Constitutional Delay of Growth and Puberty: Towards Evidence-based Treatment (CDGP)

Boys with constitutional delay of growth and puberty (CDGP) should be offered evidence-based effective and safe treatment option. This study compares the effects of low-dose testosterone and aromatase inhibitor letrozole on pubertal progression. The hypothesis is that, in boys CDGP showing earliest signs of puberty, peroral letrozole (2.5 mg/d for 6 mo) induces faster biochemical and clinical progression of puberty as compared to low-dose intramuscular testosterone Rx (~1mg/kg/mo for 6 mo). In addition, 10 or more boys who select watchful waiting instead of medication will provide background data on the natural progression of CDGP, and their data will not be used in primary statistical comparisons.

Study Overview

• Status: Completed
• Conditions: Constitutional Delay of Growth and Puberty
• Intervention / Treatment: Drug: Testosterone; Drug: Letrozole

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Central Hospital
  • Kotka, Finland
    • Kotka Central Hospital
  • Kuopio, Finland, 70211
    • Kuopio University Central Hospital
  • Turku, Finland, 20521
    • Turku University Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Constitutional delay of growth and puberty
• Age 14 years or more
• mean testicular volume 2.5 ml or more and less than 4 ml
• serum testosterone level less than 5 nM OR

as above, but serum testosterone 1 nM or more with normal DHEAS level, even if the mean testicular volume is less than 2.5 ml OR

as above, but tanner stage G2 and testosterone level less than 3 nM

Exclusion Criteria:

• Chronic diseases
• Primary or secondary hypogonadism
• Chromosomal anomalies
• Chronic medication that potentially adversely affects bone mineralization (excluding inhaled corticosteroid treatment)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Testosterone; ~1mg/kg every 4 weeks for 6 months	Drug: Testosterone; 1mg/kg every 4 weeks for 6 months; Other Names: Sustanon 250
Active Comparator: Letrozole; 2.5mg daily for 6 months	Drug: Letrozole; 2.5mg daily for 6 months. Safety criteria: if testosterone level is above 30nM at 3 months, the dosage is reduced to 2.5mg every other day; Other Names: Letrozole Bluefish; Letrozole Orion; Letrozole Accord; Letrozole Sandoz; Femar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
testicular volume	Testes will be measured with a ruler to the nearest millimeter and volume will be calculated at 0, 6, and 12 mo	one year
clinical and biochemical measures of pubertal progression	Activity of the hypothalamic-pituitary-gonadal axis, evaluated by; genital and pubic hair stage of puberty according to Tanner;; growth velocity (cm/yr);; basal and gonadotropin-releasing hormone (GnRH)-stimulated gonadotropin levels;; urinary luteinizing hormone levels;; testosterone;; inhibin B;; anti-mullerian hormone (AMH)	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone health	Several endpoints related to bone health	one year
Psychosocial well-being	Psycho-social well-being will assessed with questionnaires.	one year
Puberty-related metabolical and clinical changes	Biochemical and metabolical changes will be compared btw testosterone and letrozole treatment groups.	one year

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: Foundation for Paediatric Research, Finland
• Investigators: Principal Investigator: Taneli Raivio, MD, PhD, Helsinki University Central Hospital; Study Director: Matti Hero, MD, PhD, Helsinki University Central Hospital; Study Chair: Tero Varimo, MD, PhD, Helsinki University Central Hospital; Study Chair: Päivi Miettinen, MD, PhD, Helsinki University Central Hospital; Study Chair: Jorma Toppari, MD, PhD, University of Turku; Study Chair: Hanna Huopio, MD, PhD, Kuopio University Central Hospital; Study Chair: Sirpa Tenhola, MD, PhD, Kymeenlaakso Central Hospital; Study Chair: Raimo Voutilainen, MD, PhD, Kuopio University Central Hospital

Publications and helpful links

General Publications

• Huttunen H, Varimo T, Huopio H, Voutilainen R, Tenhola S, Miettinen PJ, Raivio T, Hero M. Serum testosterone and oestradiol predict the growth response during puberty promoting treatment. Clin Endocrinol (Oxf). 2022 Feb;96(2):220-226. doi: 10.1111/cen.14605. Epub 2021 Oct 1.
• Kohva E, Varimo T, Huopio H, Tenhola S, Voutilainen R, Toppari J, Miettinen PJ, Vaaralahti K, Viinamaki J, Backman JT, Hero M, Raivio T. Anti-Mullerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone. Hum Reprod. 2020 Feb 29;35(2):257-264. doi: 10.1093/humrep/dez231.
• Varimo T, Huopio H, Kariola L, Tenhola S, Voutilainen R, Toppari J, Toiviainen-Salo S, Hamalainen E, Pulkkinen MA, Laaperi M, Tarkkanen A, Vaaralahti K, Miettinen PJ, Hero M, Raivio T. Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial. Lancet Child Adolesc Health. 2019 Feb;3(2):109-120. doi: 10.1016/S2352-4642(18)30377-8. Epub 2019 Jan 4.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2013
• Primary Completion (Actual): March 20, 2017
• Study Completion (Actual): February 5, 2018

Study Registration Dates

• First Submitted: February 18, 2013
• First Submitted That Met QC Criteria: February 21, 2013
• First Posted (Estimate): February 22, 2013

Study Record Updates

• Last Update Posted (Actual): February 6, 2018
• Last Update Submitted That Met QC Criteria: February 5, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Puberty; Testosterone; Letrozole; Constitutional; Delay
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Androgens; Letrozole; Testosterone
• Other Study ID Numbers: EudraCT:2012-002477-59