Gonadotropin-releasing Hormone Stimulation Test Research Articles

Is cranial imaging necessary in girls between 6-8 years diagnosed with central precocious puberty?

There is no clear consensus on whether a cranial MRI should be performed in all cases of central precocious puberty(CPP). In this study, we aimed at evaluating the incidence of intracranial lesions and analyzing cranial imaging results in females with CPP. In the retrospective study medical records of the case, the age at the time of admission, anthropometric measurements, bone age, Tanner stages, serum follicle-stimulating hormone (FSH), serum luteinizing hormone(LH), serum estradiol (E2) levels, the peak LH level during the gonadotropin-releasing hormone (GnRH) stimulation test and the cranial MRI findings at the time of the diagnosis of CPP were collected. The mean age diagnosis of the 154 girls included in the study was 6.9 ±1.08. Nine (5.8%) of 154 patients were diagnosed with organic-caused CPP. Four of the nine cases diagnosed with organic CPP had a previously known CNS pathology. The other five cases did not have any neurological findings at the time of diagnosis. Incidental lesions were detected at cranial MRI of nine of the 145 cases diagnosed with idiopathic CPP. The basal E2, basal LH, basal FSH, peak LH and peak LH/FSH levels of the cases with organic CPP were higher than those with idiopathic CPP. In our study, approximately 90% of organic CPP due to intracranial lesions were between 6-8 years. Therefore, we believe that cranial imaging should be performed in all females with CPP.

The Use of Morning Urinary Gonadotropins and Sex Hormones in the Management of Early Puberty in Chinese Girls.

ContextAlthough gonadotropin-releasing hormone stimulation test (GnRHST) is the gold standard in diagnosing central precocious puberty (CPP), it is invasive, expensive, and time-consuming, requiring multiple blood samples to measure gonadotropin levels.ObjectiveWe evaluated whether urinary hormones could be potential biomarkers for prepuberty or postpuberty, aiming to simplify the current diagnosis and prognosis procedure.MethodsWe performed a cross-sectional study of a total of 355 girls with CPP in National Clinical Research Center for Child Health in China, including 258 girls with positive and 97 girls with negative results from GnRHST. Twenty patients received GnRH analogue (GnRHa) treatment and completed a 6-month follow up. We measured luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, prolactin, progesterone, testosterone, and human chorionic gonadotropin in the first morning voided urine samples.ResultsTheir urinary LH levels and the ratios of LH to FSH increased significantly with the advancement in Tanner stages. uLH levels were positively associated with basal and peak LH levels in the serum after GnRH stimulation. A cutoff value of 1.74 IU/L for uLH reached a sensitivity of 69.4% and a specificity of 75.3% in predicting a positive GnRHST result. For the combined threshold (uLH ≥ 1.74 + uLH-to-uFSH ratio > 0.4), the specificity reached 86.6%. After 3 months of GnRHa therapy, the uLH and uFSH levels decreased accordingly.ConclusionuLH could be a reliable biomarker for initial CPP diagnosis and screening; uLH could also be an effective marker for evaluating the efficacy of clinical treatment.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.

Single random measurement of urinary gonadotropin concentration for screening and monitoring girls with central precocious puberty.

PurposeThe gold standard for assessing pubertal activation is the gonadotropinreleasing hormone (GnRH) stimulation test (GnRHST), which is invasive, time-consuming, and inconvenient. This study evaluated whether a single random measurement of urinary luteinizing hormone (LH) concentration could substitute for the GnRHST in diagnosing and monitoring central precocious puberty (CPP) in girls.MethodsFifty-five girls with breast buds before 8 years of age were assessed by both the GnRHST and urinary gonadotropin assays. Based on the GnRHST results, 29 girls were assigned to the CPP group (peak LH≥5 IU/L), and 26 were placed in the premature thelarche (PT) group (peak LH<5 IU/L). Auxological data and urine and serum samples were collected at baseline and after treatment with a GnRH agonist for 12 and 24 weeks.ResultsAlthough the auxological data did not differ between the 2 groups, the serum levels of insulin-like growth factor-1, basal LH, follicle-stimulating hormone (FSH), estradiol, and peak LH; urinary LH; and peak serum LH/FSH and urinary LH/FSH ratios were higher in the CPP group than in the PT group. Pearson correlation analysis showed a positive correlation between the urinary and serum LH concentrations (r=0.660, P<0.001). Receiver-operating characteristic curve analyses showed that a urinary LH concentration of 0.725 IU/L was a cutoff that significantly predicted positivity on the GnRHST. Urinary LH and FSH concentrations declined significantly during GnRH agonist treatment.ConclusionsA single, random measurement of urinary gonadotropin concentration could be a reliable tool for initial screening and therapeutic monitoring of CPP in girls.

Resolution of Abnormal Gonadotropin Secretion After Surgical Cure in Men With ACTH-Dependent Cushing Syndrome

Background: Hypothalamic-pituitary-gonadal (HPG) dysfunction is known to occur in male patients with Cushing Syndrome (CS) but the underlying mechanisms of HPG dysfunction remain unclear. We performed frequent blood sampling and GnRH stimulation tests to assess gonadotropin secretion in males before and after surgical cure of CS. Methods: We evaluated eight males age 32.5±12 years (mean ± SD) enrolled for surgical cure of ACTH-dependent CS at a tertiary care research center. Urinary free cortisol (UFC) was measured before and after surgery. Blood was sampled every 20 minutes for 24-hours with measurement of LH and FSH, before and 2 weeks to 160 weeks (median 80 weeks) after surgery. Patients received 100 μg of gonadotropin releasing hormone (GnRH) iv with measurement of LH and FSH at 0, 10 and 20 min before and 15, 30, 45, 60, 120 and 180 min after administration. Non-normative data was log-transformed before analysis using paired two-tail t-tests. A p-value of <0.05 was considered significant. Gonadotropin values are expressed in U/L as equivalents of the 2nd International Preparation of human menopausal gonadotropins with normal adult male ranges of 6-26 and 5-25 IU/L for LH and FSH, respectively. Results: Mean UFC was elevated ~ 6 times above the upper normal limit before surgery and returned to the reference range after surgery. 24-hour LH rose from 7.82 ± 1.48 preoperatively to 13.07 ± 2.96 IU/L (mean ± sem) after surgery (p=0.026) while mean FSH was unchanged (8.48 ± 1.51 vs 6.92 ± 1.29, p=0.37). LH pulse frequency, a marker of pulsatile GnRH secretion, recovered from a subnormal value of 6.88 ± 0.55 pulses/24 hr before to 12.13 ± 0.72 pulses/24 hr after surgery (p<0.0001) while LH pulse amplitude did not change (6.47 ± 1.21 vs 4.76 ± 0.88 IU/L, p=0.21). In response to GnRH there was a robust increase in LH that was not affected by curative surgery for CS (27.0 ± 7.2 vs 21.2 ± 7.6 IU/L; p=0.14) as was also the case for FSH (3.7 ± 1.2 vs 2.3 ± 0.5 IU/L; p=0.48), consistent with the absence of an effect of CS on gonadotroph responsiveness to LHRH. Conclusion: In men with Cushing Syndrome, hypogonadism is associated with inhibition of endogenous GnRH secretion but preservation of the pituitary response to GnRH. Hypothalamic suppression of the HPG axis is reversible after cure of CS.

Clinical risk score for central precocious puberty among girls with precocious pubertal development: a cross sectional study

BackgroundThe gold standard for the diagnosis of central precocious puberty (CPP) is gonadotropin-releasing hormone (GnRH) or GnRH analogs (GnRHa) stimulation test. But the stimulation test is time-consuming and costly. Our objective was to develop a risk score model readily adoptable by clinicians and patients.MethodsA cross-sectional study based on the electronic medical record system was conducted in the Children’s Hospital, Fudan University, Shanghai, China from January 2010 to August 2016. Patients with precocious puberty were randomly split into the training (n = 314) and validation (n = 313) sample. In the training sample, variables associated with CPP (P < 0.2) in univariate analyses were introduced in a multivariable logistic regression model. Prediction model was selected using a forward stepwise analysis. A risk score model was built with the scaled coefficients of the model and tested in the validation sample.ResultsCPP was diagnosed in 54.8% (172/314) and 55.0% (172/313) of patients in the training and validation sample, respectively. The CPP risk score model included age at the onset of puberty, basal luteinizing hormone (LH) concentration, largest ovarian volume, and uterine volume. The C-index was 0.85 (95% CI: 0.81–0.89) and 0.86 (95% CI: 0.82–0.90) in the training and the validation sample, respectively. Two cut-off points were selected to delimitate a low- (< 10 points), median- (10–19 points), and high-risk (≥ 20 points) group.ConclusionsA risk score model for the risk of CPP had a moderate predictive performance, which offers the advantage of helping evaluate the requirement for further diagnostic tests (GnRH or GnRHa stimulation test).

The efficacy of pulsatile gonadotropin-releasing hormone therapy in male patients with hypogonadism caused by hypopituitarism

To evaluate the efficacy of pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with hypogonadism caused by hypopituitarism so as to guide clinical treatment. Clinical manifestations, laboratory examinations, and imaging features were collected from 22 patients with hypopituitarism that led to hypogonadism who were treated with pulsatile GnRH. Data were analyzed and the patients were followed up. The average age at which patients began to use pulsatile GnRH was 22.8±3.7 years old. The duration of pulsatile GnRH administration ranged from 3 to 60 months, with an average of 20.5±12.1 months. The dosage of GnRH administered was 10-12 µg/90 minutes. Patients were followed up for 26-81 months, with an average of 50.5±17.3 months. After pulsatile GnRH treatment, the clinical manifestations and hormone levels of these patients improved to varying degrees. The luteinizing hormone (LH) and testosterone (T) levels of 7 patients increased to the normal range, sperm could be detected in seminal fluid samples of 5 patients, and 2 patients successfully reproduced. Within the good-response group, 71.4% of patients achieved spermatogenesis within an average of 13 months of treatment. In patients who had poor response to gonadotropin therapy prior to pulsatile GnRH therapy, 25% achieved spermatogenesis, and 37.5% reached the normal range of LH and T. The levels of LH after pulsatile GnRH treatment was positively correlated with the peak levels of LH and testicular volume prior to treatment (P<0.01). Pulsatile GnRH therapy can improve gonadal function in most patients with hypogonadism caused by hypopituitarism. Patients were able to achieve spermatogenesis, especially in patients who were poor-responders to gonadotropin treatment. Patients with greater basal testicular volume may respond better to pulsatile GnRH treatment. The GnRH stimulation test not only helps to evaluate the reserve function of pituitary GnRH cells at a certain time but may also serve as a prognostic factor. The results of this study form a basis for guiding clinical therapeutic choices.

Hypergonadotropic hypogonadism in Nigerian men with type 2 diabetes mellitus

Background. Studies have reported a higher preva-lence of hypogonadism in men with type 2 diabetes mellitus (T2DM) than non-diabetic men. The pattern of hypogonadism in men with T2DM using gonado-tropin-releasing hormone (GnRH) stimulation test in Sub-Saharan Africa is unknown. Objective. This study was conducted to determine the prevalence and pattern of hypogonadism in Nigerian men with T2DM. Methods. A cross-sectional study involving 358 men with T2DM and 179 non-diabetic men as controls. Androgen Deficiency in the Ageing Male (ADAM) questionnaire was administered. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) both at 0 hours and 4 hours after subcutaneous buserelin injec-tion, fasting total testosterone (TT), fasting plasma glucose and glycated haemoglobin were measured. Ninety-nine men with T2DM selected by randomiza-tion using a computer underwent GnRH stimulation test, with subcutaneous injection of 100 micrograms of buserelin. Results. The mean TT of T2DM men was significantly lower compared to the controls (8.79 ± 3.35 nmol/L vs 15.41 ± 3.79 nmol/L, p < 0.001). The prevalence of hypogonadism in T2DM men was 80.4%, comprising 38.5% of severe hypogonadism and 41.9% mild hypogonadism. The mean LH and FSH levels were significantly higher in T2DM men than the controls (9.62 ± 6.82 IU/L vs 8.24 ± 5.91 IU/L, p = 0.022 and 8.50 ± 8.17 IU/L vs 5.17 ± 3.89 IU/L, p < 0.001 respectively). There was a statistically significant exaggerated response in mean (±SD) LH and FSH levels at 4 hours after buserelin in-jection compared to the 0-hour levels (58.58 ± 40.72 IU/L vs 8.38 ± 6.10 IU/L, p < 0.001 and 23.03 ± 18.02 IU/L vs 8.41 ± 7.45 IU/L, p < 0.001 respectively) in men with T2DM who had GnRH stimulation tests. Conclusion. This study shows that the prevalence of hypogonadism in men with T2DM is significantly higher than in non-diabetic men with mild hypogonadism accounting for most cases. Hypergonadotropic hypo-gonadism occurs more frequently in men with T2DM in Nigeria.

Sensitivity and specificity of using pelvic ultrasonographic parameters combined with basal gonadotropin levels to diagnose central precocious puberty in Thai girls.

The criterion standard gonadotropin-releasing hormone (GnRH) stimulation tests to diagnose central precocious puberty (CPP) are time-consuming, inconvenient, and expensive. To determine predictive cut-off values codetermined by ultrasonographic parameters and basal gonadotropin levels in girls with premature sexual development and compare them results of criterion standard tests in a study of diagnostic accuracy. Retrospective review of hormonal investigations and ultrasonographic uterine and ovarian parameters in a consecutive sample of girls at a single center, tertiary care hospital in Bangkok, Thailand. We separated data from 68 girls (age range 2-12 years) into 2 groups based on their response to a GnRH analogue agonist stimulation test. A "prepubertal response" group included girls with premature thelarche and thelarche variants (n = 18, 6.37 ± 1.77 years) and a "pubertal response" group, including girls with CPP (n = 50, 8.46 ± 1.46 years); excluding patients with pathological causes (n = 0). The basal level of luteinizing hormone (LH) had the largest area under receiver operating characteristic curves (AUC) of 0.84; 95% confidence interval [CI] 0.74-0.93) compared with basal levels of follicle stimulating hormone (AUC 0.77; 95% CI 0.64-0.90) or estradiol (0.70; 95% CI 0.56-0.85). An optimal cut-off of 0.25 IU/L LH was related to a pubertal response to GnRH analogue agonist stimulation tests with 75.0% sensitivity, 88.9% specificity, 94.7% positive predictive value (PPV), and 57.1% negative predictive value. Uterine and ovarian cut-off volumes of 3.5 cm3 and 1.5 cm3 were related to a pubertal response with 88.6% and 76.2% PPV, respectively. A uterine width cut-off of 1.7 cm combined with a basal LH cut-off of 0.25 IU/L increased specificity and PPV to 100%. Combining uterine and ovarian ultrasonographic parameters with basal gonadotropin levels, especially uterine width and basal LH level, appears useful for diagnosis of CPP.

Time Points for Gonadotropin-Releasing Hormone Stimulation Test Results in Korean Children.

The gold standard for the laboratory diagnosis of central precocious puberty is based on the measurement of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation. We sought to investigate the laboratory data for GnRH stimulation testing using samples collected from Korean children at different time points. Sampling times were at the basal time point (0) and 15, 30, 45, 60, 90, and 120 min after GnRH stimulation. Pubertal response was defined as occurring when the peak LH concentration was 5 IU/L or more and rose to at least 2 times the basal LH concentration after GnRH stimulation. During the study period, 19,990 test results from 1958 Korean children (1841 females aged 1.3–8.9 years and 117 males aged 7.3–9.9 years) were obtained. Among the 1958 children, 1232 (62.9%) showed pubertal responses. The receiver operating characteristic curve that demonstrated the greatest area under the curve (AUC) among all examined time points was 45 min after GnRH stimulation in males (AUC 0.982, 95% CI 0.938–0.998) and 60 min in females (AUC 0.975, 95% CI 0.967–0.981). The combination of 45 min and 60 min showed the greatest AUC (0.996, 95% confidence interval 0.991–0.998), with a sensitivity level of 99.1% and a specificity of 100% for all children. The results of this study provide a possibility for a reduction in sampling time points (45 min and 60 min) to identify the presence of a pubertal response after GnRH stimulation in Korean children.

Diagnostic evaluation of central precocious puberty in girls

The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for confirming the activation of the hypothalamic-pituitary-gonadal axis in central precocious puberty (CPP). However, it is time-consuming and costly. Our aim was to search for a simpler diagnostic modality for CPP by 1) evaluating the performance of basal serum luteinizing hormone (LH), 2) constructing a practical scoring system, and 3) determining the optimal single sampling time for serum LH in the GnRH stimulation test. Data of girls aged between 3 and 9yearsat the time of the GnRH stimulation test, who attended our endocrine clinic at the MacKay Children's Hospital for signs of puberty between July 2014 and June 2019, were analyzed retrospectively. We recorded patients' age, height, weight, breast Tanner stage (BS), bone age, serum LH, and follicle-stimulating hormone (FSH). Receiver operating characteristic (ROC) curves and the Youden index were used to obtain the optimal basal serum LH level. Binary logistic regression was employed to construct a practical scoring system. Cross-sectional, cumulative frequency, and ROC curves were used to simplify the GnRH stimulation test. Overall, 381 sets of GnRH stimulation tests were performed in 313 patients. Basal serum LH≥0.2 IU/L demonstrated 70% sensitivity and 70% specificity for predicting positive GnRH stimulation test results. The practical scoring system (3×BS+3×LH+4×FSH) showed 76% sensitivity and 72% specificity. The serum LH level at 30min after intravenous gonadorelin exhibited 99% sensitivity and 100% specificity. Single sampling of serum LH at 30th minute post-injection of GnRH demonstrated a diagnostic performance equivalent to the traditional GnRH stimulation test in diagnosing CPP. Therefore, this approach could become the simplest diagnostic modality.

Machine learning identifies girls with central precocious puberty based on multisource data.

ObjectiveThe study aimed to develop simplified diagnostic models for identifying girls with central precocious puberty (CPP), without the expensive and cumbersome gonadotropin-releasing hormone (GnRH) stimulation test, which is the gold standard for CPP diagnosis. Materials and methodsFemale patients who had secondary sexual characteristics before 8 years old and had taken a GnRH analog (GnRHa) stimulation test at a medical center in Guangzhou, China were enrolled. Data from clinical visiting, laboratory tests, and medical image examinations were collected. We first extracted features from unstructured data such as clinical reports and medical images. Then, models based on each single-source data or multisource data were developed with Extreme Gradient Boosting (XGBoost) classifier to classify patients as CPP or non-CPP.ResultsThe best performance achieved an area under the curve (AUC) of 0.88 and Youden index of 0.64 in the model based on multisource data. The performance of single-source models based on data from basal laboratory tests and the feature importance of each variable showed that the basal hormone test had the highest diagnostic value for a CPP diagnosis.ConclusionWe developed three simplified models that use easily accessed clinical data before the GnRH stimulation test to identify girls who are at high risk of CPP. These models are tailored to the needs of patients in different clinical settings. Machine learning technologies and multisource data fusion can help to make a better diagnosis than traditional methods.

Girls with Premature Thelarche Younger than 3 Years of Age May Have Stimulated Luteinizing Hormone Greater than 10 IU/L

Objective:Premature thelarche (PT) is defined as isolated breast development in girls before eight years of age. Gonadotropin-releasing hormone (GnRH) stimulation test is sometimes used to distinguish between PT and central precocious puberty (CPP), although the interpretation of the test at early ages is challenging. The objective of this study was to determine the follicle stimulating hormone (FSH) and luteinizing hormone (LH) responses to GnRH stimulation in girls with PT below 3 years of age.Methods:A standardized GnRH stimulation test, bone age and pelvic ultrasound were evaluated and those without pubertal progression after a minimum of one-year follow up were included in the study.Results:On GnRH stimulation test, the median (range) baseline LH was 0.29 (0.10-0.74) IU/L, baseline FSH was 4.96 (3.18-7.05) mIU/mL, and the peak median LH was 5.75 (3.31-8.58) IU/L with the peak mean±standard deviation FSH was 40.38±20.37 mIU/mL. Among the patients, 33.3% (n=10) had baseline LH >0.3 IU/L, 67% (n=20) had peak LH >5 IU/l and 16.6% (n=5) >10 IU/L. The mean peak LH/FSH ratio was 0.17±0.09 and was ≤0.43 in all participants.Conclusion:Although consensus statements usually define baseline LH >0.3-0.5 IU/L, peak LH >5 IU/L, and LH/FSH ratios >0.66-1.0 as diagnostic cut-offs for CPP, in children below 3 years of age, the baseline and peak LH values may be similar to pubertal values, possibly due to mini-puberty. A dominant FSH response on GnRH stimulation test is more valuable than the peak LH response in the diagnosis of PT.

Diagnostic value of pituitary volume in girls with precocious puberty

BackgroundTo date, the gonadotropin-releasing hormone (GnRH) stimulation test is still the gold standard for precocious puberty (PP) diagnosis. However, it has many disadvantages, including low sensitivity, high cost, and invasive operation. This study aims to evaluate whether magnetic resonance imaging (MRI)-derived variables, including pituitary volume (PV), could be used as diagnostic factors for PP in girls, providing a non-invasive diagnostic approach for PP.MethodsA total of 288 young female patients who presented to the Clinic of Pediatric Endocrinology for evaluation of PP from January 2015 to December 2017 were enrolled. The sample included 90 girls diagnosed with premature thelarche (PT), 133 girls determined as idiopathic central precocious puberty (ICPP), 35 early pubertal girls, and 30 normal girls. All patients received pituitary MRI examinations.ResultsThe largest PV and pituitary height were shown in the ICPP and pubertal groups, followed by the PT group. The receiver operating characteristic (ROC) curve analysis showed that PV is a predictive marker for ICPP, with a sensitivity of 54.10% and a specificity of 72.20% at the cutoff value of 196.01 mm3. By univariate analysis, PV was positively associated with peak luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), age, bone age, and body mass index (BMI) (all P < 0.05). However, bone age and peak LH were the only significant predictors of PV as demonstrated by the stepwise multivariate regression analysis (Model: PV = 9.431 * bone age + 1.230 * peak LH + 92.625 [P = 0.000, R2 = 0.159]).ConclusionsThe PV in the ICPP group was significantly higher than in PT and control groups, but there was no reliable cutoff value to distinguish ICPP from PT. Pituitary MRI should be combined with clinical and laboratory tests to improve the diagnostic value of PV for PP.

Factors affecting bone maturation in Chinese girls aged 4\u20138\xa0years with isolated premature thelarche

BackgroundIn isolated premature thelarche (IPT) girls, bone age (BA) is considered consistent with chronological age. However, some IPT girls confirmed by gonadotropin-releasing hormone (GnRH) stimulation test could show another trend. We analysed BA and possible potentiating factors in a selected group of girls aged 4–8 years with IPT.MethodsIPT girls confirmed by GnRH stimulation test aged 4–8 years hospitalized from January 2015 to April 2018 at Shenzhen Children’s Hospital were included in this retrospective study. They were divided into two groups with advanced BA of 2 years as the cut-off. Body mass index (BMI) and hormone levels were the main outcome measures, and regression analysis was used to identify independent risk factors. IPT girls were divided into subgroups according to the levels of BMI standard deviation score (SDS), insulin-like growth factor-1 (IGF-1) SDS and dehydroepiandrosterone sulfate (DHEAS) SDS for comparisons of advanced BA.ResultsOverall, 423 subjects were included and classified into the advanced BA group (48.7%, n = 206) and control group (51.3%, n = 217). The advanced BA group had significantly higher BMI SDS, serum DHEAS SDS, IGF-1 SDS, androstenedione and fasting insulin and significantly lower sex hormone binding globulin (all p < 0.001). Serum IGF-1 SDS (OR = 1.926, p<0.001), BMI SDS (OR = 1.427, p = 0.001) and DHEAS SDS (OR = 1.131, p = 0.005) were independent risk factors for significantly advanced BA. In the multiple linear regression model, serum IGF-1 SDS, BMI SDS and DHEAS SDS were the strongest predictors of advanced BA, accounting for 19.3% of the variance. According to BMI, 423 patients were classified into three groups: normal weight (56.03%, n = 237), overweight (19.15%, n = 81) and obesity (24.82%, n = 105). The proportion of advanced BA in obesity group was significantly higher than those of normal weight and overweight groups (χ2 = 18.088, p<0.001). In the subgroup with normal weight, higher serum IGF-1 SDS (p = 0.009) and DHEAS SDS (p = 0.003) affected BA advancement independent of BMI SDS.ConclusionsGirls with IPT confirmed by GnRH stimulation test aged 4–8 years might have significantly advanced BA. Obesity was highly associated with advanced BA. Age-specific serum IGF-1 SDS and DHEAS SDS were risk factors for BA advancement independent of BMI.

Gonadotropin-releasing hormone stimulation test and diagnostic cutoff in precocious puberty: a mini review.

The gonadotropin-releasing hormone (GnRH) stimulation test is a valuable tool in diagnosing and differentiating causes of early pubertal occurrences. Utility of the test can be limited in some instances, however, including the early phases of pubertal hypothalamic-pituitary-gonadal axis activation, in girls showing commonly overlapping pictures, and in obese children due to excess circulating estrogen that suppresses luteinizing hormone (LH). A lack of consistent baseline and stimulated gonadotropin cutoffs observed in different studies also contributes to limitations in testing. Nevertheless, early detection of true pathological causes for pubertal disorders is needed to allow prompt treatment and better prognosis. While basal LH can be beneficial as a good screening tool for detecting pubertal disorder, it does not preclude the need for GnRH testing. The aim of this review was to highlight the role of GnRH stimulation tests and varying testing cutoffs in diagnosis of precocious puberty and its classification.

Fenilketonüri ve Puberte Prekoks Birlikteliği: Bir vaka sunumu

Phenylketonuria (PKU) is one of the most common preventable causes of intellectual disability resulting from deficiency of phenylalanine hydroxylase enzyme activity. Precocious puberty (PP) is characterized by premature breast and pubic hair development, and advanced bone age development before 8 years of age for girls and 9 years of age for boys. We present a 7 years old girl with phenylketonuria and overweight, who has developed early puberty. PKU was confirmed by plasma amino acid analysis at newborn.At the age of 7, the first signs of PP appeared (T3). Laboratory tests were detected as luteinizing hormone 0.36 mIU/mL; follicule stimulating hormone 1.1 mIU/mL; estradiol 20 pg/mL; and bone age was 9 years. The response to gonadotropin-releasing hormone stimulation test was characteristic for true PP (LH 5.4 mIU/mL; FSH 8 mIU/mL). According to our current knowledge, the reason for this union isn’t clear. However, this association may be incidental or secondary to overweight and may also be secondary to phenylketonuria - good / bad metabolic control. It’s thought that PP cases may be seen more frequently due to the increase of obesity frequency in PKU patients.

Influence of the hypothalamus–pituitary–gonadal axis reactivation and pubertal hormones on gray matter volume in early pubertal girls

Objective Puberty is a sensitive period of brain development accompany with pubertal hormones fluctuation. However, the underlying mechanisms of the impact of hypothalamus–pituitary–gonadal (HPG) axis reactivation and associated elevated pubertal hormones on brain structure are still unclear. Here, we investigated the brain structure differences between girls with and without HPG axis reactivation and the influence of pubertal hormones on these brain regions. Methods 126 girls aged 8–9.5 years underwent a gonadotropin-releasing hormone (GnRH) stimulation test to identify the HPG axis status and categorized into HPG+ group (n = 80) and HPG- group (n = 46). T1-weighted gradient echo three dimensional MRI was performed using a 3.0-Tesla scanner to assess the difference in GMV between the two groups. Correlation analyses were conducted to explore the relations between the brain regions showing significant GMV differences and serum hormone concentrations. Result The HPG+ group showed significantly higher GMV in the bilateral lingual gyrus and lower GMV within the right orbital inferior frontal gyrus compare to the HPG − group. Furthermore, GMV in the right orbital inferior frontal gyrus was positively associated with plasma concentrations of follicle stimulating hormone (FSH) in HPG+ group. Conclusion The present study suggests that the reactivated HPG axis could affects regional structural brain changes in early pubertal girls. FSH production play an important role in bilateral lingual gyrus, which are involved in vision processing, semantic processing and emotional expression.

Altered Brain Structure and Functional Connectivity Associated with Pubertal Hormones in Girls with Precocious Puberty

Pubertal hormones play an important role in brain and psychosocial development. However, the role of abnormal HPG axis states in altering brain function and structure remains unclear. The present study is aimed at determining whether there were significant differences in gray matter volume (GMV) and resting state (RS) functional connectivity (FC) patterns in girls with idiopathic central precocious puberty (CPP) and peripheral precocious puberty (PPP). We further explored the correlation between these differences and serum pubertal hormone levels. To assess this, we recruited 29 idiopathic CPP girls and 38 age-matched PPP girls. A gonadotropin-releasing hormone (GnRH) stimulation test was performed, and pubertal hormone levels (including luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin, and cortisol) were assessed. All subjects underwent multimodal magnetic resonance imaging of brain structure and function. Voxel-based morphometry (VBM) analysis was paired with seed-to-voxel whole-brain RS-FC analysis to calculate the GMV and RS-FC in idiopathic CPP and PPP girls. Correlation analyses were used to assess the effects of pubertal hormones on brain regions with structural and functional differences between the groups. We found that girls with CPP exhibited decreased GMV in the left insula and left fusiform gyrus, while connectivity between the left and right insula and the right middle frontal gyrus (MFG), as well as the left fusiform gyrus and right amygdala, was reduced in girls with CPP. Furthermore, the GMV of the left insula and peak FSH levels were negatively correlated while higher basal and peak E2 levels were associated with increased bilateral insula RS-FC. These findings suggest that premature activation of the HPG axis and pubertal hormone fluctuations alter brain structure and function involved in the cognitive and emotional process in early childhood. These findings provide vital insights into the early pathophysiology of idiopathic CPP.

Basal serum luteinizing hormone value as the screening biomarker in female central precocious puberty.

PurposePrecocious puberty refers to the development of secondary sex characteristics before ages 8 and 9 years in girls and boys, respectively. Central precocious puberty (CPP) is caused by premature activation of the hypothalamus-pituitary-gonadal (HPG) axis and causes thelarche in girls before the age of 8. A gonadotropin-releasing hormone (GnRH) stimulation test is the standard diagnostic modality for diagnosing CPP. However, the test cannot always be used for screening because it is expensive and time-consuming. This study aimed to find alternative reliable screening parameters to identify HPG axis activation in girls <8 years old (CPP) and for girls 8–9 years old (early puberty, EP).MethodsFrom January 2013 to June 2015, medical records from 196 girls younger than 9 years old with onset of breast development were reviewed, including 126 girls who had a bone age (BA) 1 year above their chronological age. All patients underwent a GnRH stimulation test, and 117 underwent pelvic sonography. The girls were divided into 4 groups based on age and whether the GnRH stimulation test showed evidence of central puberty. Subanalyses were also conducted within each group based on peak luteinizing hormone (LH) level quartiles.ResultsBasal serum LH level was the most sensitive marker for screening CPP and EP. The cutoff values were 0.245 IU/L for CPP under 8 years old (P=0.049, area under the curve [AUC]=0.764, 88% sensitivity, 48% specificity) and 0.275 IU/L for EP between 8–9 years old (P=0.005, AUC=0.813, 79% sensitivity, 77% specificity). Peak LH level decreased as BMI z-score among subgroups increased when there was no difference in BA; however, higher BA eliminated this effect.ConclusionsBasal serum LH level is a useful screening parameter for diagnosing CPP and EP in girls. Peak LH levels were lower with increasing BMI z-score, although older BA eliminated this effect.