INSL3 as a Biomarker of Pubertal Activation: Role in Evaluating Precocious and Delayed Puberty (INSL3GNRH)
INSL3 as an Early Marker of Pubertal Activation: Evaluation of Its Potential Role as a New Biomarker in the Diagnosis of Central Precocious Puberty and Delayed Puberty.
This is an observational study in children up to 16 years old who are suspected of having central precocious puberty or delayed puberty. The main questions it aims to answer are:
- Can the level of insulin-like peptide 3 (INSL3) predict if a child's puberty has truly started?
- Can this marker help reduce the need for more complex and invasive tests?
Participants will:
- Give one extra blood sample just before starting the standard gonadotropin-releasing hormone (GnRH) stimulation test (during the baseline blood draw).
- Have this extra sample used to measure the INSL3 hormone.
- Complete the rest of the GnRH test as prescribed by their doctor.
Researchers will compare the INSL3 hormone levels in children who have a positive GnRH test to those who have a negative test. This will help researchers learn if INSL3 can be used as a new, simple tool to diagnose early or delayed puberty.
Descripción general del estudio
Estado
Condiciones
Descripción detallada
Diagnosing the exact onset of puberty, especially in its early stages, is a clinical challenge. Currently, the gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for evaluating hypothalamic-pituitary-gonadal (HPG) axis activation. However, this test is invasive, time-consuming, expensive, and may have limited sensitivity during the very early phases of Central Precocious Puberty (CPP) or Delayed Puberty (DP).
INSL3 is produced constitutively by Leydig cells in males and theca cells of growing antral follicles in females. Unlike other hormones which are secreted with acute and pulsatile patterns, INSL3 exhibits minimal circadian variation and reflects the continuous maturation of gonadal tissues.
The purpose of this study is to evaluate INSL3 as an early marker of pubertal activation. By correlating basal INSL3 levels, measured via ELISA, with the outcomes of standard GnRH tests and other clinical parameters, the investigators hope to determine if INSL3 can accurately predict HPG axis activation. Ultimately, validating this biomarker could lead to a simpler, single-sample diagnostic approach, reducing the burden of dynamic stimulation testing in pediatric practice.
Tipo de estudio
Inscripción (Estimado)
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Federico Baronio, MD, PhD
- Número de teléfono: 00390512144816
- Correo electrónico: federico.baronio@aosp.bo.it
Ubicaciones de estudio
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Bologna, Italia, 40138
- Reclutamiento
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Bologna 40138
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Contacto:
- Federico Baronio, MD, PhD
- Número de teléfono: 00390512144816
- Correo electrónico: federico.baronio@aosp.bo.it
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Método de muestreo
Población de estudio
Pediatric patients of both sexes, aged 0 to 16 years, who are followed for suspected Central Precocious Puberty (CPP) or suspected Delayed Puberty (DP) at the Pediatric Endocrinology Unit of the IRCCS Azienda Ospedaliero-Universitaria of Bologna. These patients must have a clinical indication to undergo a standard GnRH stimulation test as part of their routine diagnostic workup for pubertal evaluation.
Descripción
Inclusion Criteria:
- Age between 0 and 16 years at the time of enrollment.
- Males with suspected Central Precocious Puberty (CPP), defined by a testicular volume ≥4 mL before 9 years of age.
- Females with suspected CPP, defined by the onset of thelarche before 8 years of age.
- Males with suspected Delayed Puberty (DP), defined by testicular volume <4 mL by 14 years of age.
- Females with suspected DP, defined by the absence of thelarche by 13 years of age.
- Written informed consent for study participation and personal data processing provided by the parents/legal guardians, with the assent of the participating minor.
Exclusion Criteria:
- Presence of congenital or acquired conditions known to primarily alter pubertal development or gonadal function, regardless of HPG axis physiology (e.g., disorders of sex development, anorchia, previous ovariectomy, uncorrected bilateral cryptorchidism, previous iatrogenic gonadotoxicity).
- Primary endocrine diseases interfering with hypothalamic-pituitary-gonadal axis regulation (e.g., congenital hypogonadotropic hypogonadism, panhypopituitarism).
- Use of hormonal therapies or drugs capable of modifying gonadal function or the response to the GnRH test (e.g., exogenous sex steroids, androgens/anabolic steroids).
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Modelos observacionales: COHORT
- Perspectivas temporales: PROSPECTIVE
Cohortes e Intervenciones
Grupo / Cohorte |
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Suspected Central Precocious Puberty (CPP)
Pediatric patients (males under 9 years, females under 8 years) with clinical signs of early pubertal onset, undergoing a standard GnRH stimulation test. |
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Suspected Delayed Puberty (DP)
Pediatric patients (males 14 years and older, females 13 years and older) with absent signs of puberty, undergoing a standard GnRH stimulation test. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Baseline INSL3 Concentration as a Predictor of GnRH Test Outcome
Periodo de tiempo: Baseline (prior to GnRH test administration)
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Assessment of baseline Insulin-like peptide 3 (INSL3) levels (measured in pg/ml) and their association with the gonadotropin response to the standard GnRH stimulation test (evaluated by peak LH, peak FSH in mU/ml, and LH/FSH ratio) to determine Hypothalamic-Pituitary-Gonadal (HPG) axis activation in patients with suspected precocious or delayed puberty. |
Baseline (prior to GnRH test administration)
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Diagnostic Accuracy of Combined INSL3 and Clinical Parameters
Periodo de tiempo: Baseline
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Evaluation of whether integrating baseline INSL3 (pg/ml) with other clinical and laboratory parameters (bone age in years, uterine longitudinal diameter in cm and volume in ml, basal LH/FSH in mU/ml, estradiol in pg/ml, and testosterone in ng/ml) improves the ability to distinguish patients with a positive GnRH test from those with a negative test. |
Baseline
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Correlation Between INSL3 and Pubertal Development Parameters
Periodo de tiempo: Baseline
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Assessment of the correlation between baseline INSL3 levels (pg/ml) and key physiological parameters of pubertal development, including bone age, baseline gonadotropins, sex steroids, and, in females, uterine dimensions. |
Baseline
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Colaboradores e Investigadores
Patrocinador
Publicaciones y enlaces útiles
Publicaciones Generales
- Anand-Ivell R, Tremellen K, Dai Y, Heng K, Yoshida M, Knight PG, Hale GE, Ivell R. Circulating insulin-like factor 3 (INSL3) in healthy and infertile women. Hum Reprod. 2013 Nov;28(11):3093-102. doi: 10.1093/humrep/det349. Epub 2013 Sep 5.
- Albrethsen J, Johannsen TH, Jorgensen N, Frederiksen H, Sennels HP, Jorgensen HL, Fahrenkrug J, Petersen JH, Linneberg A, Nordkap L, Bang AK, Andersson AM, Juul A. Evaluation of Serum Insulin-like Factor 3 Quantification by LC-MS/MS as a Biomarker of Leydig Cell Function. J Clin Endocrinol Metab. 2020 Jun 1;105(6):dgaa145. doi: 10.1210/clinem/dgaa145.
- Albrethsen J, Ljubicic ML, Juul A. Longitudinal Increases in Serum Insulin-like Factor 3 and Testosterone Determined by LC-MS/MS in Pubertal Danish Boys. J Clin Endocrinol Metab. 2020 Oct 1;105(10):dgaa496. doi: 10.1210/clinem/dgaa496.
- Bay K, Hartung S, Ivell R, Schumacher M, Jurgensen D, Jorgensen N, Holm M, Skakkebaek NE, Andersson AM. Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. J Clin Endocrinol Metab. 2005 Jun;90(6):3410-8. doi: 10.1210/jc.2004-2257. Epub 2005 Mar 8.
- Anand-Ivell R, Wohlgemuth J, Haren MT, Hope PJ, Hatzinikolas G, Wittert G, Ivell R. Peripheral INSL3 concentrations decline with age in a large population of Australian men. Int J Androl. 2006 Dec;29(6):618-26. doi: 10.1111/j.1365-2605.2006.00714.x. Epub 2006 Oct 3.
- Ferlin A, Garolla A, Rigon F, Rasi Caldogno L, Lenzi A, Foresta C. Changes in serum insulin-like factor 3 during normal male puberty. J Clin Endocrinol Metab. 2006 Sep;91(9):3426-31. doi: 10.1210/jc.2006-0821. Epub 2006 Jun 27.
- Bay K, Andersson AM. Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders. Int J Androl. 2011 Apr;34(2):97-109. doi: 10.1111/j.1365-2605.2010.01074.x.
- Penny R, Olambiwonnu NO, Frasier SD. Episodic fluctuations of serum gonadotropins in pre- and post-pubertal girls and boys. J Clin Endocrinol Metab. 1977 Aug;45(2):307-11. doi: 10.1210/jcem-45-2-307.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
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Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- INSL3GNRH
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
De-identified individual participant data (IPD) underlying the results of this study will be shared upon reasonable request to the Principal Investigator. The shared data will include clinical, auxological, biochemical, and instrumental parameters used for the analyses, provided in a completely anonymous format to protect participant privacy.
Marco de tiempo para compartir IPD
Following the publication of the study results.
Criterios de acceso compartido de IPD
Data will be shared upon reasonable request submitted to the Principal Investigator.
Tipo de información de apoyo para compartir IPD
- PROTOCOLO DE ESTUDIO
- SAVIA
Información sobre medicamentos y dispositivos, documentos del estudio
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