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Frontiers in Endocrinology 2021The gonadotropin-releasing hormone (GnRH) stimulation test is the benchmark for diagnosing precocious puberty (PP). However, it is invasive, time-consuming, costly, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The gonadotropin-releasing hormone (GnRH) stimulation test is the benchmark for diagnosing precocious puberty (PP). However, it is invasive, time-consuming, costly, and may create an unpleasant experience for participants. Moreover, some overlaps may occur between PP and premature thelarche (PT) in the early stage of PP. Female pelvic ultrasonography may provide additional information to help differentiate PP from PT and subsequently initiate early treatment. In this study, we aimed to first directly compare pelvic ultrasonography parameters between PP and PT groups and secondly, investigate their diagnostic accuracy compared with the GnRH stimulation test.
METHODS
A systematic search of the PubMed/MEDLINE, EMBASE, Scopus, and Cochrane Library databases was performed up to March 31, 2021. All types of studies, except for case reports and review articles, were included. The GnRH stimulation test was used to confirm PP diagnosis. Those whose organic conditions might cause PP were excluded. The mean, standard deviation, sensitivity, and specificity of each parameter were documented. Forest plots were constructed to display the estimated standardized mean differences (SMDs) from each included study and the overall calculations. A bivariate model was used to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR).
RESULTS
A total of 13 studies were included for analysis. The SMDs (95% confidence interval - CI) in ovarian volume, fundal-cervical ratio, uterine length, uterine cross-sectional area, and uterine volume between PP and PT groups were 1.12 (0.78-1.45; p < 0.01), 0.90 (0.07-1.73; p = 0.03), 1.38 (0.99-1.78; p < 0.01), 1.06 (0.61-1.50; p < 0.01), and 1.21 (0.84-1.58; p <0.01), respectively. A uterine length of 3.20 cm yielded a pooled sensitivity of 81.8% (95% CI 78.3%-84.9%), specificity of 82.0% (95% CI 61.0%-93.0%), PLR of 4.56 (95% CI 2.15-9.69), NLR of 0.26 (95% CI 0.17-0.39), and DOR of 19.62 (95% CI 6.45-59.68). The area under the summary receiver operating characteristics curve was 0.82.
CONCLUSION
Female pelvic ultrasonography may serve as a complementary tool to the GnRH stimulation test in differentiating PP from PT.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232427, ID: CRD42021232427.
Topics: Child; Diagnosis, Differential; Female; Humans; Puberty, Precocious; Sensitivity and Specificity; Ultrasonography; Uterus
PubMed: 34539579
DOI: 10.3389/fendo.2021.735875 -
Endocrine Connections Sep 2021To evaluate the characteristics and significance of serum kisspeptin and makorin ring finger protein 3 (MKRN3) levels for the diagnosis of central precocious puberty...
OBJECTIVE
To evaluate the characteristics and significance of serum kisspeptin and makorin ring finger protein 3 (MKRN3) levels for the diagnosis of central precocious puberty (CPP) in girls.
METHOD
Thirty four individuals with CPP, 17 individuals with premature thelarche (PT), and 28 age-matched prepubertal girls as normal control (NC) were recruited in this case-control study. Physical measurements included BMI and tests for breast, bone, and sexual characteristics. Biochemical measurements included serum LH, FSH, estradiol, insulin-like growth factor-1, MKRN3, and kisspeptin. Blood samples were taken from individuals with CPP and PT before the gonadotrophin-releasing hormone stimulation test and at 30, 60, 90, and 120 min after injection with triptorelin.
RESULTS
Serum kisspeptin levels were higher in the CPP group when compared to the NC group (P = 0.020), while serum MKRN3 levels were lower in the two groups (P = 0.028). There were no significant differences between the CPP and PT groups as well as the PT and NC groups (all, P > 0.05). The cut-off value of serum kisspeptin differentiating patients with CPP from those without CPP was 0.40 nmol/L, with 82.4% sensitivity and 57.1% specificity, while the cut-off value of serum MKRN3 was 0.33 pmol/L, with 79.4% sensitivity and 53.6% specificity. The area under the curves (AUCs) of both kisspeptin and MKRN3 for differentiating those girls with CPP from PT were less than 0.5.
CONCLUSIONS
Serum levels of kisspeptin and MKRN3 may play an auxiliary role in predicting CPP. However, the two measurements were not able to differentiate girls with CPP from PT and prepubertal control. This study emphasizes the need to search for markers to simplify the accurate diagnosis of CPP in girls.
PubMed: 34414898
DOI: 10.1530/EC-21-0182 -
Frontiers in Endocrinology 2021Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple... (Review)
Review
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.
Topics: Abnormalities, Multiple; Child; Craniofacial Abnormalities; Female; Humans; Magnetic Resonance Imaging; Pituitary Diseases; Pituitary Gland; Puberty, Precocious; Syndrome; Tomography, X-Ray Computed; Triptorelin Pamoate
PubMed: 34122353
DOI: 10.3389/fendo.2021.685888 -
Hormone Research in Paediatrics 2021Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal...
BACKGROUND
Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal serum luteinizing hormone (LH) ≥0.3 IU/L or LH-releasing hormone (LHRH)-stimulated LH ≥5 IU/L). Stimulation testing is the diagnostic gold standard but is time-consuming and costly. Serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are increased in girls with CPP.
OBJECTIVE
The aim of the study was to assess the utility of serum IGF-1 and IGFBP-3 in identifying CPP in girls aged 6-8 years.
METHODS
The study was a single-center retrospective study. Girls with confirmed CPP (n = 44) and isolated premature precocious adrenarche/ precocious thelarche (PA/PT, n = 16) had baseline biochemical profiling and LHRH stimulation testing. Serum IGF-1 and IGFBP-3 results were converted to standard deviation scores (SDS). Correlations were calculated and receiver operating characteristic curves were plotted.
RESULTS
Girls with CPP had higher basal and peak LH, IGF-1 SDS, and growth velocity (p < 0.05). IGF-1 SDS correlated positively with basal and peak LH (p < 0.05). IGF-1 SDS (1.75-2.15) differentiated CPP and PA/PT with 89% sensitivity and 56% specificity (basal LH) and 94% specificity and 55% sensitivity (peak LH). IGFBP-3 SDS did not differ between groups or by CPP parameters.
CONCLUSIONS
In clinical practice, IGF-1 SDS may be an additional tool for identifying CPP in girls aged 6 to 8 years when baseline clinical and laboratory diagnostic criteria are inconclusive, possibly avoiding more time-consuming and costly procedures.
Topics: Child; Female; Follicle Stimulating Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Luteinizing Hormone; Puberty, Precocious; Retrospective Studies; Sensitivity and Specificity
PubMed: 34098553
DOI: 10.1159/000516361 -
Annals of Pediatric Endocrinology &... Sep 2021The gold standard for assessing pubertal activation is the gonadotropinreleasing hormone (GnRH) stimulation test (GnRHST), which is invasive, timeconsuming, and...
PURPOSE
The gold standard for assessing pubertal activation is the gonadotropinreleasing hormone (GnRH) stimulation test (GnRHST), which is invasive, timeconsuming, 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.
METHODS
Fifty-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.
RESULTS
Although 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.
CONCLUSION
A single, random measurement of urinary gonadotropin concentration could be a reliable tool for initial screening and therapeutic monitoring of CPP in girls.
PubMed: 34015906
DOI: 10.6065/apem.2040208.104 -
Hormone Research in Paediatrics 2020Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty... (Meta-Analysis)
Meta-Analysis
BACKGROUND/AIMS
Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty to establish reproductive function and regulate the hypothalamic-pituitary-gonadal axis. Premature activation of GnRH secretion leads to idiopathic/central gonadotropin-dependent precocious puberty (CPP). We aimed to compare the blood KP concentrations in girls with CPP and healthy controls.
METHODS
A systematic review and meta-analysis was performed. We searched MEDLINE, EMBASE, The Cochrane Library, and SciELO. Random-effects model and standardized mean difference (SMD) were used. Heterogeneity was assessed through I2. Meta-regression considered patient age, KP fraction, and analytical method for KP measurement.
RESULTS
The 11 studies included comprised 316 CPP patients and 251 controls. Higher KP levels in the CPP group were found (SMD 1.53; CI 95% = 0.56-2.51). Subgroup analysis revealed association with patient age (p = 0.048), indicating a positive correlation between elevation in KP concentration and age in CPP group. A group of patients with precocious thelarche (PT) from 5 of the included studies comprising 121 patients showed higher levels of KP (1.10; -0.25-2.45: CI 95%) and high heterogeneity (I2 = 91%). The CPP/PT ratio for KP level indicates KP 36% higher on CPP than PT patients.
CONCLUSIONS
A consistent difference in KP levels between girls with CPP and controls was identified. While there are important limitations in KP assays which argue against its use as a diagnostic tool, the KP levels in CPP versus control and PT children are consistent with the predicted mechanisms and pathophysiology of CPP.
Topics: Case-Control Studies; Child; Female; Humans; Kisspeptins; Puberty, Precocious
PubMed: 33887744
DOI: 10.1159/000515660 -
BMJ Case Reports Mar 2021A 7-month-old female infant presented with failure to thrive. She was breastfed till 3 months of age, thereafter switched to soy-based milk formula. There was no history...
A 7-month-old female infant presented with failure to thrive. She was breastfed till 3 months of age, thereafter switched to soy-based milk formula. There was no history to suggest excess energy losses, recurrent infections or chronic diarrhoea. Three months after switching to exclusive soy-based milk formula, parents noticed significant enlargement of both breasts. Clinical examination was unremarkable except for enlargement of both breasts. None of the other secondary sexual characteristics were present. Initial blood investigations showed hyponatraemic hypokalaemic hypochloraemic metabolic alkalosis, which corrected after 2 days with intravenous hydration. The patient subsequently maintained normal electrolyte balance with recommended intake of cow's milk-based standard formula milk.Further exploration of her soy-based milk revealed that it was low in sodium and calories, unsuitable for children. This was not a standard and approved infant soy-based formula milk. She achieved excellent weight gain and reduction of breast size on cessation of soy-based milk formula.
Topics: Animals; Breast Feeding; Cattle; Child; Failure to Thrive; Female; Humans; Infant; Infant Formula; Milk; Milk Hypersensitivity
PubMed: 33758044
DOI: 10.1136/bcr-2020-239651 -
Asian Biomedicine : Research, Reviews... Feb 2021The criterion standard gonadotropin-releasing hormone (GnRH) stimulation tests to diagnose central precocious puberty (CPP) are time-consuming, inconvenient, and...
BACKGROUND
The criterion standard gonadotropin-releasing hormone (GnRH) stimulation tests to diagnose central precocious puberty (CPP) are time-consuming, inconvenient, and expensive.
OBJECTIVES
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.
METHODS
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.
RESULTS
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 cm and 1.5 cm 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%.
CONCLUSION
Combining uterine and ovarian ultrasonographic parameters with basal gonadotropin levels, especially uterine width and basal LH level, appears useful for diagnosis of CPP.
PubMed: 37551300
DOI: 10.2478/abm-2021-0004 -
Pediatric Endocrinology, Diabetes, and... 2021Knowledge of uterine and ovarian growth patterns during early age and puberty helps in investigating disorders of pubertal development i.e. precocious puberty, premature... (Observational Study)
Observational Study
INTRODUCTION
Knowledge of uterine and ovarian growth patterns during early age and puberty helps in investigating disorders of pubertal development i.e. precocious puberty, premature thelarche, or pubarche. There is a paucity of data for uterine and ovarian parameters. Aim of the study: The aim of this study is to present normative data for Uterine length, Mean ovarian volume (MOV), and fundo cervical ratio (FCR) from 5 to 16 years in healthy girls from north India and to correlate these parameters with age, weight, height, and pubertal Tanner staging.
MATERIAL AND METHODS
A cross-sectional observational study was performed on 130 healthy girls age 5 to 16 years. Age, anthropometric parameters were measured and the pubertal stage was categorized using Tanner staging. All subjects underwent pelvic ultrasonography for the measurement of uterine and ovarian parameters.
RESULTS
Normative data of uterine length, MOV, and FCR were presented as mean, SD, median, and 95% confidence interval as per age and Tanner stage. A progressive increase in uterine length, MOV & FCR was observed with increasing age, weight, height, and Tanner stage (p < 0.001). A sudden significant increment in uterine length and MOV was observed between the age of 11-12 and 12-13 years (p < 0.001). Uterine length of < 4 cm, MOV < 2 cm3 and FCR < 1 were specific to identify pre-pubertal girls.
CONCLUSIONS
Normative data of uterine and ovarian parameters generated in our study by ultrasonography would be useful for screening girls with abnormalities of pubertal development.
Topics: Adolescent; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; India; Ovary; Puberty, Precocious; Ultrasonography; Uterus
PubMed: 33599435
DOI: 10.5114/pedm.2020.103112 -
Endocrine Connections Feb 2021The objective of this study was to analyze whether some auxological characteristics or a single basal gonadotropin measurement will be sufficient to distinguish the...
OBJECTIVE
The objective of this study was to analyze whether some auxological characteristics or a single basal gonadotropin measurement will be sufficient to distinguish the prepubertal from pubertal status.
METHODS
Auxologycal characteristics were recorded and serum LH and FSH were measured by immunochemiluminescence assays before and after GnRH stimulation test in a sample of 241 Caucasian girls with breast budding between 6- and 8-years old. Peak LH levels higher than 5 IU/L were considered a pubertal response. Area under the curve, cut-off points, sensitivity, and specificity for auxologycal variables and basal gonadotropins levels were determined by receiver operating curves.
RESULTS
There were no significant differences in age at onset, weight, height, BMI and height velocity between both groups. Bone age was significantly higher in pubertal girls (P < 0.05), although with limited discriminatory capacity. The sensitivity and specificity for the basal LH levels were 89 and 82%, respectively, for a cut off point of 0.1 IU/L. All girls in the pubertal group had a basal LH higher than 1.0 IU/L (positive predictive value of 100%). There was a wide overlap of basal FSH and LH/FSH ratio between prepubertal and pubertal girls.
CONCLUSIONS
Auxologycal characteristics should not be used only in the differential diagnosis between prepubertal from pubertal status in 6- to 8-year-old girls. We found a high specificity of a single basal LH sample and it would be useful for establishing the diagnosis of puberty in this age group, reducing the need for GnRH stimulation testing.
PubMed: 33416514
DOI: 10.1530/EC-20-0651