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

Adiposity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02790112
• Other study ID #: 2015/14OCT/549
• Secondary ID: RESEARCH GRANT
• Status: Enrolling by invitation
• Phase: N/A
• First received: April 25, 2016
• Last updated: May 30, 2016
• Start date: April 2016
• Est. completion date: October 2018

Study information

• Verified date: May 2016
• Source: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 418
• Est. completion date: October 2018
• Est. primary completion date: April 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adiposity
• Obesity
• Puberty, Precocious

Intervention

Other:
• GnRHas
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.

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc	Brussels

Sponsors (2)

Lead Sponsor	Collaborator
Cliniques universitaires Saint-Luc- Université Catholique de Louvain	Belgian Study Group for Pediatric Endocrinology

Country where clinical trial is conducted

Belgium, 

References & Publications (23)

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Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR; ESPE-LWPES GnRH Analogs Consensus Conference Group, Antoniazzi F, Berenbaum S, Bourguignon JP, Chrousos GP, Coste J, Deal S, de Vries L, Foster C, Heger S, Holland J, Jahnukainen K, Juul A, Kaplowitz P, Lahlou N, Lee MM, Lee P, Merke DP, Neely EK, Oostdijk W, Phillip M, Rosenfield RL, Shulman D, Styne D, Tauber M, Wit JM. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009 Apr;123(4):e752-62. doi: 10.1542/peds.2008-1783. Epub 2009 Mar 30. Review. — View Citation

Chiavaroli V, Liberati M, D'Antonio F, Masuccio F, Capanna R, Verrotti A, Chiarelli F, Mohn A. GNRH analog therapy in girls with early puberty is associated with the achievement of predicted final height but also with increased risk of polycystic ovary syndrome. Eur J Endocrinol. 2010 Jul;163(1):55-62. doi: 10.1530/EJE-09-1102. Epub 2010 Mar 31. — View Citation

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Colmenares A, Gunczler P, Lanes R. Higher prevalence of obesity and overweight without an adverse metabolic profile in girls with central precocious puberty compared to girls with early puberty, regardless of GnRH analogue treatment. Int J Pediatr Endocrinol. 2014;2014(1):5. doi: 10.1186/1687-9856-2014-5. Epub 2014 Apr 17. — View Citation

Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A, Kelestimur F, Macut D, Micic D, Pasquali R, Pfeifer M, Pignatelli D, Pugeat M, Yildiz BO; ESE PCOS Special Interest Group. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol. 2014 Oct;171(4):P1-29. doi: 10.1530/EJE-14-0253. Epub 2014 May 21. Review. — View Citation

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Dreyfus J, Jacobs DR Jr, Mueller N, Schreiner PJ, Moran A, Carnethon MR, Demerath EW. Age at Menarche and Cardiometabolic Risk in Adulthood: The Coronary Artery Risk Development in Young Adults Study. J Pediatr. 2015 Aug;167(2):344-52.e1. doi: 10.1016/j.jpeds.2015.04.032. Epub 2015 May 9. — View Citation

Franceschi R, Gaudino R, Marcolongo A, Gallo MC, Rossi L, Antoniazzi F, Tatò L. Prevalence of polycystic ovary syndrome in young women who had idiopathic central precocious puberty. Fertil Steril. 2010 Mar 1;93(4):1185-91. doi: 10.1016/j.fertnstert.2008.11.016. Epub 2009 Jan 9. — View Citation

Ibáñez L, Lopez-Bermejo A, Díaz M, Suárez L, de Zegher F. Low-birth weight children develop lower sex hormone binding globulin and higher dehydroepiandrosterone sulfate levels and aggravate their visceral adiposity and hypoadiponectinemia between six and eight years of age. J Clin Endocrinol Metab. 2009 Oct;94(10):3696-9. doi: 10.1210/jc.2009-0789. Epub 2009 Sep 8. — View Citation

Klein KO, Barnes KM, Jones JV, Feuillan PP, Cutler GB Jr. Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. J Clin Endocrinol Metab. 2001 Oct;86(10):4711-6. — View Citation

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Lazar L, Lebenthal Y, Yackobovitch-Gavan M, Shalitin S, de Vries L, Phillip M, Meyerovitch J. Treated and untreated women with idiopathic precocious puberty: BMI evolution, metabolic outcome, and general health between third and fifth decades. J Clin Endocrinol Metab. 2015 Apr;100(4):1445-51. doi: 10.1210/jc.2014-3748. Epub 2015 Feb 4. — View Citation

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Magiakou MA, Manousaki D, Papadaki M, Hadjidakis D, Levidou G, Vakaki M, Papaefstathiou A, Lalioti N, Kanaka-Gantenbein C, Piaditis G, Chrousos GP, Dacou-Voutetakis C. The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. J Clin Endocrinol Metab. 2010 Jan;95(1):109-17. doi: 10.1210/jc.2009-0793. Epub 2009 Nov 6. — View Citation

Ong KK, Elks CE, Wills AK, Wong A, Wareham NJ, Loos RJ, Kuh D, Hardy R. Associations between the pubertal timing-related variant in LIN28B and BMI vary across the life course. J Clin Endocrinol Metab. 2011 Jan;96(1):E125-9. doi: 10.1210/jc.2010-0941. Epub 2010 Oct 20. — View Citation

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of life	Self-perception profile for adults, Messer & Harter 2012	1 day	Yes
Primary	Single nucleotide polymorphisms (SNP) analyses	DNA analyses	1 day	Yes
Secondary	Adult height in meters	Measured at consultation	1 day	Yes
Secondary	Body mass index in kg/m2	Calculated at consultation	1 day	Yes
Secondary	Body composition in %	Dual energy x-ray absorptiometry (DXA): fat (visceral) and lean mass.	1 day	Yes
Secondary	Glucose in mg/dl	Fasting blood sampling	1 day	Yes
Secondary	Total Cholesterol in mg/dl	Fasting blood sampling	1 day	Yes
Secondary	LDL-Cholesterol in mg/dl	Metabolic assessment (fasting blood sampling)	1 day	Yes
Secondary	HDL-Cholesterol in mg/dl	Fasting blood sampling	1 day	Yes
Secondary	Insulin in microU/ml	Fasting blood sampling	1 day	Yes
Secondary	Total bone mineralization in Tscore	Dual energy x-ray absorptiometry (DXA):	1 day	Yes
Secondary	Lumbar bone mineralization in Tscore	Dual energy x-ray absorptiometry (DXA):	1 day	Yes
Secondary	Femoral neck bone mineralization in Tscore	Dual energy x-ray absorptiometry (DXA):	1 day	Yes
Secondary	Ovaries volume in ml	Pelvic ultrasound (at 2nd-5th day of the menstrual cycle)	1 day	Yes
Secondary	Ovaries follicles diameter in mm	Pelvic ultrasound (at 2nd-5th day of the menstrual cycle)	1 day	Yes
Secondary	Chronic anovulation in number	Number of mentruals cycles in a year	1 day	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	Ovaries follicles counting	Pelvic ultrasound (at 2nd-5th day of the menstrual cycle)	1 day	Yes
Secondary	Abdominal perimeter in cm	Measured at consultation	1 day	Yes
Secondary	Hip perimeter in cm	Measured at consultation	1 day	Yes
Secondary	Blood pressure in mmHg	Measured at consultation	1 day	Yes
Secondary	Testicular volume in ml	Measured at consultation	1 day	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	Uterine diameter in mm	Pelvic ultrasound (at 2nd-5th day of the menstrual cycle)	1 day	Yes
Secondary	Uterine volume in ml	Pelvic ultrasound (at 2nd-5th day of the menstrual cycle)	1 day	Yes
Secondary	Endometrius thickness in mm	Pelvic ultrasound (at 2nd-5th day of the menstrual cycle)	1 day	Yes