The Value of Urinary Gonadotropins in the Diagnosis of Central Precocious Puberty: A Meta-Analysis

Review question / Objective: Precocious puberty is defined as the onset of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. It can be differentiated into central precocious puberty (CPP) and peripheral precocious puberty, and it is more common in girls than in boys. CPP may result in a decreased final adult height, an early age at menarche, and psychological and health problems in adulthood. Gonadotropin-releasing hormone (GnRH) GnRH stimulation test has been indispensable in the diagnosis of CPP. GnRH stimulation test is not only invasive, time-consuming and expensive, but also sometimes difficult to have patients cooperate. Nocturnal urinary LH and FSH can represent gonadotropin excretion in children with normal and early puberty. And urinary sample collection and evaluation are more convenient, more acceptable, cheaper, and noninvasive. This meta-analysis aims to assess the value of first-voided urinary luteinizing hormone (LH) and the ratio of urinary luteinizing hormone and follicle-stimulating hormone (FSH) in the diagnosis of female CPP and to compare the accuracy between urinary gonadotropins and serum GnRH-stimulated gonadotropins.

Body image, self-perception and satisfaction among girls with Turner syndrome-A prospective cross-sectional study

Objectives Delayed puberty & short stature in girls with Turner syndrome(TS) can lead to low body image, self-esteem & satisfaction. We aimed to evaluate body image, self-perception, and satisfaction among girls with TS using Multi-Dimensional Body Image Self Relations Questionnaire -Appearance Scale (MBSRQ-AS). Methods Patients with karyotype-proven diagnosis of TS between 15-21 years were included after they achieved final adult height. We used MBSRQ-AS instrument with 5 sub-scales: Appearance Evaluation(AE), Appearance Orientation(AO), Body Areas Satisfaction Scale(BASS), Overweight Preoccupation(OWP) and Self Classified Weight(SCW) sub-scales. Mean scores were compared to available sex matched population norms & compared between different sub-cohorts. Results Of 59 eligible girls, 37 girls agreed to participate with mean age : 17.35 ±1.6 years. Turner girls had significantly lower scores compared to sex-matched population norms in AO [mean(SD): 3.32(0.42) vs 3.91(0.6)]; (p<0.001) and SCW [mean(SD): 3.26(0.71) vs 3.57(0.73); (p=0.01)] sub-scales. In contrast, they had slightly higher scores in BASS [ mean(SD): 3.38(0.74) vs 3.23(0.74); (p=0.23)] & OWP [mean(SD): 3.12(0.39) vs 3.03(0.96); (p=0.21)] sub-scales though not statistically significant. Girls with classic 45 X karyotype and those who were overweight/obese had lower scores in AE & AO sub-scales compared to normal population (p<0.05). Conclusion Compared to sex-matched population norms, Turner girls are not reporting negative effects due to their appearance & report general satisfaction with most areas of their body; however, Turner girls with classic karyotype or who were obese/overweight were generally unhappy with their physical appearance. They also seem to not focus their attention on their appearance.

Final Height in Pubertal Short Stature Boys Treated with GH Combination with Letrozole: A retrospective study

BackgroundThe growth potential of pubertal short stature boys is limited by the effect of estrogen on epiphyseal fusion. This study aims to identify the efficacy and safety of growth hormone (GH) combination with letrozole on final adult height (FAH) in pubertal short stature boys. MethodsThis is a retrospective study. Among pubertal short stature boys who treated with GH and letrozole were be followed up in our hospital, 20 cases reached FAH. ResultsBaseline chronological age were 12.12±1.14yr, bone age were 13.00±0.93yr. The treatment duration was 1.94±0.67yr. The height standard deviation score for bone age was increased from -1.46±0.51 to -0.12±0.57 (p<0.000). The predicted FAH before treatment, predicted FAH after treatment, FAH, and genetic target height were 161.02 ±4.12 cm, 172.11±4.20 cm, 172.67±2.72cm and 167.67±3.56 cm, respectively. There was significant differences between predicted FAH before treatment and after treatment (p<0.000), as well as predicted FAH before treatment and genetic target height (p<0.000).The predicted FAH after treatment was higher than that of genetic target height (p<0.001), as well as FAH and genetic target height (p<0.000). ConclusionsThe GH combination with letrozole can enhance the FAH in pubertal short stature boys. No significant side effects were observed.

Growth-Related Characteristics of Patients <18 Years of Age with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency (21OHD): Real World Evidence from the I-CAH Registry

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a rare, autosomal recessive disease of the adrenal cortex leading to a lack of cortisol production and compensatory ACTH secretion, which drives excess androgen production. The chronic exposure to excess androgen, coupled with supraphysiologic glucocorticoid doses, can lead to advanced skeletal maturation with reduced growth in puberty, premature epiphyseal closure, and shorter final adult height. The I-CAH Registry, launched in 2007, currently has &gt;1500 cases of CAH from 26 countries. Aim of the current study was to identify growth-related characteristics of children and adolescents with 21OHD CAH registered in the I-CAH registry and who were based in Europe. Methods: The I-CAH registry was queried on 8-Oct-2019 using the following criteria: CYP21A enzyme deficiency; European site, male or female, age &lt;18 years; and ≥1 growth-related assessment. Descriptive analyses were conducted using data from all patient visits, with age subgroups defined as follows: 0 to &lt;2 years (0-2yr), 2 to 11 years (2-11yr), and 12 to 17 years (12-17yr). Since I-CAH data are longitudinal, patients who aged during registry enrollment may be included in &gt;1 subgroup. Analyses included standard deviation scores (SDS) for patients’ height for chronological age (CA), weight for CA, and height for bone age (BA) using World Health Organization growth chart data for reference values. Results: Of 232 patients in 10 European countries, 126 (54%) were female and most were from Germany (25%), United Kingdom (23%), Netherlands (14%), and Italy (11%). The 232 patients had a total of 2042 visits, with 44% (900 visits) in the 0-2yr group, 42% (860 visits) in the 2-11yr group, and 14% (282 visits) in the 12-17yr group. No discernible pattern by age group was found for height for CA based on mean/median SDS scores. For weight for CA, mean/median SDS scores showed an increasing trend in older patients: 0-2yr (0.22/-0.06 [896 visits]); 2-11yr (0.47/0.55 [855 visits]); and 12-17yr (0.55/0.66 [278 visits]). Mean/median SDS scores for height for BA decreased with age: 0-2yr (0.31/0.05 [36 visits]); 2-11yr (-0.32/-0.23 [172 visits]); and 12-17yr (-0.49/-0.26 [44 visits]). Paired BA and CA values from 259 patient visits showed a trend towards bone age being greater than CA, starting at approximately 48 months of age and leveling out around 120-130 months. Mean BA was advanced by 9.7 months compared to CA (SD: 21.2 months, 95%; CI: 7.1 to 12.3 months, [p&lt;0.0001]). Conclusions: As previous research has indicated, I-CAH registry data suggest that children and adolescents with classic 21OHD CAH in Europe have advanced BA relative to CA, with height relative to BA tending to decrease with older age. The I-CAH registry offers the opportunity to study a variety of growth determinants and measurements with an option for subgroup analysis.

Hydrocortisone Suspension Provides Similar Growth Outcomes as Hydrocortisone Tablets in Young Children With Congenital Adrenal Hyperplasia: A Cross Sectional Study

Young children with CAH require small doses (0.1–1.25mg) and incremental adjustments of hydrocortisone (HC) to control excess androgen production and avoid the negative effects of overtreatment. A recent 6 hour pharmacokinetic/pharmacodynamic study reported that alcohol-free HC suspension provides similar cortisol exposure to tablets (1), but more data is needed to assess its clinical efficacy. We performed a chart review to determine the effect of the alcohol-free HC suspension compared to tablets on height, weight, BMI, bone age z-scores and corrected height z-scores to target height z-scores in children aged 2 yrs and 4 yrs in a cohort with classic CAH. Independent 2-sample t-tests examined cumulative and average HC dose at 2 and 4 yrs. Triple logistic modeling of longitudinal heights were used to calculate predicted near-adult height. Adjusted linear regression models assessed the effect of HC suspension compared to tablets on final adult height. Charts of 130 children (70 females, 100 salt wasting and 30 simple virilizing) were reviewed. At 2 yrs, 97 were treated with tablets and 33 with suspension (17 previously switched from tablets). At 4 yrs, 89 were treated with tablets and 41 with suspension (25 switched). No significant differences in height or BMI z-scores at both 2 and 4 yrs, before or after adjusting for age at diagnosis and sex were found. Bone age z-scores averaged 7.2 SDs lower for patients treated with HC suspension only compared to patients on HC tablets at age 4 (p&lt;0.001), and 5.93 SDs lower for patients switched from tablets to suspension compared to tablets (p&lt;0.001). The suspension group received 16% lower (p=0.055) and 25% lower (p=0.002) cumulative HC doses by the ages of 2 yrs and 4 yrs respectively. Average daily HC dose was lower by 3.44 and by 4.46 mg/m2/d over the first 2 and 4 yrs of life respectively. No significant differences were found between patients treated with tablets and suspension in the predicted final adult height, its z-score or its corrected z-score to target height after adjusting for age at diagnosis, sex and diagnosis. Our data indicates that treatment with alcohol-free HC suspension decreased androgen exposure as shown by lower bone age z-scores, generated no significant differences in SDS in observed height, BMI or predicted near-adult height, and allowed for lower average and cumulative daily HC dose compared to HC tablets in children with CAH. Reference: (1) Sarafoglou et al., J Clin Pharmacol.2015;55(4):452–7.

Anastrozole Improves Final Adult Height in Severe Hypothyroidism With Rapid Pubertal Progression

Severe prolonged hypothyroidism due to Hashimoto thyroiditis may lead to rapid pubertal progression and compromised adult height after initiation of levothyroxine (LT4) therapy. There are no reports of aromatase inhibitor use to augment height in these patients. We describe a patient with severe hypothyroidism and growth failure who experienced rapid pubertal and bone age maturation on initiation of LT4 therapy. Anastrozole was added after 2 years to delay epiphyseal fusion. A boy aged 12 years and 1 month presented to the endocrine clinic with short stature and a markedly delayed bone age of 6 years. Brain magnetic resonance imaging showed a 1.5 × 1.0 × 1.2-cm enlarged lobular anterior pituitary. On examination, his height was –3.5 SD score (SDS) and weight was –2.87 SDS. Laboratory studies showed elevated thyrotropin (TSH) 850.6 μIU/mL, low free thyroxine 0.25 ng/dL, and elevated antithyroid antibodies. LT4 was initiated with normalization of TSH after 6 months. After 2 years of treatment he demonstrated catch-up growth with rapid bone age maturation, and his predicted adult height was compromised at 164.6 cm vs a midparental target height of 175.4 cm. Anastrozole 1 mg once daily was initiated. After 1.5 years of anastrozole treatment, the rate of his bone age advancement had slowed and his linear growth remained robust. The patient’s near-final height (167 cm) was 2.4 cm taller than his height prediction prior to starting anastrozole. Anastrozole slowed the rate of bone age advancement in a patient with severe hypothyroidism and rapidly progressive puberty during treatment with LT4, leading to improvement in near-final height.

Long-term outcomes after gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty

Objective Gonadotropin-releasing hormone agonist (GnRHa) treatment improves the potential for gaining height in patients with central precocious puberty (CPP). However, most studies have focused on girls because CPP in boys is relatively rare. Therefore, we aimed to determine the effect of GnRHa treatment on auxological outcomes in boys with CPP. Methods Eighty-five boys with CPP were treated with leuprolide or triptorelin acetate 3.75 mg over 2 years. Anthropometry, bone age, sexual maturity rating, and predicted adult height (PAH) were assessed every 6 months. Furthermore, 20 boys were followed up after treatment discontinuation until achievement of the final adult height (FAH). Results The mean chronological age (CA) and bone age (BA) of the patients with CPP at treatment initiation were 9.5 ± 0.5 years and 11.7 ± 0.9 years, respectively. The mean duration of treatment was 2.87 ± 0.63 years. The PAH at treatment initiation was 172.1 cm (-0.23 ± 1.05 PAH standard deviation score). The PAH at treatment discontinuation (176.2 ± 6.6 cm) was significantly higher than the pretreatment PAH. In addition, the mean final adult height in the 20 boys who were followed up after discontinuation of treatment was 173.4 ± 5.8 cm, which was significantly higher than the initial PAH (170.1 ± 4.5 cm; p = 0.006). In multivariate analysis, the height gain (the difference between the FAH and PAH at treatment initiation) significantly correlated with the target height. Conclusion Long-term GnRHa treatment significantly improved the growth potential and FAH in boys with CPP.