Gonadotropin-releasing Hormone Stimulation Research Articles

Clinical and Analytical Presentation of Central Precocious Puberty: A 20-Year Cross-Sectional Study

Objectives − This study aims to compare the clinical and analytical presentation of Central precocious puberty (CPP), considering age.Methods − An observational, cross-sectional study was conducted on children diagnosed with CPP at a level III hospital, between January 2002 and April 2022. Clinical, auxological, sociodemographic, laboratory, and imaging parameters were analyzed.Results − Out of the 52 children studied, the majority were girls (N=44). The median age of puberty onset in girls was 6.79 years and the mean age at first consultation of 8.13 years, with a significantly lower age at hospital referral (7.65 years; P=0.045) compared to boys. Idiopathic etiology was predominant in both. In girls, breast development appeared at older mean ages (P=0.009), while pubic hair growth and accelerated growth were associated with younger ages at puberty onset (P=0.021; P=0.018, respectively). Basal and peak levels of gonadotropin hormones were higher in girls, although not statistically significant. In girls, age at puberty onset correlated negatively with standard deviation of body mass index (P=0.023), while age at first consultation correlated positively with bone age (P<0.001), and was associated with younger ages at Gonadotropin-Releasing Hormone stimulation test (P=0.020).Conclusion − This study provides innovative and relevant findings that enhance understanding of CPP presentation according to age, thereby improving clinical management of this condition.

A Phase3, Open-Label, Single-Arm Trial of the Efficacy and Safety of Triptorelin 6-Month Formulation in Chinese Children with Central Precocious Puberty.

This phase3 study assessed the efficacy, safety, and pharmacokinetics of the 6-month prolonged release (PR) formulation in Chinese children with central precocious puberty (CPP). In this open-label study (NCT05029622), Chinese children (girls < 9years, boys < 10years) received two doses of triptorelin pamoate 22.5mg (day1 and month6). Primary endpoint was the proportion at month6 with luteinizing hormone (LH) suppression (stimulated peak LH ≤ 5IU/L after gonadotropin-releasing hormone stimulation). Secondary endpoints included safety assessments, hormone level changes, and clinical parameters from baseline. Overall, 66 children completed the study (93.9% girls; median age 8.0 [range 5-9] years). At month6, all patients had LH suppression; this was maintained at month12 in 98.5% of patients. Mean basal and peak LH and follicle-stimulating hormone levels were suppressed throughout follow-up. All patients at months3 to 12had sex hormone suppression to prepubertal levels. Stable or reduced breast development was seen for 98.4% and 93.5% of girls at month6 and 12, respectively; all boys had regression or stable genital development until month12. Compared with baseline (9.82cm/year), mean growth velocity was 5.88cm/year at month6 and 5.17cm/year at month12. Mean bone age/chronological age ratio decreased from 1.27 at baseline to 1.23 and 1.21 at month6 and 12, respectively. In girls, 64.5% showed decreased uterine length at month6 and 12 versus baseline, while 75.0% of boys showed stable testicular volume versus baseline. Thirteen patients (19.7%) had 22 drug-related treatment emergent adverse events (TEAEs); no grade ≥ 3 TEAEs were reported. The efficacy and safety profile of triptorelin 6-month PR in Chinese children with CPP was consistent with data previously reported in non-Chinese children with CPP, supporting this as a viable treatment option for Chinese children with CPP. Trial registration:ClinicalTrials.gov identifier, NCT05029622.

Revising LH cut-off for the diagnosis of central precocious puberty via triptorelin stimulation assay.

Precocious puberty (PP) in girls is defined by thelarche before age 8. The diagnostic gold standard is an increased LH level following gonadotropin-releasing hormone (GnRH) stimulation. Alternatively, GnRH analogues like triptorelin can be used, though their interpretation varies. Since 2000, we have used a triptorelin-induced LH cut-off of 15 IU/L, 4 h post-stimulus. However, many girls showed LH values below this threshold despite evident pubertal progression. To establish a new LH threshold post-triptorelin stimulation for earlier diagnosis of central precocious puberty (CPP) in girls showing pubertal progression and to evaluate additional parameters for diagnostic accuracy. We enrolled 186 girls with thelarche onset between ages 1-8 and a GnRH analogue assay performed between 2015-2019 without signs of axis activation. Within this cohort, 62 patients repeated the triptorelin test due to rapid pubertal progression. The assay involved administering 100 mcg/m² of triptorelin and measuring LH, FSH, and estradiol levels before and four hours post-injection. Patients with axis activation at the second test had significantly higher post-stimulus LH levels at the first test compared to those below 15 IU/L. They also had higher basal LH levels, elevated LH/FSH ratio, and increased growth velocity. Statistical analysis identified a new post-stimulus LH threshold of 5 IU/L. We propose a LH value of 5 IU/L after triptorelin administration as a new threshold for early CPP diagnosis. While the LH/FSH ratio and growth velocity are associated with axis activation, they did not significantly enhance diagnostic accuracy when combined with the LH value.

Diagnostic utility of the average peak LH levels measured during GnRH stimulation test.

Gonadotropin-releasing hormone (GnRH) test is the gold standard test to evaluate the hypothalamus-pituitary-gonadal (HPG) axis for the diagnosis of central precocious puberty (CPP). However, the diagnosis of cases with clinical features of CPP whilst have borderline peak luteinizing hormone (LH) remain challenges. We aimed to evaluate diagnostic performance of the average of LH levels measured during GnRH stimulation test. Cases with diagnosis of CPP and premature thelarche (PT) who had a GnRH stimulation test results were retrospectively reviewed. Anthropometric measurements (weight, height, and body mass index), age and sex-specific standard deviation scores, growth velocity, puberty stages, bone ages, serum FSH, LH, and estradiol levels were measured by electrochemiluminescence immunological method (ECLIA), and the GnRH stimulation test results, which performed by obtaining venous blood samples at basal, 20th, and 40th minutes for FSH and LH measurement, were recorded. A total of 76 girls (38 CPP, 38 PT) were included. We detected an average peak LH cut-off value of 4.25 IU/L with 94.7 % sensitivity and 97.4 % specificity, a 97.3 % positive predictive value, and a 94.9 % negative predictive value in GnRH test to differentiate cases with CPP from PT. This is the first study evaluating the diagnostic utility of the average of LH levels measured during GnRH stimulation test. We showed that the average of two LH measurements has a high diagnostic performance. Therefore, it can be used as a valid and reliable diagnostic tool for assessment of HPG axis activation, particularly for cases with a borderline peak LH level.

P-708 melatonin alleviates circadian rhythm disruption-induced enhanced luteinizing hormone pulsatility and ovarian dysfunction in vivo and in vitro

Abstract Study question Is melatonin deficiency a reversible cause of abnormal pattern of luteinizing hormone (LH) pulsatility and ovarian dysfunction caused by circadian rhythm disruption (CRD)? Summary answer Melatonin could rescue the augmented LH pulsatility and reproductive abnormalities caused by CRD. What is known already Melatonin, mainly synthesized and released by pineal gland, engages in regulating circadian rhythms. When circadian rhythms are disrupted, the nocturnal productions of melatonin are suppressed. Evidence suggests that circadian rhythm disruption (CRD) is associated with reproductive dysfunctions, while melatonin plays a vital role for female reproduction as a free radical scavenger and a neuroendocrine regulator. The gonadotrophin-releasing hormone (GnRH) drives pulsatile luteinizing hormone (LH) secretion, which is also essential for fertility. Study design, size, duration We used 90 CBA/CaJ mice to establish the chronic jet-lag model in which mice were exposed to an 8 hr time shift every 3 days. After 8 weeks of jet-lag induction, some of the mice were given melatonin treatment for 4 weeks. Furthermore, we used a perfusion system in vitro to mimic the process of CRD-induce high-frequency GnRH pulses stimulation of LβT2 gonadotrope cells. Participants/materials, setting, methods Repetitive tail-tip blood collection was used to evaluate the pattern of LH pulsatility. Blood plasma samples were collected from 4 mice at 4-hour intervals to measure levels of melatonin. Follicular development was evaluated by ovarian histology. Reproductive hormones was detected by ELISA. Immunohistochemistry and western blot were used to detect the expression of melatonin receptor 1A (MT1). The LβT2 cells were exposed to pulsatile GnRH at high pulse frequencies to mimic augmented pulsatile GnRH stimulation. Main results and the role of chance CRD mice exhibited reproductive-endocrine dysfunction, including irregular estrous cycles, reduced number of corpus lutea (CL), and decreased levels of estradiol and progesterone. Additionally, CRD enhanced the frequency and amplitude of LH pulsatility and pituitary LH beta-subunit expression. Melatonin administration alleviated these CRD-induced reproductive abnormalities and reversed the augmented LH pulsatility. The expression of MT1 decreased in the anterior pituitaries of CRD mice but increased after melatonin treatment, indicating the essential role of MT1 in melatonin’s reversal of CRD-induced enhanced LH pulsatility. Limitations, reasons for caution Further research is needed to validate the applicability and safety of these findings in humans. Wider implications of the findings The results suggest that melatonin may be a beneficial option for patients with reproductive-endocrine abnormalities, particularly those with circadian rhythm disruption. Trial registration number 82101719

Value of single-phase gonadotropin-releasing hormone stimulation test in diagnosis of central precocious puberty in girls with different levels of body mass index

To investigate the value of single-phase gonadotropin releasing hormone (GnRH) stimulation test in the diagnosis of central precocious puberty (CPP) in girls with different levels of body mass index (BMI). A retrospective analysis was performed for the data of 760 girls with breast development before 7.5 years of age who attended the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2023. According to the results of GnRH stimulation test and clinical manifestations, they were divided into a CPP group (297 girls) and a non-CPP group (463 girls). According to the values of BMI, the girls were divided into a normal weight group (540 girls), an overweight group (116 girls), and an obese group (104 girls). The receiver operating characteristic (ROC) curve was used to investigate the value of single-phase GnRH stimulation test in the diagnosis of CPP in girls with different levels of BMI. Luteinizing hormone (LH)/follicle-stimulating hormone at 30 minutes after GnRH stimulation had an area under the curve (AUC) of 0.985 in the diagnosis of CPP, which was higher than the AUC at 0, 60, and 90 minutes (P<0.05). LH at 30 minutes had a similar diagnostic value to LH at 60 minutes (P>0.05). LH at 30 minutes was negatively correlated with BMI and BMI-Z value (P<0.05).The AUC for diagnosing CPP in normal weight, overweight, and obese girls at 30 minutes LH was 0.952, 0.965, and 0.954, respectively (P<0.05). The 30-minute GnRH stimulation test has a good value in the diagnosis of CPP in girls with different levels of BMI and is expected to replace the traditional GnRH stimulation test, but the influence of BMI on LH level should be taken seriously.

Kisspeptin and DLK1 levels for monitoring treatment of girls with central precocious puberty.

Kisspeptin and delta-like 1 homolog (DLK1) are neuropeptides that reportedly play an important role in pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal axis, respectively. Consequently, serum kisspeptin and DLK1 levels may be novel biomarkers for differentiating between central precocious puberty (CPP) and premature thelarche (PT) in girls and used to monitor CPP treatment. To compare baseline serum kisspeptin and DLK1 levels in girls with CPP at diagnosis and after treatment to age-matched girls with PT. This prospective longitudinal study included girls with precocious puberty and girls with PT who experienced breast development before 8 years of age and peak luteinizing hormone levels of ≥6 versus <6 IU/L after a gonadotropin-releasing hormone (GnRH) stimulation test. Serum kisspeptin and DLK1 levels were determined in both groups at baseline and after 6 months of GnRH analog treatment in the CPP group and analyzed by enzyme-linked immunosorbent assay. The study divided a total of 48 girls into CPP (n=24; mean age, 7.7±0.7 years) and PT (n=24; mean age, 7.4±0.8 years) groups. The baseline median serum kisspeptin levels were 50.5 pg/mL (range, 38.2-77 pg/mL) and 49.5 pg/mL (range, 39.7-67.6 pg/mL), respectively (P=0.89), while the baseline median serum DLK1 levels were 6.5 ng/mL (range, 5.9-7.5 ng/mL) and 6 ng/mL (4.4-14.4 ng/mL), respectively (P=0.68). After 6 months of GnRH analog treatment in the CPP group, the median serum kisspeptin level was lower (46.4 ng/mL; range, 37.1-60 ng/mL) than that at baseline (P=0.002), while the median serum DLK1 level was higher (7 ng/mL; range, 6.7-8.9) than that at baseline (P=0.002). Our findings suggest that baseline serum kisspeptin and DLK1 levels are not reliable biomarkers for differentiating between CPP and PT. However, significant changes in serum kisspeptin and DLK1 levels may be used to monitor CPP treatment.

Effectiveness of the triptorelin stimulation test compared with the classic gonadotropin-releasing hormone stimulation test in diagnosing central precocious puberty in girls.

The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for diagnosing central precocious puberty (CPP). Gonadorelin (Relefact) is used for the test but is not always readily available; triptorelin is used as an alternative. The purpose of this study was to evaluate the diagnostic validity of the triptorelin test compared with the GnRH test in the diagnosis of CPP in girls. This retrospective study included 100 girls with premature thelarche (PT) who underwent a hypothalamic-pituitary-gonadal axis evaluation. In the overall group, 50 girls were tested with intravenous gonadorelin (Relefact) and 50 girls were tested with subcutaneous triptorelin acetate (Decapeptyl). Luteinizing hormone (LH) and follicle-stimulating hormone levels were measured at baseline and 30, 45, 60, and 90 minutes after gonadorelin injection or 30, 60, 90, and 120 minutes after triptorelin injection. Clinical characteristics of age, height, weight, body mass index, and bone age were similar between the 2 groups. The highest LH level was reached 60 minutes after stimulation in both groups. Approximately 20% of the gonadorelin group and 24% of the triptorelin group were diagnosed with CPP (P=0.52). Among those diagnosed with CPP, the mean peak LH concentrations were 8.15 mIU/mL and 9.73 mIU/mL in the gonadorelin and triptorelin groups, respectively. The triptorelin test showed similar trends of LH elevation and diagnostic rate compared with the traditional GnRH test for diagnosing CPP. This suggests that the triptorelin test may be a valid alternative to the GnRH test for differentiating CPP from self-limiting PT. Our study also demonstrated that a triptorelin stimulation test for up to 120 minutes was sufficient to diagnose CPP.

Irisin combined index to diagnose central precocious puberty in girls: a cross-sectional study

BackgroundTo investigate serum irisin levels in girls at different developmental status and explore the significance of irisin for the diagnosis of central precocious puberty (CPP) in girls.MethodsIn this cross-sectional study 111 girls were enrolled, including 43 cases of CPP, 44 cases of peripheral precocious puberty (PPP) and 24 cases of girls with normal sexual development as controls. The data on age, weight and height, measured blood levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and irisin were collected. Pelvic Doppler ultrasound was performed to evaluate uterine length, transverse diameter, anteroposterior diameter. The girls were divided into non-CPP group and CPP group according to gonadotropin-releasing hormone (GnRH) stimulation test.ResultsSerum irisin levels were significantly higher in CPP group than in PPP group and normal control group. Serum irisin level was positively correlated with basal LH level, basal FSH level, peak LH level, peak LH /FSH ratio, uterine volume, bone age, and bone age index. The area under the curve, cut-off value, sensitivity and specificity of serum irisin were 0.958, 219.255 pg/ml, 100% and 80.6%. The combined diagnosis of CPP in girls by serum irisin and serum basal LH combined with uterine volume had an AUC, sensitivity, and specificity of 0.994, 97.6%, and 100%, superior to that of the single index.ConclusionsSerum irisin level in girls with CPP is significantly increased. An irisin combined index could help the diagnosis of CPP in girls.

Central precocious puberty in a boy with X-linked adrenoleukodystrophy caused by a novel ABCD1 mutation

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder caused by pathogenic variants in the ABCD1 gene. The symptoms include primary adrenal insufficiency (PAI), progressive spinal cord disease, inflammatory demyelinating cerebral disease, and primary hypogonadism. It is exceptionally rare that pediatric PAI is accompanied by central precocious puberty (CPP). The purpose of this study was to better understand the diversity of clinical manifestations of X-ALD and to identify the ABCD1 gene mutation in a case of a boy with X-ALD accompanied by CPP. We collected clinical, laboratory and imaging data, and used whole-exome sequencing (WES) analysis to evaluate the pathogenicity of the variant. We also predicted the potential deleterious effects of the novel mutation using Mutation Taster and generated three-dimensional protein structures using Swiss-Model and PyMOL Viewer software. The patient presented with PAI accompanied by CPP. Adrenal gland CT revealed adrenal hypoplasia. Gonadotropin-releasing hormone stimulation tests revealed CPP. WES revealed a novel variant (c.1376dup) in the ABCD1 gene, which resulted in a reading frameshift and a premature termination codon (p.Leu461ProfsTer95). Sanger sequencing confirmed that the variant was inherited from his heterozygous mother. Mutation Taster predicted that the variant could be harmful. The overall three-dimensional structures of the mutant wild-type proteins were visually distinct. Our results shed light on additional aspects of X-ALD. The premature activation of the hypothalamic-pituitary-gonadal axis may possibly be related to the pathogenic ABCD1 gene mutation.

Meta-analysis of machine learning models for the diagnosis of central precocious puberty based on clinical, hormonal (laboratory) and imaging data.

Central precocious puberty (CPP) is a common endocrine disorder in children, and its diagnosis primarily relies on the gonadotropin-releasing hormone (GnRH) stimulation test, which is expensive and time-consuming. With the widespread application of artificial intelligence in medicine, some studies have utilized clinical, hormonal (laboratory) and imaging data-based machine learning (ML) models to identify CPP. However, the results of these studies varied widely and were challenging to directly compare, mainly due to diverse ML methods. Therefore, the diagnostic value of clinical, hormonal (laboratory) and imaging data-based ML models for CPP remains elusive. The aim of this study was to investigate the diagnostic value of ML models based on clinical, hormonal (laboratory) and imaging data for CPP through a meta-analysis of existing studies. We conducted a comprehensive search for relevant English articles on clinical, hormonal (laboratory) and imaging data-based ML models for diagnosing CPP, covering the period from the database creation date to December 2023. Pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), summary receiver operating characteristic (SROC) curve, and area under the curve (AUC) were calculated to assess the diagnostic value of clinical, hormonal (laboratory) and imaging data-based ML models for diagnosing CPP. The I2 test was employed to evaluate heterogeneity, and the source of heterogeneity was investigated through meta-regression analysis. Publication bias was assessed using the Deeks funnel plot asymmetry test. Six studies met the eligibility criteria. The pooled sensitivity and specificity were 0.82 (95% confidence interval (CI) 0.62-0.93) and 0.85 (95% CI 0.80-0.90), respectively. The LR+ was 6.00, and the LR- was 0.21, indicating that clinical, hormonal (laboratory) and imaging data-based ML models exhibited an excellent ability to confirm or exclude CPP. Additionally, the SROC curve showed that the AUC of the clinical, hormonal (laboratory) and imaging data-based ML models in the diagnosis of CPP was 0.90 (95% CI 0.87-0.92), demonstrating good diagnostic value for CPP. Based on the outcomes of our meta-analysis, clinical and imaging data-based ML models are excellent diagnostic tools with high sensitivity, specificity, and AUC in the diagnosis of CPP. Despite the geographical limitations of the study findings, future research endeavors will strive to address these issues to enhance their applicability and reliability, providing more precise guidance for the differentiation and treatment of CPP.

Non-classical 11β-hydroxylase deficiency caused by a novel heterozygous mutation: a case report and review of the literature.

11β-hydroxylase deficiency (11β-OHD) constitutes a rare form of congenital adrenal hyperplasia (CAH), typically accounting for ~5-8% of CAH cases. Non-classical 11β-OHD is reported even more rarely and frequently results in misdiagnosis or underdiagnosis due to its mild clinical symptoms. A clinical, biochemical, radiological, and genetic study was conducted on a 9-year-old girl presenting with mild breast development, axillary hair growth, and advanced bone age. Additionally, a comprehensive review and synthesis of the literature concerning 11β-OHD were conducted. The patient presented with breast enlargement, axillary hair development, and accelerated growth over the past year. Laboratory tests revealed levels of cortisol, luteinizing hormone, testosterone, and progesterone that were below normal. A gonadotropin-releasing hormone (GnRH) stimulation test suggested the possibility of central precocious puberty. Radiologic examination revealed a 2-year advance in bone age, while bilateral adrenal ultrasonography showed no abnormalities. Her mother exhibited hirsutism, while her father's physical examination revealed no abnormalities. Whole-exon genetic testing of the child and her parents indicated a heterozygous mutation of c.905_907delinsTT in exon 5 of the 11β-hydroxylase gene (CYP11B1) in the child and her mother. This mutation resulted in a substitution of aspartic acid with valine at amino acid position 302 of the coding protein. This frameshift resulted in a sequence of 23 amino acids, culminating in a premature stop codon (p.Asp302ValfsTer23). A review of the previous literature revealed that the majority of heterozygous mutations in 11β-OHD were missense mutations, occurring primarily in exons 2, 6, 7, and 8. The most common mutation among 11β-OHD patients was the change of Arg-448 to His (R448H) in CYP11B1. Furthermore, bioinformatics analyses revealed that heterozygous mutation of c.905_907delinsTT had deleterious effects on the function of CYP11B1 and affected the stability of the protein, presumably leading to a partial impairment of enzyme activity. The results of the in vitro functional study demonstrated that the missense mutant (p.Asp302ValfsTer23) exhibited partial enzymatic activity. We report a novel heterozygous mutation of CYP11B1 (c.905_907delinsTT), enriching the spectrum of genetic variants of CYP11B1. This finding provides a valuable case reference for early diagnosis of non-classical patients with 11β-OHD.

Modulatory Effects of Ethinyl Estradiol Plus Drospirenone Contraceptive Pill on Spontaneous and GnRH-Induced LH Secretion

Background: Combined oral contraceptives (COCs) work mostly by preventing the pre-ovulatory gonadotropin surge, but the action of COCs on spontaneous episodic and GnRH (gonadotropin-releasing hormone)-induced LH (luteinizing hormone) release has been poorly evaluated. Oral contraceptives are known to act on the spontaneous hypothalamic–pituitary functions reducing both GnRH and gonadotropin release and blocking ovulation. Aim: To evaluate spontaneous and GnRH-induced LH release during both phases of the menstrual cycle or under the use of the contraceptive pill. Methods: A group of 12 women, subdivided into two groups, volunteered for the study. Group A (n = 6, controls) received no treatments, while Group B (n = 6) received a 21 + 7 combination of ethinyl-estradiol (EE) 30 µg + drospirenone (DRSP) 3 mg. Both groups were evaluated twice: Group A during follicular and luteal phases, Group B during pill assumption and during the suspension interval, performing a pulsatility test, GnRH stimulation test, and hormonal parameters evaluation. Spontaneous and GnRH-induced secretory pulses were evaluated, as well as the instantaneous secretory rate (ISR). Results: COC treatment lowered LH and FSH (follicle stimulating hormone) levels significantly if compared to the follicular phase of spontaneous cycles. During the suspension interval, hormone levels rapidly rose and became comparable to those of the follicular phase of the control group. The LH pulse frequency under COC administration during the suspension interval was similar to that observed during the follicular phase (2.6 ± 0.3 pulses/180 min and 2.3 ± 0.2 pulses/180 min, respectively). The GnRH-induced LH peaks were greater in amplitude and duration than those observed after ISR computation in both groups. The GnRH-induced LH release during the luteal phase of the control subjects was higher than in the follicular phase (51.2 ± 12.3 mIU/mL and 14.9 ± 1.8 mIU/mL, respectively). Conversely, subjects under COC showed a GnRH-induced LH response similar during COC and during the suspension interval. Conclusions: Our data support that the EE + DRSP preparation acts on both spontaneous pulsatile release and GnRH-induced LH release during the withdrawal period of the treatment, and that after 5–7 days from the treatment suspension, steroidal secretion from the ovary is resumed, such as that of androgens. This suggests that in hyperandrogenic patients, a suspension interval as short as 4 days might be clinically better.

Development and application of a nomogram model for predicting the risk of central precocious puberty in obese girls.

The purpose of this study is to develop and assess a nomogram risk prediction model for central precocious puberty (CPP) in obese girls. We selected 154 cases of obese girls and 765 cases of non-obese girls with precocious puberty (PP) who underwent the gonadotropin-releasing hormone stimulation test at the Jiangxi Provincial Children's Hospital. Univariate analysis and multivariate analysis were conducted to identify predictors of progression to CPP in girls with PP. A predictive model was developed and its predictive ability was preliminarily evaluated. The nomogram was used to represent the risk prediction model for CPP in girls with obesity. The model was validated internally using the Bootstrap method, and its efficacy was assessed using calibration curves and clinical decision analysis curves. In obese girls with PP, basal luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels, as well as uterine volume, were identified as independent risk factors for progression to CPP. In non-obese girls, the basal LH level, bone age, and uterine volume were identified as independent risk factors for progression to CPP. With an AUC of 0.896, the risk prediction model for obese girls, was found to be superior to that for non-obese girls, which had an AUC of 0.810. The model displayed strong predictive accuracy. Additionally, a nomogram was used to illustrate the CPP risk prediction model for obese girls. This model performs well in internal validation and is well calibrated, providing a substantial net benefit for clinical use. A medical nomogram model of CPP risk in obese girls comprised of basal LH value, basal FSH value, and uterine volume, which can be used to identify those at high risk for progression of CPP in obese girls and develop individualized prevention programs.

A Short-Duration Gonadotropin-Releasing Hormone Stimulation Test for the Diagnosis of Central Precocious Puberty.

Background and Objectives: The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard method for diagnosing central precocious puberty (CPP), although it requires multiple blood samplings over 120 min. This study aimed to evaluate if a shorter test may have an equivalent diagnostic accuracy. Materials and Methods: We retrospectively reviewed the GnRH tests of 188 consecutive pediatric patients (169 females) referred for signs of early pubertal development. The diagnostic accuracy of the hormonal levels was evaluated at different time points (15, 0, 60, 90, and 120 min after the GnRH stimulus). Results: A diagnosis of CPP was made in 130 cases (69%), with 111 (85%) being female. Sensitivity and specificity ratings higher than 99% for the diagnosis of CPP were achieved for LH levels ≥4.7 mU/mL at 30 and 60 min after the stimulus (area under the ROC curve (AUC) = 1), with no further increase in the diagnostic accuracy in the remaining time points. No sex differences in diagnostic accuracy were found. The LH/FSH ratio at 30 min showed a sensitivity of 94.9%, with an AUC of 0.997 and a value ≥0.76. Conclusions: A short-duration GnRH test of 60 min provided optimal results for the diagnosis of CPP. Extending the test for an extra hour is therefore unnecessary and inadvisable.

Confirming the association between low serum 25OHD levels in girls with central precocious puberty and its severity

BackgroundTo assess the differences in vitamin D levels in girls with rapidly progressive (RP) or slowly progressive (SP) central precocious puberty (CPP) and to compare whether the factors related to RP-CPP influenced the vitamin D status. A cross-sectional study was performed among girls with CPP classified as RP-CPP or SP-CPP.MethodsThe baseline data, gonadotropin-releasing hormone (GnRH) stimulation test results, serum 25-hydroxyvitamin D (25OHD) levels, and season of sample collection were analyzed.ResultsThe mean 25OHD level in 340 girls was 15.89 ± 6.87 ng/mL, of whom only 10 (2.9%) had normal levels (≥ 30 ng/mL). A total of 114 girls in the SP-CPP group and 226 in the RP-CPP group had similar chronological age, disease course, height SDS, bone mineral density, baseline follicle-stimulating hormone (FSH), peak FSH, and 25OHD levels. Developmental age, body mass index (BMI), BMI SDS, peak luteinizing hormone (LH)/FSH, insulin-like growth factor 1 (IGF-1), and IGF-1 SDS were independent risk factors for RP-CPP. Significant differences were observed among the different serum 25OHD levels in terms of season, disease course, IGF1 level, and BMI SDS (P < 0.05). Moreover, the sampling season was strongly correlated with serum 25OHD levels (r = 0.402, P < 0.001).ConclusionThe vitamin D levels were generally deficient or insufficient in girls with CPP, but were not related to the different types of CPP. High BMI levels, IGF1 levels, or peak LH/FSH ratio, but not vitamin D levels, could promote the progression of RP-CPP. Seasonal factors mainly influenced the vitamin D levels.

Use of the Subcutaneous Triptorelin Stimulation Test for Diagnosis of Central Precocious Puberty.

The gold standard gonadotropin-releasing hormone (GnRH) stimulation test uses the response to intravenously injected gonadorelin to diagnose central precocious puberty (CPP). However, gonadorelin is not always readily available. This study investigated the diagnostic efficacy of the subcutaneous triptorelin test and the optimal blood sampling time for diagnosis of CPP. This study retrospectively examined the medical records of 220 girls who had undergone either the triptorelin or gonadorelin test and compared their clinical characteristics. We retrospectively compared clinical parameters between girls diagnosed with CPP (n = 111) and idiopathic premature thelarche (IPT) (n = 109) using three different diagnostic methods: the gonadorelin, triptorelin 120 min, and triptorelin 180 min tests. The diagnostic ability of the stimulated luteinizing hormone (LH) concentration in the triptorelin test for CPP was evaluated using receiver operating characteristic (ROC) analysis. The CPP group exhibited higher basal and peak gonadotropin levels, more advanced bone age, and a lower body mass index standard deviation score than the IPT group. In the gonadorelin test group, all girls with CPP exhibited a peak LH response 30-60 min after intravenous gonadorelin injection. In the triptorelin test group, most girls with CPP exhibited a peak LH response 60-180 min after subcutaneous triptorelin injection (n = 68). On the ROC curve, a peak LH concentration of ≥ 4.52 IU/L at 120 min had the highest CPP diagnostic accuracy, with sensitivity and specificity of 100% and 95.83%, respectively.

Age-related changes in hormonal profiles and testicular diameter of West African Dwarf buck treated with gonadotropin-releasing hormone

This study aimed to investigate the impact of age-related peripheral and Gonadotropin Releasing Hormone (GnRH) -stimulated hormonal profiles on testicular size in West African dwarf bucks. Twelve 3-month-old bucks were randomly divided into two groups: the GnRH- treated group (n = 6) and the control group (n = 6). Over the course of 10 months, from month 3 to month 12, the testicular diameter of all bucks was measured monthly, and blood samples were collected monthly for hormone analysis. The results showed that testicular diameter increased with age and higher concentrations of Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and Testosterone (T). The GnRHtreated group reached its peak testicular diameter (28.36±1.44 mm) earlier at 8 months compared to the control group (30.50±1.44 mm) at 10 months, aligning with the peak concentrations of FSH, LH, and T. While the GnRH stimulation led to higher FSH, LH, T, and estrogen levels in the treated group, it didn't significantly affect the final testicular diameter (p&lt;0.05). It can be concluded that hormonal levels rise with age and increasing testicular size, and GnRH stimulation can accelerate this process. Testicular size is an important factor in breeding soundness and is influenced by LH, FSH, and testosterone concentrations. These hormones can reliably indicate the reproductive capacity of the buck. Therefore, hormonal profiling should be an integral part of the breeding soundness examination.

Quantification of overnight urinary gonadotropin excretion predicts imminent puberty in girls: a semi-longitudinal study

PurposeWe explored the alternative of using overnight fold change in gonadotropin levels by comparing the last-night-voided (LNV) and first-morning-voided (FMV) urine concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as a conceptual analogy to the invasive gonadotropin-releasing hormone (GnRH) stimulation test setting.MethodsWe investigated the nocturnal changes in the immunoreactivity levels of urinary gonadotropins between early and late prepubertal stages as well as between early and late pubertal stages in FMV and LNV urine samples from 30 girls, of whom those who were prepubertal were further investigated through follow-up visits within the 1-year period from the start of the study.ResultsROC analysis revealed that the FMV total U-LH and FMV U-FSH concentrations at or above 0.3 IU/L and 2.5 IU/L, respectively, were excellent predictors of forthcoming onset of puberty within 1 year (100% sensitivity, 100% specificity, AUC: 1.00, and n = 10, for both). FMV total U-LH concentration at or above 0.8 IU/L represented the cut-off for clinical signs of puberty. FMV/LNV total U-LH and FMV/LNV U-FSH ratios at or below 4.11 and 1.38, respectively, were also good predictors of the onset of clinical puberty within 1 year. An overnight increase (FMV/LNV ratio) in total U-LH concentrations and in the U-LH/U-FSH ratio at or below 1.2-fold in pubertal girls was associated with the postmenarcheal pubertal stage.ConclusionFMV total U-LH and U-FSH above 0.3 IU/L and 2.5 IU/L, respectively, can be used as cut-off values to predict the manifestation of the clinical signs of puberty within 1 year. FMV total U-LH concentrations 0.3–0.8 IU/L and 0.6 IU/L may represent the range and the threshold, respectively, that reflect the loosening of the central brake on the GnRH pulse generator. An overnight increase of 20% or less in total U-LH concentrations and in the U-LH/U-FSH ratio in an early pubertal girl may serve as an indicator of imminent menarche, a presumed timing of which can be unraveled by future longitudinal studies.

THU193 Clinical Usefulness Of Repetitive GnRH Stimulation Test For The Diagnosis Of Central Precocious Puberty

Abstract Disclosure: S. Heo: None. Y. Shim: None. H. Lee: None. J. Hwang: None. J. Lim: None. Objective In girls, breast development under 8 years of age and peak serum luteinizing hormone (LH) is 5 IU/L or higher in gonadotropin releasing hormone (GnRH) stimulation tests is a standard method for diagnosing central precocious puberty (CPP). Although breast development and bone age progress rapidly compared to chronological age, repeated GnRH stimulation tests do not exceed 5 IU/L in some cases. We aimed to analyze the clinical characteristics of girls who repeatedly examined the GnRH stimulation test. Methods We retrospectively reviewed the medical records of 988 girls under 9 years of age who visited our hospital due to breast development more than Tanner stage II and whose bone age was more than a year advanced than the chronological age and examined GnRH stimulation test twice or more. According to peak luteinizing hormone (LH) at first GnRH stimulation test, patients were divided into 5 groups that &amp;lt; 1.0 IU/L (group 1, n=34), ≥1.0 to &amp;lt; 2.0 IU/L (group 2, n=219), ≥2.0 to &amp;lt; 3.0 IU/L (group 3, n=297), ≥3.0 to &amp;lt; 4.0 (group 4, n=252) and ≥4.0 to &amp;lt; 5.0 (group 5, n=186). We analyzed the incidence of CPP through the repetitive GnRH stimulation test and factors associated with the outcomes using a Cox proportional hazard model. Results Mean age of total of 988 girls was 7.68 ± 0.67 years and the period between the first and last GnRH stimulation test was 216.40 ± 145.14 days. CPP was diagnosed in 138 patients. Incidence of CPP were differed by groups that 0%, 1.4%, 6.1%, 20.6%, 34.9% each groups. When group 1 and each groups were compared using the Cox proportional hazard regression model, difference between bone age and chronological age (95% CI, 1.27-2.35, p&amp;lt;0.001) (BA-CA) and basal follicle-stimulating hormone (95% CI, 1.01-1.48, p=0.039) showed a statistically significant positive correlation when stratifying the peak LH at GnRH stimulation test. Conclusion In the diagnosis of CPP, the GnRH stimulation test is gold standard. But the lower the peak LH in GnRH stimulation test, the more other factors such as difference between bone age and chronological age, basal FSH should be considered in the possibility of CPP. Presentation: Thursday, June 15, 2023