
kilograms divided by the square of height in meters. Z-score and percentiles for anthro-
pometric data were calculated according to Centers for Disease Control [CDC] growth
charts. The target height was calculated with the Tanner method. Patients with a BMI
percentile ≥ 95th [or a value ≥ 30] for sex and age were defined as obese, whereas patients
with a BMI between the 85th and 95th percentiles [or a value between 25 and 29.9] were
defined as overweight.
Blood exams for hormonal and biochemical parameters were routinely analyzed by
the clinical service laboratory of the Policlinico Universitario Agostino Gemelli Hospital;
more specifically, patients underwent follow-up blood tests every 3–6 months, always in
the morning and fasting. Thyroid hormone levels [TSH, fT3, fT4] and biochemical markers
describing metabolic health, including blood glucose [mg/dL], total cholesterol [mg/dL],
high-density lipoprotein cholesterol [HDL-C, mg/dL], low-density lipoprotein cholesterol
[LDL-C, mg/dL], and triglyceride concentrations [mg/dL], were selected for analyses. The
TSH, fT3, and fT4 levels were measured by the chemiluminescence immunoassay (CLIA).
The reference values, which are considered normal according to the local laboratory, were
as follows: TSH: 0.35–3.50 µUI/mL; fT3: 3.3–4.8 pg/mL; and fT4: 8.5–14.3 pg/mL. Patients
were considered euthyroid if their serum fT4 and TSH levels were in the normal range. We
also collected antibodies against thyroid peroxidase [TPOab] and human thyroglobulin
[hTGab] measured by the chemiluminescence method when available. A TPO-ab level
> 60 IU/mL and an hTGab level > 4.5 IU/mL were considered positive.
According to the Italian Society of Diabetology [24], we considered fasting glucose
values < 100 mg/dL as normal. According to the Expert Panel on Integrated Guidelines for
Cardiovascular Health and Risk Reduction in Children and Adolescents [25], we considered
plasma lipids as follows: total cholesterol: high if >200 mg/dL; LDL cholesterol: high if
>130 mg/dL; HDL cholesterol: low if <40 mg/dL; and triglycerides: high if ≥130 mg/dL.

2.6. Statistical Analysis

All the analyzed data were collected in an Excel database, which was subsequently
used for statistical analysis. Categorical variables were expressed as numbers; continuous
variables were expressed as the mean and standard deviation. T-test and Chi-square test
were performed to determine significant differences in anthropometric and laboratory
variables between patients with and without thyroid dysfunction. Statistical analysis was
Children 2025, 12, 272 6 of 12

performed using IBM SPSS Statistics software version 25.0 [IBM Corporation, Armonk, NY,
USA]. Statistical significance was determined as alpha <0.05 in all cases.

3. Results
We collected and analyzed data from the electronic medical records of 108 patients who
were regularly followed up for thyroid dysfunction at the Pediatric Endocrinology Unit of
the Fondazione Policlinico Universitario A. Gemelli IRCCS from January 2016 to June 2024.
We also included 104 healthy controls who underwent thyroid function testing during the
same period, followed up in the same department for regular auxological check-ups.
We included pediatric patients [defined as individuals aged 0 to 18 years old] and two
patients who, at the time of this study, exceeded the pediatric age range. However, since
this is a longitudinal study and these two patients were diagnosed at the ages of 13 and
12 years old, the data collected from their most recent follow-up were included.
At the time of diagnosis, all patients were in the prepubertal stage. All the recruited
patients with hypothyroidism were on thyroid hormone replacement therapy; none of the
subjects analyzed were taking any other medications that could influence the hypothalamic–
pituitary axis.
Among the participants, 149 [70.2%] were females, and 63 [29.7%] were males, with a
mean age of 9.7 years old [ranging from 1 to 21]. Data about anthropometric parameters
[age, height, weight, BMI, and respective z-scores] and thyroid function [TSH, fT3, fT4]
were collected for all patients. Healthy controls had an overall normal TSH for their
age [26]. Additionally, metabolic data were available for some patients, including glucose
[125 patients], triglycerides [104 patients], total cholesterol [109 patients], HDL cholesterol
[96 patients], and LDL cholesterol [97 patients].
According to our classification criteria, only four patients [1.8%] had pathological
glucose levels [two patients with thyroid dysfunction and two healthy controls]. Eleven
patients [5.1%] had pathological total cholesterol levels [seven patients with thyroid dys-
function and four healthy controls]. Six patients [2.8%] had pathological LDL cholesterol
levels [four patients with thyroid dysfunction and two healthy controls]. Twelve patients
[5.6%] had pathological triglyceride levels [three patients with thyroid dysfunction and
nine healthy controls]. Twenty-three patients [10.8%] had pathological HDL cholesterol
levels [eight patients with thyroid dysfunction and fifteen healthy controls].
The Student T-test was performed to determine whether the anthropometric and
laboratory variables were statistically different in patients with and without thyroid dys-
function. For laboratory parameters, no statistically significant differences were found for
total cholesterol, LDL cholesterol, and HDL cholesterol. Statistically significant differences
were found for glucose [t [123] = 2; p = 0.045] and triglycerides [t [102] = 2; p = 0.046], both
of which had higher values in the hypothyroidism group [Figure 1].
Although the differences observed are statistically significant, we do not consider
them to be clinically meaningful because most of the values were in the normal range,
and for pathological values, no significant associations with one or the other group were
found according to the Chi-square test. For the other parameters, statistically significant
differences were found for the age [t [204] = 6.7; p < 0.001] and height z-scores [t [210] = −2.6;
p = 0.01] [Figures 2 and 3].
 Children 2025, 12, x FOR PEER REVIEW 7 of 13

Children 2025, 12, 272 7 of 12

Figure 1. Differences in the mean glucose and triglycerides between patients with and without
thyroid dysfunction in our cohort.

Although the differences observed are statistically significant, we do not consider

them to be clinically meaningful because most of the values were in the normal range, and
for pathological values, no significant associations with one or the other group were found
according to the Chi-square test. For the other parameters, statistically significant
differences were found for the age [t [204] = 6.7; p < 0.001] and height z-scores [t [210] =
−2.6; p = 0.01] [Figures 2 and 3].
Figure 1. Differences in the mean glucose and triglycerides between patients with and without
Figure 1. Differences in the mean glucose and triglycerides between patients with and without
thyroid dysfunction in our cohort.
thyroid dysfunction in our cohort.

Although the differences observed are statistically significant, we do not consider

them to be clinically meaningful because most of the values were in the normal range, and
for pathological values, no significant associations with one or the other group were found
according to the Chi-square test. For the other parameters, statistically significant
differences were found for the age [t [204] = 6.7; p < 0.001] and height z-scores [t [210] =
−2.6; p = 0.01] [Figures 2 and 3].

Children 2025, 12, x FOR PEER REVIEW 8 of 13

Figure2. 2.
Figure Differences
Differences in mean
in mean age age between
between patients
patients withwith and without
and without thyroid
thyroid dysfunction
dysfunction in ourin
our cohort.
cohort.

Figure 2. Differences in mean age between patients with and without thyroid dysfunction in our
cohort.

Figure 3. Differences in mean height z-scores between patients with and without thyroid dysfunction
Figure 3. Differences in mean height z-scores between patients with and without thyroid
in our cohort.
dysfunction in our cohort.

The mean age was higher in the thyroid dysfunction group [12.3 ± 5.2 years] than in
The mean age was higher in the thyroid dysfunction group [12.3 ± 5.2 years] than in
the normal thyroid group [7.1 ± 6 years]. The mean height z-score was higher in the normal
the normal thyroid group [7.1 ± 6 years]. The mean height z-score was higher in the normal
thyroid function group [−0.02 ± 1.39] than in the thyroid dysfunction group [−0.53 ± 1.44].
thyroid function group [−0.02 ± 1.39] than in the thyroid dysfunction group [−0.53 ± 1.44].
These differences in z-scores for height were not explained by differences in genetic targets.
These differences in z-scores for height were not explained by differences in genetic
The mean genetic target was 159.98 cm for women with thyroid dysfunction and 160.1 cm
targets. The mean genetic target was 159.98 cm for women with thyroid dysfunction and
for women with normal thyroid function. The mean genetic target was 172.0 cm for males
160.1 cm for women with normal thyroid function. The mean genetic target was 172.0 cm
with thyroid dysfunction and 172.06 cm for males with normal thyroid function. The T-test
for males with thyroid dysfunction and 172.06 cm for males with normal thyroid function.
The T-test revealed no statistically significant differences in the genetic target values
between boys and girls in the two groups [p = 0.109 for females, p = 0.083 for males].
No statistically significant differences were found for the BMI z-scores between the
normal thyroid function group [mean 0.58] and the thyroid dysfunction group [mean 0.49]
[p = 0.615]. No statistically significant differences were found for the weight z-scores
Children 2025, 12, 272 8 of 12

revealed no statistically significant differences in the genetic target values between boys
and girls in the two groups [p = 0.109 for females, p = 0.083 for males].
No statistically significant differences were found for the BMI z-scores between the
normal thyroid function group [mean 0.58] and the thyroid dysfunction group [mean
0.49] [p = 0.615]. No statistically significant differences were found for the weight z-scores
between the normal thyroid function group [mean 0.46] and the thyroid dysfunction group
[mean 0.15] [p = 0.135] [Table 2].

Table 2. Laboratory and anthropometric parameters of children with acquired hypothyroidism on

thyroid hormone replacement therapy and children with normal thyroid function (control group).

Patients with Hypothyroidism Control Group p Value

Glucose (mg/dL) 82.9 78.4 0.045
Triglycerides (mg/dL) 106.7 79.9 0.046
Age (years) 12.3 7.1 <0.001
Mean weight z-score 0.15 0.46 0.135
Mean BMI z-score 0.49 0.58 0.615
Mean height z-score −0.53 −0.02 0.01

4. Discussion
We conducted a monocentric retrospective study to analyze any potential anthropo-
metric and metabolic differences between pediatric patients with acquired hypothyroidism
undergoing levothyroxine replacement therapy and a control group of healthy children
without endocrine disorders. Our findings revealed that patients with acquired hypothy-
roidism had a lower height z-score compared to healthy controls. Additionally, they
exhibited higher blood glucose and triglyceride levels, although these values remained
within the normal range.
These alterations, particularly those concerning the height z-scores, may be linked
to the role of thyroid hormones in growth and pubertal development; congenital and/or
acquired hypothyroidism is, in fact, one of the leading causes of short stature [25,27,28].
It can be hypothesized that levothyroxine replacement therapy, while ensuring a thyroid
profile within normal limits, may not fully replicate the thyroid gland’s natural effect
on growth [28].
Hypothyroidism is a known cause of growth retardation due to the action of thy-
roid hormones on tissue receptors and the deiodinase enzyme system, which is an-
other intrinsic regulator of thyroid hormone availability essential for normal growth and
development [28,29]. Earlier detection of congenital hypothyroidism is necessary to pre-
vent the associated complications such as deficits in physical development with incomplete
catch-up growth and severe neurological impairments [29].
Newborn screening for congenital hypothyroidism has reduced the mean age at
diagnosis and improved auxologic and neurologic outcomes [30]. Previous studies have
already investigated the final height of children with congenital hypothyroidism, evaluating
the importance of prognostic factors and adherence to treatment [31]. The most important
clue significantly related to final height in congenital hypothyroidism is the age at the
onset of treatment, as a delay in treatment may lead to the loss of growth potential of the
epiphyseal cartilage [32]. Other studies have shown that not only the age at the start of
treatment but also the dosage of levothyroxine may have an influence on length growth:
children with congenital hypothyroidism diagnosed during newborn screening and treated
early with a sufficiently high daily dose of fT4 grow normally and reach a normal adult
height [33]. On the other hand, some further studies reported that the age at diagnosis and
initial dose of fT4 had a poor effect on final height [30].
Children 2025, 12, 272 9 of 12

Our investigation revealed a lower height z-score in children with hypothyroidism un-
dergoing replacement therapy (−0.53 ± 1.44) compared to the control group (−0.02 ± 1.39).
However, no differences were observed between the groups in relation to their genetic
target, for both males and females. We emphasize that all our patients with hypothyroidism
consistently adhered to the prescribed therapy, with no compliance issues, and that their
thyroid function tests remained in the normal range. The results of our investigation align
with those found in other studies. Becker et al. [12] conducted a similar analysis, highlight-
ing the negative effects of acquired hypothyroidism on growth, the severity of which was
significantly correlated with the severity of hypothyroidism at diagnosis. Although they
showed that most patients under adequate fT4 substitution experienced catch-up growth,
defined as a linear growth rate higher than expected for age, the majority of patients still
had a negative value at the end of follow-up, suggesting that adequate treatment with fT4
prevents short stature in the vast majority of children but cannot fully compensate, resulting
in a minor height loss [12]. Therefore, the irreversibility of height loss is consistent with
the findings of Pantsiotou and Rivkees, who showed reduced height growth in children
with juvenile hypothyroidism several years before diagnosis and a permanent definitive
height deficit in juvenile hypothyroidism [34]. Vincent et al. examined catch-up growth
in a multicenter study of children referred due to growth retardation and diagnosed with
Hashimoto’s hypothyroidism, reporting a median height at diagnosis of −2.7 SDS with
a significant height loss of 2.5 SDS compared to height before growth retardation and
inadequate catch-up growth after thyroid hormone replacement [35]. Our data could be
explained by the delay in the diagnosis of acquired hypothyroidism and the deficit related
to the duration of thyroxine deficiency before treatment, as described in the literature [34].
Thus, in the event of growth arrest or slowdown, it is essential to investigate thyroid
function in order to anticipate the diagnosis and start replacement treatment promptly.
Our investigation also highlights the absence of differences in the z-score for weight
and BMI in children with hypothyroidism under replacement therapy compared to the
control group. It is well known that hypothyroidism can be associated with weight gain,
decreased thermogenesis, and a decreased metabolic rate, and it has been shown to correlate
with a higher BMI and a higher prevalence of obesity [15].
A bidirectional relationship between excessive weight and thyroid disease has been
proposed in several studies. First, hypothyroidism may favor weight gain by reducing the
basal metabolic rate; secondly, obesity and increased leptin levels play an immunomod-
ulatory and pro-inflammatory role that triggers autoimmunity. Furthermore, the excess
weight alone can elevate TSH levels even in the absence of autoimmunity markers, increas-
ing the controversy regarding the cause–effect role of each player [36–38]. Jonklaas et al.
showed that the health benefits from the treatment of hypothyroidism could include a more
favorable lipid profile, decreased progression of coronary artery disease, improved cardiac
function, normalized metabolism and weight homeostasis, normalized reproductive func-
tion, and improved memory. Compared with untreated patients, patients treated for their
hypothyroidism have been shown to have decreased cardiovascular disease risk [39]. Our
investigation demonstrated that hypothyroid patients maintaining a state of euthyroidism
through replacement therapy can achieve weight, BMI, and cholesterol levels comparable
to those of the non-hypothyroid population. This underscores the importance of close
follow-up for hypothyroid patients, with repeated measurements of thyroid hormones over
time to promptly identify any need for therapy adjustments.
Our investigation also showed statistically significant differences in the triglyceride
and blood glucose levels of children with hypothyroidism under replacement therapy
compared to the control group. These statistically significant differences are, however,
clinically irrelevant. The levels of triglycerides and blood glucose among the groups are all
Children 2025, 12, 272 10 of 12

within values considered normal, so the observed difference still falls within the normal
range. Current evidence indicates an increased risk of type 2 diabetes in individuals with
hypothyroidism and lower fT4 levels within the reference range [40]. The association
between thyroid function and type 2 diabetes has long been hypothesized due to the
effects of thyroid hormones on carbohydrate and lipid metabolism, as well as insulin
secretion [41]. However, De Vries et al. demonstrated that TSH levels within the reference
range are not associated with type 2 diabetes [42]. Therefore, our findings underscore the
importance of establishing and continuously monitoring replacement therapy in patients
with primary hypothyroidism.
Our study has some limitations: it is a single-center retrospective study, and the data
are derived from Caucasian patients only. Therefore, our findings may not be generalizable
to the overall pediatric population. We did not calculate the sample size for statistical
power analysis; therefore, it is possible that our results may not be generalizable to the
broader population; it is possible that a more extensive analysis conducted on a larger
sample with a smaller age difference could yield different results. Despite these limita-
tions, we recruited a significant number of pediatric patients with hypothyroidism, and
our results lay the groundwork for future multicenter trials aimed at investigating the
auxological and metabolic characteristics of children with hypothyroidism undergoing
hormone replacement therapy.

5. Conclusions
In our retrospective analysis, we demonstrated that children with acquired hypothy-
roidism, despite receiving levothyroxine replacement therapy and achieving normal thyroid
function, had significantly lower height z-scores compared to healthy controls. This dif-
ference can be attributed to the impaired growth rate during the pre-diagnosis phase of
hypothyroidism. Although these children maintain a normal growth rate once euthy-
roidism is restored, they do not recover the height deficit incurred during the undiagnosed
period. Furthermore, while these patients displayed elevated blood glucose and triglyc-
eride levels, these values remained within the normal range. Our findings underscore
the crucial importance of the early detection and treatment of hypothyroidism, as the
timely initiation of levothyroxine therapy can help prevent the long-term negative effects
of hypothyroidism on growth and metabolic health in children.

Author Contributions: Conceptualization, E.M. and I.C.; methodology, F.A.; software, E.M.; valida-
tion, C.C., G.S. and D.R.; formal analysis, E.M. and L.C.P.; investigation, G.R.; writing—original draft
preparation, E.M.; writing—review and editing, G.S.; supervision, C.C. and D.R. All authors have
read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: This study was performed in full accordance with the
Declaration of Helsinki; a formal Ethics committee approval was not required because the General
Authorization to Process Personal Data for Scientific Research Purposes (Authorization No. 9/2014)
states that any retrospective archival studies using codes that prevent data being directly traced to
subjects do not need official authorization.

Informed Consent Statement: Patient consent was waived due to is retrospective study.

Data Availability Statement: No new data were created or analyzed in this study; data sharing is not
applicable to this article.

Conflicts of Interest: The authors declare no conflicts of interest.

Children 2025, 12, 272 11 of 12

References
1. Wassner, A.J. Pediatric hypothyroidism: Diagnosis and treatment. Paediatr. Drugs 2017, 19, 291–301. [CrossRef]
2. Armstrong, M.; Asuka, E.; Fingeret, A. Physiology, Thyroid Function; StatPearls: St. Petersburg, FL, USA, 2023.
3. Huang, S. Hypothyroidism. In Pediatric Endocrinology, 5th ed.; Lifshitz, F., Ed.; Informa Healthcare: New York, NY, USA, 2007;
pp. 405–411.
4. Exeterlaboratory. Available online: [Link]/genetics/congenital-hypothyroidism (accessed on 10 January 2024).
5. Menchise, A. WF B. Philadelphia: Wilson disease. In Nelson Textbook of Pediatrics, 20th ed.; Elsevier Inc.: Amsterdam, The
Netherlands, 2016; pp. 1939–1940.
6. Diaz, A.; Lipman Diaz, E.G. Hypothyroidism. Pediatr. Rev. 2014, 35, 336–347. [CrossRef] [PubMed]
7. De Vries, L.; Bulvik, S.; Phillip, M. Chronic autoimmune thyroiditis in children and adolescents: At presentation and during
long-term follow-up. Arch. Dis. Child. 2009, 94, 33–37. [CrossRef] [PubMed]
8. Bhattacharyya, S.S.; Singh, A. Acquired hypothyroidism in children. Indian. J. Pediatr. 2023, 90, 1025–1029. [CrossRef] [PubMed]
9. Sodero, G.; Agresti, P.; Triarico, S.; Romano, A.; Mastrangelo, S.; Attinà, G.; Maurizi, P.; Cipolla, C.; Ruggiero, A. Growth hormone
replacement therapy in pediatric brain tumor survivors. Minerva Pediatr. 2022, 74, 340–348. [CrossRef] [PubMed]
10. Chiesa, A.; de Papendieck, L.G.; Keselman, A.; Heinrich, J.; Bergada, C. Final height in long-term primary hypothyroid children.
J. Pediatr. Endocrinol. Metab. 1998, 11, 51–58. [CrossRef]
11. Saari, A.; Pokka, J.; Mäkitie, O.; Saha, M.T.; Dunkel, L.; Sankilampi, U. Early detection of abnormal growth associated with
juvenile acquired hypothyroidism. J. Clin. Endocrinol. Metab. 2021, 106, 739–748. [CrossRef]
12. Becker, M.; Blankenstein, O.; Lankes, E.; Schnabel, D.; Krude, H. Severe acquired primary hypothyroidism in children and its
influence on growth: A retrospective analysis of 43 cases. Exp. Clin. Endocrinol. Diabetes 2022, 130, 217–222. [CrossRef] [PubMed]
13. Harper, M.E.; Seifert, E.L. Thyroid hormone effects on mitochondrial energetics. Thyroid 2008, 18, 145–156. [CrossRef] [PubMed]
14. Reinehr, T. Obesity and thyroid function. Mol. Cell Endocrinol. 2010, 316, 165–171. [CrossRef]
15. Sanyal, D.; Raychaudhuri, M. Hypothyroidism and obesity: An intriguing link. Indian J. Endocrinol. Metab. 2016, 20, 554–557.
[CrossRef]
16. Pacifico, L.; Anania, C.; Ferraro, F.; Andreoli, G.M.; Chiesa, C. Thyroid function in childhood obesity and metabolic comorbidity.
Clin. Chim. Acta 2012, 413, 396–405. [CrossRef] [PubMed]
17. Sodero, G.; Rigante, D.; Pane, L.C.; Sessa, L.; Quarta, L.; Candelli, M.; Cipolla, C. Cardiometabolic Risk Assessment in a Cohort of
Children and Adolescents Diagnosed with Hyperinsulinemia. Diseases 2024, 12, 119. [CrossRef] [PubMed]
18. Witkowska-S˛edek, E.; Kucharska, A.; Rumińska, M.; Pyrżak, B. Thyroid dysfunction in obese and overweight children. Endokrynol.
Pol. 2017, 68, 54–60. [CrossRef] [PubMed]
19. Rumińska, M.; Witkowska-S˛edek, E.; Majcher, A.; Pyrżak, B. Thyroid function in obese children and adolescents and its association
with anthropometric and metabolic parameters. Adv. Exp. Med. Biol. 2016, 912, 33–41. [PubMed]
20. Staníková, D.; Krajčovičová, L.; Lobotková, D.; Vitariušová, E.; Tichá, L’.; Pribilincová, Z.; Ukropcová, B.; Ukropec, J.; Staník,
J. Thyroid hormone levels and BMI-SDS changes in adolescents with obesity. Front. Endocrinol. 2023, 14, 1304970. [CrossRef]
[PubMed]
21. Bétry, C.; Challan-Belval, M.; Bernard, A.; Charrié, A.; Drai, J.; Laville, M.; Thivolet, C.; Disse, E. Increased TSH in obesity:
Evidence for a BMI-independent association with leptin. Diabetes Metab. 2015, 41, 248–251. [CrossRef] [PubMed]
22. De Pergola, G.; Ciampolillo, A.; Paolotti, S.; Trerotoli, P.; Giorgino, R. Free triiodothyronine and thyroid stimulating hormone are
directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in
overweight and obese women. Clin. Endocrinol. 2007, 67, 265–269. [CrossRef]
23. Reinehr, T.; Isa, A.; de Sousa, G.; Dieffenbach, R.; Andler, W. Thyroid hormones and their relation to weight status. Horm. Res.
2008, 70, 51–57. [CrossRef]
24. Valerio, G.; Maffeis, C.; Saggese, G.; Ambruzzi, M.A.; Balsamo, A.; Bellone, S.; Bergamini, M.; Bernasconi, S.; Bona, G.; Calcaterra,
V.; et al. Diagnosis, treatment and prevention of pediatric obesity: Consensus position statement of the Italian Society for Pediatric
Endocrinology and Diabetology and the Italian Society of Pediatrics. Ital. J. Pediatr. 2018, 44, 88. [CrossRef]
25. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National
Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children
and adolescents: Summary report. Pediatrics 2011, 128 (Suppl. S5), S213–S256. [CrossRef]
26. Kapelari, K.; Kirchlechner, C.; Högler, W.; Schweitzer, K.; Virgolini, I.; Moncayo, R. Pediatric reference intervals for thyroid
hormone levels from birth to adulthood: A retrospective study. BMC Endocr. Disord. 2008, 8, 15. [CrossRef] [PubMed]
27. Tarım, Ö. Thyroid hormones and growth in health and disease. J. Clin. Res. Pediatr. Endocrinol. 2011, 3, 51–55. [CrossRef]
[PubMed]
28. Sodero, G.; Cipolla, C.; Camporesi, A.; Martino, L.; Costa, S.; Cannioto, Z.; Frassanito, P.; Tamburrini, G.; Veredice, C.; Maggio, L.;
et al. Endocrinologic dysfunctions and neuropsychiatric sequelae in pediatric patients with a history of central nervous system
infection (Endless): A prospective monocentric study. Pediatr. Infect. Dis. J. 2024. [CrossRef]
Children 2025, 12, 272 12 of 12

29. Delvecchio, M.; Vigone, M.C.; Wasniewska, M.; Weber, G.; Lapolla, R.; Popolo, P.P.; Tronconi, G.M.; Di Mase, R.; De Luca, F.;
Cavallo, L.; et al. Final height in Italian patients with congenital hypothyroidism detected by neonatal screening: A 20-year
observational study. Ital. J. Pediatr. 2015, 28, 82. [CrossRef]
30. Cipolla, C.; Sodero, G.; Pane, L.C.; Mariani, F.; Di Sarno, L.; Rigante, D.; Candelli, M. Auxological and metabolic parameters
of children undergoing the gonadotropin-releasing hormone stimulation test: Correlations with the final diagnosis of central
precocious puberty in a single-center study. Biomedicines 2023, 11, 1678. [CrossRef] [PubMed]
31. Bain, P.; Toublanc, J.E. Adult height in congenital hypothyroidism: Prognostic factors and the importance of compliance with
treatment. Horm. Res. 2002, 58, 136–142. [CrossRef] [PubMed]
32. Nesi-França, S.; Silveira, R.B.; Ramos, J.C.R.R.; Cardoso-Demartini, A.A.; Cat, M.N.L.; de Carvalho, J.A.R.; Pereira, R.M.; De
Lacerda, L. Pubertal development and adult height in patients with congenital hypothyroidism detected by neonatal screening in
southern Brazil. J. Pediatr. Endocrinol. Metab. 2020, 33, 1449–1455. [CrossRef] [PubMed]
33. Adachi, M.; Asakura, Y.; Tachibana, K. Final height and pubertal growth in Japanese patients with congenital hypothyroidism
detected by neonatal screening. Acta Paediatr. 2003, 92, 698–703. [CrossRef]
34. Rivkees, S.A.; Bode, H.H.; Crawford, J.D. Long-term growth in juvenile acquired hypothyroidism: The failure to achieve normal
adult stature. N. Engl. J. Med. 1988, 318, 599–602. [CrossRef] [PubMed]
35. Vincent, A.; Bouvattier, C.; Teinturier, C.; Rodrigue, D.; Busiah, K.; Olivier-Petit, I.; Bony, H.; Barat, P.; Cammas, B.; Coutant, R.;
et al. Evaluation of catch-up growth in severe pediatric Hashimoto’s hypothyroidism. Arch. Pediatr. 2023, 30, 142–148. [CrossRef]
36. Valea, A.; Carsote, M.; Moldovan, X.; Georgescu, C. Chronic autoimmune thyroiditis and obesity. Arch. Balk. Med. Union. 2018, 53,
64–69.
37. De Rosa, V.; Procaccini, C.; Calì, G.; Pirozzi, G.; Fontana, S.; Zappacosta, S.; La Cava, A.; Matarese, G. A key role of leptin in the
control of regulatory T cell proliferation. Immunity 2007, 26, 241–255. [CrossRef]
38. Marzullo, P.; Minocci, A.; Tagliaferri, M.A.; Guzzaloni, G.; Di Blasio, A.; De Medici, C.; Aimaretti, G.; Liuzzi, A. Investiga-
tions of thyroid hormones and antibodies in obesity: Leptin levels are associated with thyroid autoimmunity independent of
bioanthropometric, hormonal, and weight-related determinants. J. Clin. Endocrinol. Metab. 2010, 95, 3965–3972. [CrossRef]
[PubMed]
39. Jonklaas, J. Optimal thyroid hormone replacement. Endocr. Rev. 2022, 43, 366–404. [CrossRef] [PubMed]
40. Dueñas, O.H.R.; Van der Burgh, A.C.; Ittermann, T.; Ligthart, S.; Ikram, M.A.; Peeters, R.; Chaker, L. Thyroid function and the risk
of prediabetes and type 2 diabetes. J. Clin. Endocrinol. Metab. 2022, 107, 1789–1798. [CrossRef]
41. Hall, J.E. Guyton and Hall Textbook of Medical Physiology, 13th ed.; Elsevier: Amsterdam, The Netherlands, 2015.
42. de Vries, T.I.; on behalf of the SMART study group; Kappelle, L.J.; van der Graaf, Y.; de Valk, H.W.; de Borst, G.J.; Nathoe, H.M.;
Visseren, F.L.J.; Westerink, J. Thyroid-stimulating hormone levels in the normal range and incident type 2 diabetes mellitus. Acta
Diabetol. 2019, 56, 431–440. [CrossRef] [PubMed]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.