Central Precocious Puberty In Children Research Articles

Hypothalamic Hamartoma Cause of Precocious Puberty: About Two Cases

Hypothalamic hamartoma is a rare cause of central precocious puberty in children. The use of neuroimaging in central precocious puberty in girls is essential to detect an organic cause, however exceptional, namely hypothalamic hamartoma, Although the GnRH analogs are known to be effective therapy, there are few studies of the recovery of the pituitary-gonadal axis following long-term treatment. We report 2 cases of precocious puberty revealing the presence of a hypothalamic hamartoma, collated in the endocrinology-pediatrics department at the RABAT children's hospital, to obtain a better understanding of the clinical aspects, pathogenesis, and treatment of this entity.

7269 Interim Analysis of Gonadotropin-Releasing Hormone Agonist (GnRHa) Treatment in Children with Central Precocious Puberty: Focus on FMV Urinary LH Levels and Clinical Outcomes

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) refers to early activation of the hypothalamic–pituitary–gonadal (HPG) axis in children. There is an urgent need to understand the treatment pattern and clinical outcomes among children suffering from CPP. Studies have reported that first morning voided (FMV) urinary Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) have substantial association with CPP tested in GnRH stimulation test and can be useful in diagnosis and management of CPP in children. Gonadotropin-releasing hormone agonists (GnRHa) such as Leuprolide acetate (LA) are the recommended treatment for children suffering from CPP. The current study aimed to provide the information on level of LH and FSH in FMV urine when CPP diagnosis at baseline and the present results may also revealed trend of FMV-LH and FMV-FSH change during LA intervention in children with CPP. Here we present interim results from this study. Methods: This is an open-label, multicentre, single arm, prospective study that enrolled 31 subjects with CPP. Individuals were administered LA depot 11.25 mg, subcutaneously every 12 weeks. The study comprises a screening period; a 6-month treatment period: 24 weeks; and a post-treatment follow-up period: 12 weeks. The FMV urinary LH and FSH were diagnosed by Clopper-Pearson method with a 95% confidence interval. Results: Due to the data collection time point for the interim analysis, only 8 female subjects reached the 12-week visit time point and had a 12-week visit for FMV urinary Gn testing. Therefore, for this interim analysis, only FMV Gn decline at week 12 of the 8 subjects who had a 12-week visit will be presented. At baseline, the mean value of FMV urinary LH and FSH is 0.58 IU/L and 2.27 IU/L respectively. The FMV Gn urinary LH was demonstrated a decrease in 87.5% (95% CI: 47.35,99.68) of the children after LA intervention. Additionally, urinary FSH value of FMV urinary Gn was found to decrease in 75.00% of the children (95% CI: 34.91,96.81) compared to baseline FSH value. Conclusion: The present study reveals a decreasing trend in FMV Gn urinary LH and FSH levels in CPP children treated with LA during interim analysis. LA was shown to be safe and effective in ameliorating the level of LH and FSH in children suffering from CPP. From the study, it can be concluded that urinary LH and FSH may act as a potential biomarker for diagnosis and management of CPP. Presentation: 6/3/2024

Precocious puberty under stressful conditions: new understanding and insights from the lessons learnt from international adoptions and the COVID-19 pandemic.

Neuro-biological variations in the timing of sexual maturation within a species are part of an evolved strategy that depend on internal and external environmental conditions. An increased incidence of central precocious puberty (CPP) has been described in both adopted and "covid-19 pandemic" children. Until recently, it was hypothesised that the triggers for CPP in internationally adopted children were likely to be better nutrition, greater environmental stability, and improved psychological wellbeing. However, following data collected during and after the coronavirus (COVID-19) global pandemic, other possibilities must be considered. In a society with high levels of child wellbeing, the threat to life presented by an unknown and potentially serious disease and the stressful environment created by lockdowns and other public health measures could trigger earlier pubertal maturation as an evolutionary response to favour early reproduction. The main driver for increased rates of precocious and rapidly progressive puberty during the pandemic could have been the environment of "fear and stress" in schools and households. In many children, CPP may have been triggered by the psychological effects of living without normal social contact, using PPE, being near adults concerned about financial and other issues and the fear of getting ill. The features and time of progression of CPP in children during the pandemic are similar to those observed in adopted children. This review considers the mechanisms regulating puberty with a focus on neurobiological and evolutionary mechanisms, and analyses precocious puberty both during the pandemic and in internationally adopted children searching for common yet unconsidered factors in an attempt to identify the factors which may have acted as triggers. In particular, we focus on stress as a potential factor in the early activation of the hypothalamic-pituitary-gonadal axis and its correlation with rapid sexual maturation.

Central precocious puberty in children after COVID-19 outbreak: a single-center retrospective study.

Central precocious puberty (CPP) was an unexplored issue during COVID-19 pandemic and an important disease in the adolescence life. Our aim was to evaluate the incidence of the new cases of central precocious puberty (CPP) during COVID-19 pandemic, comparing these results with the data for the same period over the previous three years. The secondary objective was to analyze the rate of pubertal progression in children during COVID-19 outbreak. We performed a retrospective study of all children presented at our hospital for suspected CPP during COVID-19 outbreak, comparing their clinical and endocrinological data to the same over the previous three years. Secondary, endocrinological data of some patients in follow-up, with at least two visits 6 months apart during the COVID-19 period, are compared to evaluate the rate of pubertal progression. We enrolled 90 suspected enrolled CPP cases, 26 (28.9%) referred to our hospital during the COVID-19 outbreak and 64 (71.1%) in the previous 3 years. During COVID-19 outbreak 12 girls (42.9%) were at stage T3 compared to 14 (23%) of the 3 previous years (p=0.01). New CPP diagnosis were found in 11 (39.3%) children during pandemic, while 15 (24.2%) in the previous 3 years. A accelerated pubertal progression rate was observed in 22/45 (48.9%) patients, with a greater number of children at stages T3 and T4-5. Our data showed a progressive increase of newly diagnosed CPP and a significantly accelerated rate of pubertal progression in children during COVID-19 outbreak. We hypothesize that the increase in the weight and BMI during the lockdown and the psychological effects of the COVID-19 outbreak were involved in triggering and progression of puberty.

Abstract 29: Effect of gonadotropin releasing hormone analog treatment on final adult height in children with congenital adrenal hyperplasia complicated by central precocious puberty

Background: Congenital Adrenal Hyperplasia (CAH) is complicated by central precocious puberty in children which may compromise the final height.Aim: We aim to evaluate the effect of gonadotropin analog (GnRH) therapy on final height in children with CAH.Results: 8 children with CAH with advanced height and bone age and LH, either basal or stimulated, in pubertal range were included in study. GnRH analog 3.75 mg was administered every 4 weeks. Median follow up period was for 2 years. Height age and bone age was noted every 6 months and predicted adult height was calculated at the beginning and end of the treatment using Bayley and Pinneau method. Median growth velocity was 4 cm and 3.75 cm at the end of first and second year. Predicted adult height was increased by 10 cms at the end of 2 years of treatment.Conclusion: GnRH therapy significantly augments linear growth and bone age advancement in children with CAH complicated by central precocious puberty.

Management of Central Precocious Puberty in Children with Hypothalamic Hamartoma.

Hypothalamic hamartoma (HH) is a rare, congenital, and benign lesion of the tuber cinereum, typically presenting with central precocious puberty (CPP), gelastic seizure, and developmental delay. This study aimed to investigate CPP in HH patients and compare clinical features between before and after gonadotropin-releasing hormone (GnRH) agonist treatment. A total of 30 HH patients under 18 years of age who visited Severance Children’s Hospital between January 2005 and May 2020 were retrospectively reviewed. Fourteen patients were male (46.7%) and sixteen (53.3%) were female, with a mean age at diagnosis was4.2 ± 2.9 years. During follow-up, 24 patients (80.0%) were diagnosed with CPP, 15 patients (50.0%) had gelastic seizure, and 13 patients (43.3%) had developmental delay. The gelastic seizure was significantly associated with sessile type HH rather than pedunculated type HH (85.7% vs. 18.8%, p = 0.001). After GnRH agonist treatment, discrepancies between bone age and chronological age decreased (3.3 ± 1.3 years to 2.0 ± 1.7 years, p = 0.002). Additionally, height standard deviation score for bone age was increased, and predicted adult height increased significantly in females, while males showed an increasing trend. Clinical symptoms of HH were closely associated with the location of HH, and GnRH agonist treatment was safe and effective in the management of CPP caused by HH.

Central precocious puberty in spina bifida children: Guidelines for the care of people with spina bifida.

Children with spina bifida are at greater risk of developing central precocious puberty (CPP) compared to others. Therefore, early recognition and timely referral for further evaluation by a pediatric endocrinologist allows appropriate management that reduces the impact of CPP. This article discusses the diagnosis and management of CPP in children with spina bifida. This guideline was developed for SB Transition Healthcare Guidelines from the 2018 Spina Bifida Association’s Fourth Edition of the Guidelines for the Care of People with Spina Bifida.

Meta-Analysis of Paediatric Patients with Central Precocious Puberty Treated with Intramuscular Triptorelin 11.25 mg 3-Month Prolonged-Release Formulation

Background/Aims: A meta-analysis was undertaken to assess the effect of triptorelin 11.25 mg 3-month prolonged-release formulation in central precocious puberty (CPP). Methods: All available clinical studies with triptorelin 11.25 mg were included. The primary outcome was the proportion of children with suppressed luteinising hormone (LH) response (peak LH ≤3 IU/L) to the gonadotrophin-releasing hormone (GnRH) test 3 months after triptorelin 11.25 mg injection. Secondary outcomes included: the proportion with suppressed peak LH response at 6 months and the proportion with suppressed peak follicle-stimulating hormone (FSH) response (≤3 IU/L), suppressed oestradiol (≤20 pmol/L) in girls or suppressed testosterone (≤30 ng/dL) in boys at 3 months. Results: 153 children (13 boys, 140 girls) were included. The proportion with a suppressed peak LH response to the GnRH test was 87.6% (95% CI: 81.3–92.4, p < 0.0001, for a proportion >70%) and 92.8% (95% CI: 87.5–96.4, p < 0.0001, for a proportion >70%) at 3 and 6 months, respectively. FSH peak, oestradiol, and testosterone were suppressed in 86.7% (95% CI: 79.1–92.4), 97.1% (95% CI: 91.6–99.4), and 72.7% (95% CI: 39.0–94.0) of children at 3 months, respectively. Conclusion: Triptorelin 11.25 mg 3-month formulation is efficacious in suppressing LH peak and other gonadal hormones and in slowing the progression of CPP in children.

Clinical effect of recombinant human growth hormone for interventing central precocious puberty in children

Objective To investigate clinical effect of recombinant human growth hormone (rhGH) for interventing central precocious puberty in children, to provide reference for clinical treatment. Methods 80 patients with growth deceleration slows CCP were selected, when height growth rate below 4cm/year, 40 patients on the basis of joint GnRHa used rhGH treatment were selected as the observation group, and the remaining 40 patients refused to use rhGH, continued to use of GnRHa treatment were selected as the control group.After treatment predicted height, height, bone age, growth rate and other indicators were compared. Results In observation group, the actual height Ht, predicted height PAH, the growth rate Gv, serum insulin-like growth factor-1 (IGF-1) after treatment were (144.48±6.59)cm, (154.94±4.52)cm, (4.43±0.64)cm/6months, (132.25±8.84)ng/mL, compared to before treatment, the differences were statistically significant (t=6.548, P<0.01; t=5.734, P<0.01; t=28.869, P<0.01; t=20.65, P<0.01), compared with the control group, the differences were significant (t=3.943, P<0.01; t=4.759, P<0.01; t=28.247, P<0.01; t=20.882, P<0.01), there were no differences in other indices; hormones FSH, LH and other indicators of the two groups before and after treatment, and blood sugar, thyroid indicators showed no abnormality. Conclusion Recombinant human growth hormone in the treatment of central precocious puberty deceleration in children does not increase bone age, which will help improve the growth rate and predicted height, which worthy of clinical application. Key words: Human growth hormone; Gonadotropin-releasing hormone; Child development; Sex characteristics

La plasticité neuro-gliale des réseaux neuroendocrines

We discuss here the secular early onset of puberty in children, the central mechanisms of puberty as well as the clinical aspects of central precocious puberty in children. How to suspect it, how to explore it and how to treat it are the main topics of this article.

Le systeme gnrh : implications dans la puberté précoce de l’enfant

We discuss here the secular early onset of puberty in children, the central mechanisms of puberty as well as the clinical aspects of central precocious puberty in children. How to suspect it, how to explore it and how to treat it are the main topics of this article.

La kisspeptine, un nouvel acteur clé dans le contrôle de la reproduction

We discuss here the secular early onset of puberty in children, the central mechanisms of puberty as well as the clinical aspects of central precocious puberty in children. How to suspect it, how to explore it and how to treat it are the main topics of this article.

A potential mechanism for the sexual dimorphism in the onset of puberty and incidence of idiopathic central precocious puberty in children: sex-specific kisspeptin as an integrator of puberty signals

The major determinants of the variability in pubertal maturation are reported to be genetic and inherited. Nonetheless, nutritional status contributes significantly to this variability. Malnutrition delays puberty whereas obesity has been associated to a rise in Idiopathic Central Precocious Puberty (ICPP) in girls. However, epidemiology data indicate that contribution of obesity to early puberty varies significantly among ethnic groups, and that obesity-independent inheritable genetic factors are the strongest predictors of early puberty in any ethnic group. In fact, two human mutations with confirmed association to ICPP have been identified in children with no history of obesity. These mutations are in kisspeptin and kisspeptin receptor, a ligand/receptor pair with a major role on the onset of puberty and female cyclicity after puberty. Progressive increases in kisspeptin expression in hypothalamic nuclei known to regulate reproductive function has been associated to the onset of puberty, and hypothalamic expression of kisspeptin is reported to be sexually dimorphic in many species, which include humans. The hypothalamus of females is programmed to express significantly higher levels of kisspeptin than their male counterparts. Interestingly, incidence of ICPP and delayed puberty in children is markedly sexually dimorphic, such that ICPP is at least 10-fold more frequent in females, whereas prevalence of delayed puberty is about 5-fold higher in males. These observations are consistent with a possible involvement of sexually dimorphic kisspeptin signaling in the sexual dimorphism of normal puberty and of pubertal disorders in children of all ethnicities. This review discusses the likelihood of such associations, as well as a potential role of kisspeptin as the converging target of environmental, metabolic, and hormonal signals, which would be integrated in order to optimize reproductive function.

Central Precocious Puberty in Children Living in Spain: Incidence, Prevalence, and Influence of Adoption and Immigration

No epidemiological data are available on central precocious puberty (CPP) in the general population or in adopted or immigrant children in Spain. We aimed to study the incidence and prevalence of CPP, assess the risk of developing this disorder among adopted and immigrant children, and analyze the predictive variables of CPP associated with intracranial pathology. An observational study of children diagnosed with CPP in Spain was carried out between January 2008 and January 2010. A computer program was designed to process clinical and biological data and information on 250 patients treated in 34 pediatric endocrinology units throughout the country. Of the patients registered, 226 were girls and 24 were boys. The global incidence rate of CPP was 5.66 cases per million person-years at risk, with an annual incidence ranging between 0.02 and 1.07 new cases per 100,000. The relative risk of CPP in domestic and internationally adopted children compared with those born in Spain was 27.82 (19.99-38.77), whereas the relative risk among immigrants was 1.55 (0.97-2.38). A logistic regression model developed for the study showed that the combined effect of four variables had a significant influence over the presence of organic disease: being male, having been adopted, age at diagnosis, and estimation of adult height. CPP is a rare disease whose risk markedly increases with both national and international adoption but is not influenced by immigration. These results suggest a psychological influence on CPP.

New developments in the use of peptide gonadotropin-releasing hormone antagonists versus agonists

Gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH), and thus controls the hormonal and reproductive functions of the gonads. The blockade of the effects of GnRH may be sought for a variety of reasons; for example, to control premature LH surges and to reduce the cancellation rate with the aim of improving the pregnancy rate per treatment cycle or in the treatment of sex hormone-dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. GnRH analogues are indicated for clinical situations in which the suppression of endogenous gonadotropins (precocious puberty, contraception and controlled ovarian hyperstimulation) or sexual steroids (endometriosis, prostate hyperplasia, cancer and uterine fibroids) is desired. The immediate suppression of the pituitary that is achieved by GnRH antagonists without an initial stimulatory effect is the main advantage of these compounds over the agonists. GnRH antagonists have been developed for clinical use with acceptable pharmacokinetic, safety and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy, but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All of the current indications for GnRH agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence has been in assisted reproduction and prostate cancer.

Gonadotropin-releasing hormone antagonists: impact of IVF practice and potential non-assisted reproductive technology applications.

To provide the clinician with updated knowledge of the most recent findings on the clinical use of gonadotropin-releasing hormone antagonists. Gonadotropin-releasing hormone antagonists, which have recently been introduced in clinical practice, cause an immediate suppression of gonadotropin secretion by competitive blocking of pituitary gonadotropin-releasing hormone receptors. Thus, they are effective in preventing the premature luteinizing hormone surges during ovarian stimulation for in-vitro fertilization and may improve the patient's response to lower doses of gonadotropins. Better patient acceptance, shorter treatment cycles and fewer follicles and oocytes are also reported. Data existing so far concerning the necessity of luteal phase support after the use of gonadotropin-releasing hormone antagonists show that it might not be mandatory when used in clomiphene citrate costimulated cycles or in intrauterine insemination cycles. The use of gonadotropin-releasing hormone antagonists seems to be safe for pregnant women and their offspring. All sex-hormone-dependent disorders, currently treated with gonadotropin-releasing hormone agonists, may in future be indications for a gonadotropin-releasing hormone antagonist, including endometriosis, leiomyoma, and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. The vast majority of the available clinical data up till now, however, are in assisted reproduction and prostate cancer. It is expected that the availability of gonadotropin-releasing hormone antagonist will lead to the use of 'softer' ovarian stimulation protocols, which will be shorter, cheaper and safer compared with the conventional protocols.

Determination of ABT-861 by High-Performance Liquid Chromatography and a Model for Ion-Pair Formation with Trifluoroacetic Acid

ABT-861 is a gonadotropin releasing hormone (GnRH) antagonist candidate drug synthesized at Abbott Laboratories for use in medical conditions responsive to hormonal manipulation (e.g., prostate cancer in elderly males, endometriosis in females, and central precocious puberty in children). A high-performan ce liquid chromatography (HPLC) method employing gradient elution with ultraviolet (UV) detection is developed for the assay of ABT-861 and determination of impurities in the bulk powder and injectable formulations. The chromatographic conditions employed in this work include the use of a 250 × 4.6 mm, 5-µm ODS Vydac HPLC column at 35°C, an acetonitrile-water (0.1 % TFA in each phase, v/v) eluent, and a 60-min run time using UV detection. The chromatographic conditions are used for the determination of ABT-861 and its degradation products and manufacturing impurities in the bulk powder and injectable formulations. The limit of detection is found to be approximately 9 ng at 225 nm. Method validation includes linearity of detector response with amount injected, precision, and standard addition-recovery data. Under the chromatographic conditions employed, diastereomeric and manufacturing impurities and degradation products are separated from ABT-861, demonstrating that the method is stability-indicating. Thus, the current method is seen to be suitable for the routine analysis of ABT-861 and related impurities, providing good selectivity and sensitivity.

Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1.

To establish the prevalence of endocrinologic disorders in children with neurofibromatosis type 1 (NF1) and the relationship between these disorders and cerebral abnormalities on magnetic resonance imaging. A prospective follow-up study. Setting. A multidisciplinary neurofibromatosis clinic. A total of 122 children diagnosed with NF1 according to diagnostic criteria set by the National Institutes of Health. Central precocious puberty (CPP) was diagnosed in 3 children and growth hormone deficiency (GHD) in 3 children. Optic pathway gliomas were observed in 15 children; in 9 of the 15 cases, the optic chiasm was involved. Of the 3 children with CPP, only 1 showed a chiasma glioma on magnetic resonance imaging. In 1 case with GHD, an optic chiasm glioma was detected on neuroimaging. Two of the 9 children with an optic chiasm glioma presented with CPP or GHD. It has been suggested that CPP in children with NF1 is found exclusively in the presence of a chiasma glioma. We conclude that chiasma glioma may not be obligatory in children with NF1 and CPP or GHD. Moreover, we report a prevalence of GHD in children with NF1 of 2.5%, which has not been established earlier.

Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty.

To assess the efficacy and safety of a long-acting gonadotropin-releasing hormone analogue (GnRHa), leuprolide acetate for depot suspension (Lupron Depot), in the treatment of central precocious puberty in children, and to determine the reversibility of GnRHa therapy after it has been discontinued. Children with documented central precocious puberty were treated with Lupron Depot for 1.6 to 3.5 years. Their course of pubertal development, growth rate, skeletal maturation, and response to gonadorelin hydrochloride testing were compared before and during treatment. For those girls who finished treatment, an assessment of the reversibility of the GnRHa was performed by documenting a return to pubertal responses to gonadorelin testing, and by documenting menarche at an appropriately mature bone age. Community teaching hospital. Ten girls with central precocious puberty defined as pubertal maturation statistically advanced for age combined with a pubertal gonadotropin response to gonadorelin testing. Children who had been treated for less than 1.5 years were excluded, as were those with congenital adrenal hyperplasia. Patients who finished treatment have been followed up for up to 5 years, and will continue in follow-up throughout their reproductive life. SELECTION SAMPLE: A consecutive group of children with documented central precocious puberty was studied. Lupron Depot was administered as a single monthly subcutaneous injection to each patient. Treatment was usually discontinued by 10 to 11 years of age, at which time pubertal progression was allowed to resume. Mean peak serum concentrations of follicle-stimulating and luteinizing hormone responses to gonadorelin testing decreased significantly after the initial dose (from 21.8 +/- 4.5 [+/- SEM] to 2.4 +/- 0.2 IU/L for follicle-stimulating hormone and from 50.1 +/- 11.2 to 5.0 +/- 0.8 IU/L for luteinizing hormone) and remained suppressed for the duration of treatment. The progression of puberty slowed or reversed in all patients. Mean growth rate for chronologic age was significantly increased initially by 3.9 SDs and decreased to 0.9 SDs during treatment. The mean rates of skeletal maturation divided by the change in chronologic and height age changes over time were advanced (1.4 +/- 0.1 and 1.1 +/- 0.15, respectively) at the onset of therapy and decreased significantly to 0.7 +/- 0.1 and 0.8 +/- 0.1, respectively, on treatment. There was an increase in mean predicted height of 3.4 cm for all patients, and this was statistically significant. Thus, treatment with Lupron Depot at least maintained the predicted height at the onset of therapy. Girls who completed their course of treatment had pubertal gonadotropin responses to gonadorelin testing within 2 to 6 months, and menarche within the first year if skeletal maturation reached 13.0 to 13.5 years. No significant side effects of therapy were noted. Treatment of central precocious puberty in children using Lupron Depot is safe and efficacious. Its effects are readily reversible after treatment is discontinued, and menarche occurs at a normal bone age. Measurement of serum luteinizing hormone concentrations using an assay that is specific for the beta-subunit is necessary to monitor chemical suppression of luteinizing hormone during treatment. Longer-term studies, including reproductive history, will be needed before the potential effects of treatment on fertility can be assessed.