Highlights
· Female patients with permanent congenital hypothyroidism (PCH) experienced a later age at menarche delayed treatment in PCH patients was associated with a later age at menarche.
· The age at treatment initiation was identified as the only screening factor influencing the timing of menarche and puberty onset in female PCH patients.
Introduction
Thyroid hormones are required for proper growth and development, as well as mental health [1]. In neonates, lack or abnormal function of thyroid hormones can result in developmental delays if not identified through congenital hypothyroidism (CH) screening and treated with levothyroxine [2,3].
Following the initiation of CH screening in 1970 and its adoption in almost all countries worldwide, several studies evaluated the efficacy of treatment or the impact of age at treatment in the growth and development of CH patients [4-7].
Most studies have reported that early detection and treatment of CH neonates lead to normal growth and development [6]. Longitudinal studies of large samples of CH patients in our region also showed that early initiation of treatment with appropriate levothyroxine doses can result in normal growth in CH patients [8-10].
Although there is a substantial amount of research covering growth in congenital CH patients, findings regarding the effectiveness of treatments on final height (FH) or timing of puberty in CH patients remain controversial [11-14]. Some investigators found no associations of screening and treatment variables with FH or age at menarche [11-13], while identified associations [14-16]. However, improving CH screening programs or management to reduce associated complications is an important and challenging issue for healthcare professionals [17].
Findings from CH screening programs in Iran have indicated a greater prevalence of CH in this region compared to other populations [18]. Furthermore, there appear to be some differences in the etiology of CH, with a predominance of thyroid dyshormonogenesis, distinct from the findings reported in most global studies [19]. In this region of the world, parental consanguinity or the genetic background of the population has been suggested as the main risk factor for CH [19].
Growth parameters, particularly FH and age at menarche, are important in screening and management systems for CH, as well as for identifying associated factors and considering the conflicting findings reported in this field. Based on that, the present study compared the age at menarche and the FH standard deviation score (SDS) between CH patients and healthy female adolescents in Isfahan province of Iran. Additionally, this study sought to determine associations between these growth parameters and CH screening-related variables or demographic factors among patients.
Materials and methods
1. Study design and population
In this cross-sectional study, we included a matched group of female CH patients and healthy adolescent females who recently entered puberty. The study was conducted in the city of Isfahan, Iran in 2022.
In this study, females with permanent CH who were referred to the Isfahan Endocrine and Metabolism Research Center, endocrine clinics of Imam Hossien Children's Hospital, or pediatric endocrinologists of Isfahan City for their annual follow-ups were included.
To select patients, all female patients with permanent CH diagnosed at >6 years of age were assessed for signs of puberty. If the onset of menarche (first menstrual period) had occurred, the related age was recorded. Additionally, information related to growth parameters was evaluated.
Individuals with missing data or lack of cooperation were excluded from this study. In addition, among CH patients, those who did not use medication for >6 months, those with transient CH, those with inappropriate follow-up, those in whom treatment initiation occurred >90 days after birth, and those with chronic disease or genetic syndromes were also excluded from the study.
The healthy population included female schoolchildren selected from different schools in Isfahan City using a random-cluster multistage sampling method, with a probability proportional to their size. This approach was selected to obtain a representative sample of the target population of children and adolescents in the region.
Schoolchildren with known chronic diseases, such as hypertension, heart, kidney, endocrine, or pulmonary diseases; genetic diseases; severe short stature; or use of medications (such as growth hormones) that can affect growth were excluded.
Ages at puberty onset and menarche, heights at puberty onset and menarche, and the FH and its SDS were evaluated and compared in the 2 studied groups.
In CH patients, the associations of screening-related variables with age at menarche and FH were evaluated. These variables comprised age at diagnosis, age at treatment initiation and its classification (<14 days, appropriate; 15–45 days, acceptable; >45 days, delayed), levothyroxine dosage at baseline (10 or 15 μg/kg) (17), etiology of CH (dysgenesis or dyshormonogenesis), quality of treatment (frequency of thyroid-stimulating hormone [TSH] level>10 IU/L during treatment in each year) during the first 3 years of life, and anthropometric data at baseline.
2. Ethics statement
The study protocol was approved by the Ethics Committee of Isfahan Medical University (grant no. 3401312; code of ethics: IR.MUI.MED.REC.1401.278). Written informed consent was obtained from each participant or their parents after describing the aim and methods of the study. The authors had access to information that could identify individual participants during or after data collection.
3. Puberty
Age at puberty onset was defined by Tanner stage II breast development [20]. All participants were clinically examined by expert pediatric endocrinologists (MH and PK) for evaluation of puberty stage.
4. FH and target height assessment
Height was measured using a Seca Technologies (Hamburg, Germany) stadiometer (precision of 0.1 cm), with the child barefoot in light clothing with her head, shoulder blades, buttocks, and heels touching the board and her head in the Frankfurt plane. In this study, the FH was defined as the height when the growth velocity was <2 cm/yr calculated over a minimum of 9 months at a chronological age >16 years or bone age >15 years [21]. Target height (TH) was calculated as (mother's height + father's height)/2 ± 6.5 cm; this formula was devised by Tanner and is known as Tanner TH formula [22].
5. Statistical analysis
Data were analyzed using IBM SPSS Statistics ver. 23.0 (IBM Co., Armonk, NY, USA). The results for birth weight, birth height, height at puberty, height at menarche, and FH were presented as mean (standard deviation [SD]) and z-score with SD (SDS). Continuous and categorical variables are presented as mean±SD and number (%) and were compared in the 2 groups by Student t-test and the chi-square test, respectively. For variables with abnormal distribution, non-parametric tests were used. For correlation analysis, Pearson test was used.
The difference between FH and TH was calculated, and the children were divided into 2 groups of those with FH higher or lower than the TH. The variables related to CH screening were compared between these 2 groups. P<0.05 was considered statistically significant.
Results
In this study, 113 of 207 CH patients and 453 of 598 healthy female adolescents attained their FH. The mean±SD ages of the CH patients and the healthy group were 13.47 (3.20) and 13.82 (1.43) years, respectively (P>0.05) (data not shown).
Based on CH screening results, mean birth weight, birth height, and head circumference of the healthy population were 2,912.74±1,276.09 g, 48.05±15.02 cm, and 35.12±3.47 cm, respectively.
The mean±SD height and height z-scores in CH patients at 3 years of age were 98.8±5.7 cm and 0.82±1.74, respectively. In 5.7% and 14.7%, respectively, the height percentiles were <5% and >95%.
Table 1 presents the characteristics of patients with CH. Treatment was initiated within the first 45 days of life (i.e., appropriate or acceptable age for treatment initiation) in 96% of patients, with only 4% experiencing delayed treatment. The mean age at treatment initiation was 18.90±15.20 days. Parental consanguinity was reported in 38.6% of children with CH, and dyshormonogenesis was identified as the cause in 67% of the cases.
Table 2 summarizes the characteristics of the studied population in the 2 groups (female CH patients and healthy controls), focusing on ages at puberty onset and menarche, heights at puberty onset and menarche, and FH. The mean ages at puberty onset and menarche were significantly higher in CH patients compared to the healthy control group (P<0.05). However, there was no significant difference between the 2 groups in terms of height at puberty onset, height at menarche, or FH (P>0.05).
Fig. 1 presents the z-scores for heights at puberty onset and menarche and the FH in the 2 study groups. There were no significant differences in these values between the groups (P>0.05).
Using Spearman correlation analysis, the association between age at menarche, age at puberty onset, and FH SDS with screening-related variables revealed no significant relationship between CH screening variables and the aforementioned factors (P>0.05). However, a significant association was found between birth weight and FH z-score (r=0.35, P=0.001). Significant associations were also found for height at puberty onset (r=0.69, P<0.001) and height at menarche (r=0.60, P<0.001) with the FH z-score (Table 3).
There was a significant association between age at menarche and age classification at treatment (P=0.04). The mean±SD ages at menarche in CH patients with appropriate, acceptable, and delayed age at treatment initiation, respectively, were 11.91±1.20, 12.34±1.30, and 13.20±1.64 years (P=0.07). Notably, this P-value was marginally significant. Meanwhile, the difference was significant between appropriate and delayed age at treatment initiation based on least significant difference post hoc tests (P<0.05).
The mean±SD TH in CH patients was 159.65±17.36 cm. The difference between FH and TH was not significantly different among CH patients (P=0.83) (data not shown).
Table 4 presents the baseline and screening characteristics of the CH patients who had an FH either above or below their TH. No significant differences were observed between the groups (P>0.05).
Discussion
In this study, we determined the FH SDS and age at menarche in adolescent girls with CH and compared the values with those of an age-matched healthy population. Our results showed that the FH SDS did not differ between groups. The age at menarche was significantly higher in CH patients with delayed age at treatment initiation compared to that in the healthy population. There was no significant association of CH screening and treatment variables with FH SDS and age at menarche.
Growth evaluation is an important issue in patients with CH due to the important role of thyroid hormones in this field. Evidence indicates that the first growth evaluation in CH patients was performed by Dickerman and De Vries [23] in 1997, who evaluated 30 patients with CH and found that only 17 of them had reached their FH.
We also assessed associations between growth parameters and screening-related variables in our CH population [8,9]. Heidari et al. [9] concluded that proper outcomes can be achieved through on-time treatment with an appropriate dose of levothyroxine. Notably, the studied populations in previous studies were all preschool-aged children with CH, while we included older CH patients in our investigation [8,9].
In 2001, Salerno et al. [11] evaluated age at menarche and FH in 45 patients (41 females) with CH. They reported that the menarche age (12.5±1.2 years) and FH of CH patients were similar to those of the healthy population. The studied variables were not associated with the etiology or severity of CH or the age at levothyroxine treatment initiation. Salerno et al. [11] suggested that proper screening and management of CH could lead to normal growth, and it was hypothesized that genetic factors most strongly influence final stature. Our results regarding the lack of association between the etiology of CH and both FH and TH were similar to those in their study.
Bain and Toublanc [14] also reported normal values for FH and age of puberty onset in patients with CH. They showed that younger age at initiation of levothyroxine treatment was associated with greater FH.
Delvecchio et al. [15] in Italy revealed that the mean age at puberty onset was 10.2 years in CH female patients, and that the FH was generally higher than the TH. These authors concluded that height at puberty onset is an important predictive factor for FH in CH patients. In their study, the FH in CH female patients was 161.7±0.9 cm, and its z-score was -0.10. The current study also found a significant association between height at puberty onset and FH.
Adachi et al. [12] in Japan investigated the FH SDS in 27 patients with CH (18 female) and reported an FH SDS of +0.17 (0.99) in the female population. They also showed that the etiology of CH and its severity, as well as levothyroxine dose, were not significantly associated with FH SDS, and that early diagnosis and treatment of patients with CH resulted in normal growth. Our results were similar to theirs.
Similarly, Lee et al. [13] in Korea reported an FH SDS of -0.11±1.09 for female CH patients, independent of CH etiology, initial TSH and T4 values, and age at treatment initiation. They emphasized the importance of early diagnosis and treatment of CH.
In a Brazilian study by Nesi-França et al. [16], the ages of onset of puberty and menarche in female CH patients were 9.7±1.2 and 12.1±1.1 years, respectively. They found that those with higher TSH levels during puberty tended to be older at menarche.
The findings of the current study regarding the similar FHs in the 2 studied groups and similar ages at menarche and puberty onset in CH patients with appropriate and acceptable ages of levothyroxine initiation were consistent with findings of previous reports from different countries. Patients with delayed age at treatment had higher ages at menarche and puberty onset. Considering that the FH was not different in the studied group, and that we found differences in ages at menarche and puberty onset only in those with delayed treatment initiation, in CH patients with appropriate management, height at puberty onset, duration of puberty, and height of parents could be the most important factors for FH prediction.
A recent clinical trial study by Esposito et al. [24] compared 2 doses of levothyroxine administration on the growth parameters in children with CH. However, these investigators showed that levothyroxine dose was not associated with growth parameters in these patients.
Most of the studies reported in this field are cross-sectional and retrospective, with few clinical or cohort studies available.
Our findings are similar to those reported recently by Lee et al. [13] in Korea, who found no significant difference between FH and TG of CH patients. Conversely, previous studies from France and Italy have reported higher FH than TH in CH patients [14,15]. Delvecchio et al. [15] reported that this trend is mainly due to FH increases in the Italian population during the last 2 decades and is not related to CH screening or management strategies. Bain and Toublanc [14] also reported higher FH than TH in CH patients, and they concluded that age at treatment initiation in CH patients is an important factor for TH [14]. However, more studies are needed to determine the key factors related to FH in this group of patients.
Given the high prevalence of CH in Iran [18], we recommend a related cohort study or development of a CH patient registry.
The main limitation of this study was that we did not conduct an assessment of bone age at puberty onset or menarche. The strength of this study is that the mentioned factors were evaluated in our region for the first time. As the CH population in this region has distinct characteristics concerning etiology and high consanguinity, the results of this study will be used as baseline information for future studies.
In conclusion, this study found that, while untreated CH patients had significantly higher ages at menarche compared to the healthy population, the age at menarche in properly managed CH patients was similar to that in the healthy group. However, CH patients who experienced delayed treatment had a higher age at menarche. This suggests that genetic factors and height at the onset of puberty are important factors associated with FH in this population. Additional studies are needed in this group of patients, including evaluation of bone age at puberty onset and of its association with FH.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Full text via PMC
Download Citation
Print
