Association between growth hormone and psychological issues in children with short stature

doi:10.21203/rs.3.rs-1618650/v1

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Research Article

Association between growth hormone and psychological issues in children with short stature

https://doi.org/10.21203/rs.3.rs-1618650/v1

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Purpose

The use of growth hormone in children with idiopathic short stature is still controversial. We aimed to assess the benefits and downsides of growth hormone in these children at a psychological level.

Methods

The children and adolescents with short stature were recruited from the Second Affiliated Hospital of Wenzhou Medical University. They were divided into two groups: the growth hormone deficit group(GHD-G), and the idiopathic short stature group(ISS-G). The Symptom Checklist-90 scale (SCL-90) was used to evaluate the psychological situation.

Results

The results showed that the average score of GHD-G was lower than that of ISS-G, but there was no significant difference (P > 0.05). Linear regression analysis showed that the higher the growth hormone stimulation peak(GHSP), the higher the score of the SCL-90(β = 0.027, 95%CI = 0.007 to 0.047, P value = 0.00962). The results didn’t change after adjusting the factors like age, sex, and laboratory testing( β = 0.023, 95%CI = 0.003 to 0.043, P value = 0.02652). Further, when LH was more than 0.2U/L, the score of the SCL increased as the GHSP increased (β = 0.0566,95%CI = 0.0295 to 0.0837, P value = 0.0001); But when LH was less than 0.2U/L, there was not a clear relationship has been found(β=-0.0022,95%CI=-0.0268 to 0.0225, P value = 0.8631).

Conclusions

There is no evident detrimental effect of growth hormone deficit on mental health in children with short stature. Instead, increasing GHSP may hurt mental health, particularly in children before puberty. Children with idiopathic short stature who have limited height improvement following growth hormone treatment should carefully consider whether to continue using the hormone.

growth hormone

short stature

mental health

pediatrics

Children and adolescents with short stature have been found to have lower levels of life satisfaction than their peers¹. Many individuals with short stature have psychological issues, such as depression and anxiety^2–4. Chinese parents, like those in other developed Asian countries, have begun to pay attention to height disparities among their children in recent years. The psychological problems of short stature children are also garnering more and more attention.

Growth hormone is thought to play an important role in height growth in children. For over half a century, recombinant human growth hormone (rhGH) has been used to treat people of low stature⁵. The natural growth hormone(GH) is a 191-amino-acid peptide hormone secreted by the anterior pituitary gland's somatotrophic cells⁶ GH receptors are found in peripheral tissues as well as the central nervous system, especially in the hippocampus and peri-hippocampal areas of the brain. They have a role in the regulation of declarative memory and structures, like the prefrontal cortex and the amygdala, that process social perception and social cognition⁷. GH deficiency is predicted to harm central functions related to emotion and cognition⁸. These effects can be reversed by recombinant human growth hormone(rhGH) replacement therapy⁹. But other studies have shown that people who are deficient in GH have no significant psychological improvement after using rh-GH^10–12. Interestingly, in the study of acromegaly patients, it was found that they are often accompanied by emotional problems and psychological distress¹³, which may be related to high growth hormone levels.

In general, rhGH is safe and well-tolerated for related indications¹⁴. However, the benefit of rhGH in children with idiopathic short stature is still controversial. Another controversial and prominent problem is the harm caused by the abuse of growth hormones. Thousands of youngsters of normal height in China utilize growth hormones to achieve higher heights. And many adolescents with idiopathic short stature, who have not reacted adequately to growth hormone treatment continue to use it. It is still debatable whether the supraphysiological growth hormone level induced by growth hormone usage is detrimental. Although some research showed rhGH improves psychological health in ISS patients, it is still difficult to distinguish the effects of GH therapy from those of other variables¹⁵. There is very little research on psychological functioning in children on rhGH therapy. It needs to be more investigated whether these populations are susceptible to psychological issues such as depression and anxiety symptoms.

Children with short stature range from growth hormone insufficiency to normal. It provides a clinical model to examine the relationship between growth hormones and psychological health problems. To deal with this problem, we are carrying out the following research.

The participants for the research were recruited from the Department of Pediatric Endocrinology, Second Affiliated Hospital of Wenzhou Medical University. The research participants were chosen based on the following criteria: Age between 8 and 13 years, conform to the international diagnostic and classification of short stature, have basic reading comprehension abilities, did not receive growth hormone therapy. and can complete the SCL-90 scale evaluation independently. Exclusion criteria: small for gestational age, have systemic, endocrine, nutritional, or chromosomal abnormalities.

We obtained demographic and clinical information, including gender, age, height, weight, and the characteristics of parents (e.g., age at delivery, height).

A growth hormone stimulation test was performed in fasting children in the morning with clonidine and arginine. Growth hormone was measured at 0, 30, 60, 90, and 120 minutes after injections or oral administration. Subject to our entry criteria, growth hormone deficiency (GHD) was defined as the stimulation peak(GHSP) value of ༜10 µg/L.^{5, 16}Other participants met the definition of idiopathic dwarfism and were diagnosed with idiopathic dwarfism^{17, 18}. And their GHSP value of ༞10µg/L. Complete the following items before the growth hormone stimulation test: Sex hormone levels, homocysteine(HCY), IGF-1, IGFBP-3, and Thyroid hormones.

The Symptom Checklist-90 (SCL-90) is a multidimensional self-report instrument that is used to test for a variety of psychological issues and psychological symptoms¹⁹. The Chinese versions of the SCL-90 were used to measure psychological symptoms. It was tested and proved to have good reliability and validity. The SCL-90 consists of 90 items that are assessed on a 5-point scale from 0 (no problem) to 4 (a serious problem). Background characteristics such as gender, age, education level, or societal expectations have little impact on scores.¹⁰. Its’ 90 items cover nine areas: somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism.

This is an observational study. The Ethics Committee of The Second Affiliated Hospital of Wenzhou Medical University has confirmed that no ethical approval is required.

All of the analyses were performed with the IBM SPSS Statistics version 22, the statistical software packages R(http://www.R-project.org.The R Foundation)and EmpowerStats(http://wwww.empowerstats.com,X&Y Solutions, Inc., Boston, MA). P values of < 0.05 (both sides) were considered statistically significant. Descriptive statistics such as frequency, mean (M), median (Me), and standard deviation (SD) were used to describe the basic features of the data in the study. Parameters between the growth hormone deficiency group(GHD-G) and idiopathic short stature(ISS-G) were compared using the Kruskal-Wallis rank-sum test or Independent samples t-test. Categorical variables were compared by the chi-square test or the Fisher exact test.

Linear regression models were used to determine the relationship between GHSP and the SCL-90 subscale scores. All variables that were statistically significantly different on univariate analysis, as were clinically meaningful, were considered for inclusion in multivariable models. Model 1 was adjusted by age, gender, parental age at delivery, and parental height; In model 2, we additionally adjusted for the corresponding biological assessment including serums of adreno-cortico-tropic-hormone(ACTH), Follicle-stimulating hormone(FSH), estradiol(E2), luteinizing hormone(LH), prolactin(PRL), Thyroid-stimulating Hormone(TSH), free thyroxine(FT4), free triiodothyronine(FT3), testosterone(TESTO), vitamin D, time to complete the scale(Time). We also explore the interaction between the GHSP and laboratory indices.

A total of 78 children were included in this study and no data loss. The research included 50 men(64%) and 28 women(36%). The average age of the participants was 10.3 ± 1.36 years old. 3.19 ± 4.86 kg was the average birth weight. Their father’s average height is 166.8 ± 5.2cm and their mother’s average height is 155.5 ± 4.6cm. The height standard deviation score of the parents is approximate − 1SD(166.6cm for Chinese men,155.2cm for Chinese females). At the time of children’s birth, the average age of their father was 28.9 ± 4.67 years old and their mother 26.7 ± 4.62. The children that met the criteria were grouped according to the guideline¹⁶. The GHSP was less than 10 µg/L in 22 children(28.2%), greater than 10 µg/L in 56 children(71.8%).

Figure.1 depicts a percentage stacking graph of symptom severity shown by the SCL-90 subscales for all study participants. All the children had no serious psychological symptoms. The ISS-G included all individuals with moderate or higher anomalies. The most frequent psychological disorders are obsession-compulsion and anxiety.

Comparison of GHD-G and ISS-G

Table 1 illustrates the demographic and clinical features of each group. In terms of age, gender, birth weight, height, parental height, parental age at child's birth, IGF-1, IGFBP-3, HCY, vitamin D, pituitary hormone, thyroid hormones, and Time, there was no significant difference between the two groups. But GHD-G has a lower average IGF-1 and IGFBP-3 than ISS-G.

Table 1

Characteristics of participants
GHGROUP	GHD-G	ISS-G	P-value*
Cases	22	56
AGE, year	10.24 ± 1.29	10.35 ± 1.401	0.76
Man	16 (72.73%)	34 (60.71%)	0.32
BW,kg	3.27 ± 0.49	3.17 ± 0.49	0.42
Mother Height(MH),cm	155.58 ± 5.57	155.48 ± 4.23	0.94
Height, cm	127.10 ± 8.10	128.16 ± 7.41	0.58
Weight, kg	27.90 ± 5.42	25.22 ± 4.17	0.02
Father Height(FH),cm	166.32 ± 4.97	167.04 ± 5.30	0.59
Mather age at child's birth(MA)*,year	26.59 ± 4.53	26.79 ± 4.69	0.87
Father age at child's birth(FA)*,year	29.50 ± 5.30	28.71 ± 4.44	0.51
IGF-1, ng/ml	126.98 ± 48.95	137.06 ± 60.11	0.49
IGFBP-3, µg/ml	2.83 ± 0.80	2.93 ± 0.81	0.64
ACTH, pg/ml	22.64 ± 17.28	21.10 ± 13.74	0.67
FSH, IU/L	5.72 ± 16.03	2.79 ± 1.79	0.6
PRL,ng/ml	6.77 ± 5.44	7.10 ± 3.56	0.19
TSH,µIU/ml	2.36 ± 1.09	2.58 ± 3.31	0.51
FT4,ng/dl	1.26 ± 0.11	1.25 ± 0.15	0.85
FT3,pg/ml	4.08 ± 0.40	4.13 ± 0.43	0.69
TIME, seconds	384.36 ± 214.67	387.88 ± 199.22	0.95
HCY, µmol/l	7.17 ± 2.18	6.75 ± 2.02	0.42
Vitamin D, ng/ml	23.61 ± 7.60	20.36 ± 7.66	0.1
E2,pg/ml	12.71 ± 12.87	20.43 ± 26.35	0.16
TESTO, ng/ml	0.16 ± 0.31	0.18 ± 0.17	0.09
LH > 0.2IU/L	10 (45.46%)	25 (44.64%)	0.95
Values in the table are mean + SD or n (%). P-value*: The Kruskal–Wallis test was used to compare continuous variables. When expected cell values were less than 10, we used the Fisher exact probability test.

Table.2 Differences in areas of SCL-90 between GHD-G and ISS-G.
Characteristics	GHD-G(22)	ISS-G(56)	P-VALUE
The total score	0.45 ± 0.36	0.57 ± 0.64	0.4
Somatization	0.29 ± 0.42	0.46 ± 0.71	0.31
Obsession-compulsion	0.65 ± 0.47	0.77 ± 0.68	0.45
Interpersonal sensitivity	0.47 ± 0.42	0.55 ± 0.63	0.43
Depression	0.41 ± 0.45	0.44 ± 0.59	0.88
Anxiety	0.49 ± 0.5	0.6 ± 0.72	0.49
Hostility	0.53 ± 0.38	0.67 ± 0.79	0.44
Phobic anxiety	0.4 ± 0.43	0.58 ± 0.81	0.32
Paranoid ideation	0.4 ± 0.41	0.54 ± 0.75	0.42
Psychoticism	0.3 ± 0.32	0.45 ± 0.69	0.34

Table.3 Independent effect factor of the SCL-90 score
	Statistics, mean + SD or n (%).	The total score, β (95%CI) Pvalue
AGE, year	10.32 ± 1.36	0.050 (-0.045, 0.144) 0.3
BW,kg	3.20 ± 0.49	-0.166 (-0.431, 0.098) 0.22
Man	50 (64.10%)	-0.267 (-0.528, -0.006) 0.05
Mother Height(MH),cm	155.51 ± 4.61	0.010 (-0.018, 0.038) 0.47
Father Height(FH),cm	166.84 ± 5.19	-0.009 (-0.033, 0.016) 0.5
Mather age at child's birth(MA)*,year	26.73 ± 4.62	-0.022 (-0.050, 0.005) 0.12
Father age at child's birth(FA)*,year	28.94 ± 4.68	-0.025 (-0.052, 0.002) 0.08
IGF-1, ng/ml	134.21 ± 57.05	-0.000 (-0.003, 0.002) 0.71
IGFBP-3, µg/ml	2.90 ± 0.81	0.025 (-0.135, 0.186) 0.76
ACTH, pg/ml	21.54 ± 14.73	0.005 (-0.003, 0.014) 0.24
FSH, IU/L	3.62 ± 8.61	-0.006 (-0.021, 0.009) 0.44
PRL,ng/ml	7.00 ± 4.14	-0.014 (-0.045, 0.017) 0.37
TSH,µIU/ml	2.52 ± 2.85	-0.001 (-0.046, 0.044) 0.96
FT4,ng/dl	1.26 ± 0.14	0.176 (-0.772, 1.125) 0.72
FT3,pg/ml	4.11 ± 0.42	0.019 (-0.290, 0.329) 0.9
TIME,seconds	386.89 ± 202.28	0.001 (0.000, 0.002) 0.001
HCY, µmol/l	6.87 ± 2.06	0.060 (-0.001, 0.121) 0.06
Vitamin D, ng/ml	21.27 ± 7.73	0.013 (-0.003, 0.030) 0.11
E2, pg/ml	18.25 ± 23.53	0.002 (-0.003, 0.008) 0.45
TESTO, ng/ml	0.17 ± 0.22	-0.249 (-0.842, 0.343) 0.41
GHSP	14.01 ± 6.19	0.027 (0.007, 0.047) 0.01
LH > 0.2IU/L	35 (44.87%)	-0.356 (-0.601, -0.110) 0.006

Table.4 Independent effect of the GHSP in children
Outcome	GHSP*	Adjust I*	Adjust II*
The total score	0.027 (0.007, 0.047) 0.01	0.029 (0.009, 0.048) 0.005	0.023 (0.003, 0.043) 0.03
Somatization	0.033 (0.010, 0.055) 0.005	0.035 (0.013, 0.057) 0.003	0.029 (0.006, 0.052) 0.02
Obsession-compulsion	0.025 (0.003, 0.047) 0.03	0.027 (0.005, 0.048) 0.02	0.017 (-0.004, 0.039) 0.11
Interpersonal sensitivity	0.026 (0.006, 0.046) 0.01	0.027 (0.007, 0.046) 0.01	0.021 (0.001, 0.041) 0.05
Depression	0.014 (-0.006, 0.034) 0.17	0.016 (-0.004, 0.035) 0.12	0.010 (-0.010, 0.031) 0.34
Anxiety	0.027 (0.004, 0.051) 0.02	0.029 (0.006, 0.052) 0.01	0.021 (-0.003, 0.045) 0.1
Hostility	0.037 (0.013, 0.060) 0.004	0.040 (0.017, 0.063) 0.001	0.032 (0.008, 0.056) 0.01
Phobic anxiety	0.030 (0.005, 0.056) 0.02	0.031 (0.006, 0.057) 0.02	0.024 (-0.001, 0.049) 0.07
Paranoid ideation	0.029 (0.006, 0.053) 0.02	0.032 (0.009, 0.055) 0.009	0.031 (0.005, 0.056) 0.02
Psychoticism	0.030 (0.009, 0.051) 0.007	0.032 (0.011, 0.053) 0.004	0.030 (0.009, 0.051) 0.007
*β (95%CI) P-value
Exposure: GHSP
Adjust I model adjust for Age, Sex, MH, FH, MA, FA, TIME
Adjust II model adjust for: ACTH, LH, FSH, TSH, PRL, FT4, FT3, HCY, Vitamin D, E2, TESTO, Age, Sex, MH, FH, MA, FA, TIME

The GHD-G subscale scores were lower than the ISS-G subscale scores (Table 2). However, no statistically significant difference could be seen between the two groups.

Risk factor for the SCL-90 score

In univariate analysis, male, younger parental age at child's birth, longer Time, higher HCY, higher vitamin D, higher GHSP, LH > 0.2IU/L were associated with higher SCL-90 scores; other covariates were not statistically associated with increased SCL-90 scores (Table 3).

Table 4 shows correlations between the GHSP and the SCL-90 scores. Initially, we used the GHSP as the independent variable. In adjust model 1, we adjusted age, sex, MH, FH, MA, and FA. We found that except depression subscale, other subscale scores were positively correlated with GHSP (α ༜ 0.05).In adjust model 2, we additionally adjusted for ACTH, LH, FSH, TSH, PRL, FT4, FT3, HCY, E2; TESTO, vitamin D.In all models, the total score was still significantly positively associated with the GHSP ( p < 0.05 ). We found that additional adjustment for laboratory indices only minimally changed the observed association, the regression coefficient was still statistically significant, except for anxiety, phobic anxiety, and paranoid ideation.

Interaction analysis

Further analysis found that there was an interaction between the GHSP and LH (P for interaction was 0.0018): When LH was more than 0.2U/L, the score of the SCL increased as the GHSP increased(β = 0.0566,95%CI = 0.0295 to 0.0837, P value = 0.0001); but when LH was less than 0.2U/L, there was a negative correlation between the SCL score and the GHSP(β=-0.0022,95%CI=-0.0268 to 0.0225, P value = 0.8631).

The GHD-G and the ISS-G have no significant differences in psychological health. Our results showed that the SCL-90 mean score in the GHD-G was substantially higher than the ISS-G. According to regression analysis, there was a negative association between the GHSP and the SCL-90 total score (p < 0.01). there is a possible explanation. High growth hormone stimulation peak is linked to poor psychological health in youngsters. However, a cut-off value of 10ng/ml may not be a good cut-off value to identify patients at risk of developing this complication. More research could uncover a useful cut-off value for distinguishing the two²⁰.

Growth hormone is a polypeptide hormone that is essential for the development of the nervous system. It plays an important role in fundamental brain developmental processes such as neuronal cell proliferation, migration, and differentiation⁷. Growth hormone regulates the activity level of numerous brain areas, which might impact the control of psychological feelings.

Excess growth hormone (GH) secretion is a laboratory performance of acromegaly, which can have negative medical and psychological consequences. Prefrontal and middle temporal cortices are less activated in these patients, according to studies²¹. Increased global, left, and right hippocampal grey matter and white matter were seen on MRI. And the hippocampus is critical for fear conditioning's protective function^{9, 22}. It's also found in brain networks that influence emotional behavior⁹. Abnormality in the hippocampus may lead to the exaggerated conditioned fear response²³. Controlling GH excess appears to have a positive impact on the psychological situation²⁴.In other neurological functions, animal studies have shown that inhibiting GH action improves spatial learning and memory²⁵.

Some researchers argue that growth hormone therapy has little impact in terms of boosting psychological and social well-being or life quality^{11, 26–28}. Others, however, disagree with this viewpoint. Some researchers discovered that the homovanilic acid and free T4 concentrations in the cerebral fluid of patients treated with growth hormone declined, while the concentration of aspartic acid increased, comparable to depressed people following successful treatmentt^{9, 29–31}. In addition, recombinant human growth hormone (GH) treatment improved physical and psychological health in patients with idiopathic short stature (ISS). As a result, there was a high level of support among academics for the use of rhGH in children with short stature. Interestingly, our research agrees with the first view, there was no significant difference in psychological health between GH-deficient and non-deficient patients. Even higher growth hormones may aggravate the psychological situation. We did not uncover any individuals in our research with serious psychological disorders since children with idiopathic short stature do not have higher increased growth hormones. This needs to be confirmed by further follow-up studies. Fortunately, investigations in acromegaly patients provide a foundation for our follow-up hypothesis.

Each study subject has served as his or her own control in prior investigations on the relationship between growth hormones and psychology. Growth hormone is beneficial to psychological, behavioral, and cognitive development, according to their findings. However, it does not address the issue of height influence. The improvement of these psychological and psychosomatic symptoms during GH treatment might thus be linked to the secondary effects of GH substitution-induced physical improvements³². Height gain may obscure the unfavorable effect⁵. Higher levels of growth hormone were likewise shown to have no positive impact on psychological health in our research.

+Children of different ages have special developmental, physiological, and psychological distinctions from adults. When doing age and development-related research, this must be considered. The 0.2 IU/L basal LH cut-off was found to be a good cut-off for detecting the start of puberty³³. Further analysis revealed an interaction between LH and the GHSP: when LH was greater than 0.2 IU/L, there was a positive relationship between the GHSP and the SCL-90 scores; however, when LH was less than 0.2 IU/L, increased growth hormone had no negative consequences. This is in line with earlier research on preadolescents²⁷. we guess the changes in hormone levels during puberty enhance children's psychological sensitivity. However, the detailed mechanism remains to be further explored.

In our research, we discovered that the average height of children’s parents was a Chinese adult height standard deviation score of -1 SD. This means that children with parents who are under this height are more prone to develop height issues. It indicates which parents should monitor their child's height development during childhood. But larger randomized investigations are needed for confirming the conclusions of this study,

However, there are several limitations to this research. The study's relatively small size is one of its shortcomings. Although the SCL-90 mean scores differed between the GHD-G and the ISS-G, there was no statistically significant difference. An inadequate sample size might lead to erroneous conclusions and outcomes. To corroborate the results, more research might be done to extend the sample size and the category.

In conclusion, short stature can have negative psychological effects. Increased growth hormone levels do not help psychological health, and may rather damage it, according to our findings. Adolescent children will be more affected by this situation. Children with short stature can benefit from growth hormone therapy to increase their height. Height gain may boost a patient's self-esteem and mood. The potential benefits of increased height may outweigh the risks of increased growth hormone. However, in children who are not responding to treatment, the use of growth hormone may still be inappropriate. Its therapeutic value as well as the psychological issues that come from it need to be carefully assessed. For patients with minor or no height problems, Hippocrates' ethical standards, especially non-harm, should be respected.

Founding:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Zhichao Zheng, Xiaoou Shan, and Huiping Wu. The first draft of the manuscript was written by Zhichao Zheng and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval

This is an observational study. The Ethics Committee of The Second Affiliated Hospital of Wenzhou Medical University has confirmed that no ethical approval is required.

Consent to participate

Written informed consent was obtained from the parents

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Association between growth hormone and psychological issues in children with short stature

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