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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


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)

Barker DJ, Osmond C, Forsén TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med. 2005 Oct 27;353(17):1802-9. — View Citation

Brito VN, Latronico AC, Cukier P, Teles MG, Silveira LF, Arnhold IJ, Mendonca BB. Factors determining normal adult height in girls with gonadotropin-dependent precocious puberty treated with depot gonadotropin-releasing hormone analogs. J Clin Endocrinol Metab. 2008 Jul;93(7):2662-9. doi: 10.1210/jc.2007-2183. Epub 2008 May 6. — View Citation

Brockenbrough JS, Meyer SA, Li CX, Jirtle RL. Reversible and phorbol ester-specific defect of protein kinase C translocation in hepatocytes isolated from phenobarbital-treated rats. Cancer Res. 1991 Jan 1;51(1):130-6. — View Citation

Canoy D, Beral V, Balkwill A, Wright FL, Kroll ME, Reeves GK, Green J, Cairns BJ; Million Women Study Collaborators*. Age at menarche and risks of coronary heart and other vascular diseases in a large UK cohort. Circulation. 2015 Jan 20;131(3):237-44. doi: 10.1161/CIRCULATIONAHA.114.010070. Epub 2014 Dec 15. — View Citation

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

Clark EM, Ness AR, Tobias JH. Adipose tissue stimulates bone growth in prepubertal children. J Clin Endocrinol Metab. 2006 Jul;91(7):2534-41. Epub 2006 Apr 18. — View Citation

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

Copeland W, Shanahan L, Miller S, Costello EJ, Angold A, Maughan B. Outcomes of early pubertal timing in young women: a prospective population-based study. Am J Psychiatry. 2010 Oct;167(10):1218-25. doi: 10.1176/appi.ajp.2010.09081190. Epub 2010 May 17. — View Citation

Deb S, Campbell BK, Pincott-Allen C, Clewes JS, Cumberpatch G, Raine-Fenning NJ. Quantifying effect of combined oral contraceptive pill on functional ovarian reserve as measured by serum anti-Müllerian hormone and small antral follicle count using three-dimensional ultrasound. Ultrasound Obstet Gynecol. 2012 May;39(5):574-80. doi: 10.1002/uog.10114. — View Citation

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

Lakshman R, Forouhi NG, Sharp SJ, Luben R, Bingham SA, Khaw KT, Wareham NJ, Ong KK. Early age at menarche associated with cardiovascular disease and mortality. J Clin Endocrinol Metab. 2009 Dec;94(12):4953-60. doi: 10.1210/jc.2009-1789. Epub 2009 Oct 30. — View Citation

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

Lee JM, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH, Lumeng JC. Weight status in young girls and the onset of puberty. Pediatrics. 2007 Mar;119(3):e624-30. Erratum in: Pediatrics. 2007 Jul;120(1):251. — View Citation

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

Parent AS, Franssen D, Fudvoye J, Pinson A, Bourguignon JP. Current Changes in Pubertal Timing: Revised Vision in Relation with Environmental Factors Including Endocrine Disruptors. Endocr Dev. 2016;29:174-84. doi: 10.1159/000438885. Epub 2015 Dec 17. — View Citation

Sørensen K, Mouritsen A, Aksglaede L, Hagen CP, Mogensen SS, Juul A. Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty. Horm Res Paediatr. 2012;77(3):137-45. doi: 10.1159/000336325. Epub 2012 Apr 12. Review. — View Citation

Yanovski JA, Rose SR, Municchi G, Pescovitz OH, Hill SC, Cassorla FG, Cutler GB Jr. Treatment with a luteinizing hormone-releasing hormone agonist in adolescents with short stature. N Engl J Med. 2003 Mar 6;348(10):908-17. — View Citation

* Note: There are 23 references in allClick 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
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