Long-term Outcome of GnRH Analogues Treatment of Children With Idiopathic Central Precocious Puberty

Study Overview
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Brief Summary
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This study evaluates the influence of early adiposity rebound, genetic polymorphisms and GnRHa treatment on long-term outcome of girls with idiopathic central precocious puberty.

Detailed Description
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Gonadotropin-releasing hormone (GnRH) analogs are the mainstay of treatment for central precocious puberty (CPP) since 1985. The relatively short time period elapsed since the introduction of this therapy has not allowed until now to carry out exhaustive studies on the long-term evolution of treated patients. This project will analyze the long-term outcomes of patients with CPP treated or not with GnRHas on adult height, body mass index, body composition, metabolic disorders, bone mineralization, gonadal function, and fertility in comparison to a control group. Overweight before puberty is associated to earlier menarche, and conversely, earlier menarche predispose to adult obesity and metabolic disorders. Nevertheless, it is unclear if adult adiposity is a direct consequence of early puberty or if early puberty is a marker of a predisposition to excess adiposity from prepuberty through adult life. Recent data in rodent models support the hypothesis that early nutritional status determines a risk for both childhood and adult obesity and influences pubertal timing. In girls, early weight gain in childhood has been associated with early menarche. Pattern of growth rather than absolute level of fatness seem to be of most importance. So the first aim of this study is to compare the outcomes of CCP patients with or without an early adiposity rebound and to demonstrate that adiposity rebound more than CPP per se or the GnRHas therapy affect the outcomes. Moreover, recent genome-wide association studies have identified obesity-related gene variants associated with earlier age at menarche. The investigators hypothesized that there might be a genetic basis underlying the early programming of both childhood and adulthood adiposity and puberty timing. The investigators thus aim to determine if those obesity-related gene variants associated with an early but not precocious menarche could also be found in CPP, especially in girls with an early adiposity rebound and if their presence may affect adult health.

Official Title
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Influence of Early Adiposity Rebound, Genetic Polymorphisms and GnRHa Treatment on Long-term Outcome of Girls With Idiopathic Central Precocious Puberty.

Conditions
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Puberty, Precocious, Adiposity

Intervention / Treatment
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* Other: GnRHas


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of idiopathic CPP (ICPP) treated with GnRHas. A diagnosis of CPP made according to the following criteria: 1) secondary pubertal signs (Tanner stage 2) before 8 years in girls and 9 years in boys; 2) accelerated growth velocity (GV); 3) BA advanced for CA ≥ 1 year; 4) GnRH-stimulated peak LH >5 IU/L. A diagnosis of idiopathic CPP according the following criteria: 1) no hypothalamic-pituitary organic lesions at magnetic resonance imaging; 2) no known medical condition that might affect the onset of puberty. To determine whether the supposed long-term effects of treatment are instead consequences of the disease itself, untreated ICPP girls aged of ≥ 18 years, will also be included. For comparative purposes, age-matched normal (menarche > 10 y) volunteers will be recruited as a control group. Exclusion Criteria: In the treated ICCP group if 1) treatment with GnRHas for < 2 years; 2) non-compliance; 3) no gonadotropin suppression observed. For all patients: 4) small for gestational age; 5) chronic disease and/or treatment; 6) being < 4 years from menarche.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: GnRHas - Not GnRHas patients<br>Compared long term outcome of treated and untreated patients with idiopathic central precocious puberty : hormonal assessment; DNA for candidate single nucleotide polymorphisms (SNP) analyses; pelvic ultrasound; dual energy x-ray absorptiometry (DXA) | Other: GnRHas<br>* Influence of early adiposity rebound, genetic polymorphisms and GnRHa treatment on long-term outcome of treated and untreated girls with idiopathic central precocious compared to a control group. puberty.<br>|
| Other: GnRHas - controls patients<br>Compared long term outcome of treated patients with idiopathic central precocious puberty and control patients for: hormonal assessment; DNA for candidate single nucleotide polymorphisms (SNP) analyses; pelvic ultrasound; dual energy x-ray absorptiometry (DXA) | Other: GnRHas<br>* Influence of early adiposity rebound, genetic polymorphisms and GnRHa treatment on long-term outcome of treated and untreated girls with idiopathic central precocious compared to a control group. puberty.<br>|
| Other: Not GnRHas - Controls patients<br>Compared long term outcome of untreated patients with idiopathic central precocious puberty and control patients for: hormonal assessment; DNA for candidate single nucleotide polymorphisms (SNP) analyses; pelvic ultrasound; dual energy x-ray absorptiometry (DXA) | Other: GnRHas<br>* Influence of early adiposity rebound, genetic polymorphisms and GnRHa treatment on long-term outcome of treated and untreated girls with idiopathic central precocious compared to a control group. puberty.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single nucleotide polymorphisms (SNP) analyses | DNA analyses | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adult height in meters | Measured at consultation | 1 day | 
| Body mass index in kg/m2 | Calculated at consultation | 1 day | 
| Body composition in % | Dual energy x-ray absorptiometry (DXA): fat (visceral) and lean mass. | 1 day | 
| Glucose in mg/dl | Fasting blood sampling | 1 day | 
| Total Cholesterol in mg/dl | Fasting blood sampling | 1 day | 
| LDL-Cholesterol in mg/dl | Metabolic assessment (fasting blood sampling) | 1 day | 
| HDL-Cholesterol in mg/dl | Fasting blood sampling | 1 day | 
| Insulin in microU/ml | Fasting blood sampling | 1 day | 
| Total bone mineralization in Tscore | Dual energy x-ray absorptiometry (DXA): | 1 day | 
| Lumbar bone mineralization in Tscore | Dual energy x-ray absorptiometry (DXA): | 1 day | 
| Femoral neck bone mineralization in Tscore | Dual energy x-ray absorptiometry (DXA): | 1 day | 
| Ovaries volume in ml | Pelvic ultrasound (at 2nd-5th day of the menstrual cycle) | 1 day | 
| Ovaries follicles diameter in mm | Pelvic ultrasound (at 2nd-5th day of the menstrual cycle) | 1 day | 
| Chronic anovulation in number | Number of mentruals cycles in a year | 1 day | 
| SHBG by nmol/l | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| Total serum testosterone by ng/dl | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| Ovaries follicles counting | Pelvic ultrasound (at 2nd-5th day of the menstrual cycle) | 1 day | 
| Abdominal perimeter in cm | Measured at consultation | 1 day | 
| Hip perimeter in cm | Measured at consultation | 1 day | 
| Blood pressure in mmHg | Measured at consultation | 1 day | 
| Testicular volume in ml | Measured at consultation | 1 day | 
| LH in IU/L | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| FSH in IU/L | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| Oestradiol in ng/dl | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| DHEAS in micromol/l | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| 17 hydroxyprogesterone in ng/ml | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| Anti-Müllerian Hormone in ng/ml | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| Inhibine in pg/ml | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| Prolactine in microgr/L | Metabolic assessment (blood sampling before 10 am at the 2nd-5th day of the menstrual cycle or after 2 months of amenorrhea) | 1 day | 
| Uterine diameter in mm | Pelvic ultrasound (at 2nd-5th day of the menstrual cycle) | 1 day | 
| Uterine volume in ml | Pelvic ultrasound (at 2nd-5th day of the menstrual cycle) | 1 day | 
| Endometrius thickness in mm | Pelvic ultrasound (at 2nd-5th day of the menstrual cycle) | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Body Mass Index, Body Composition, Glucose Metabolism Disorders, Bone Development, Gonadal Disorders, Fertility, Overweight, Obesity, Menarche