Examination of Idiopathic Hypogonadotropic Hypogonadism (IHH)and Kallmann Syndrome (KS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sponsor:
Information provided by (Responsible Party):
William Crowley, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT00392756
First received: October 25, 2006
Last updated: May 29, 2014
Last verified: May 2014
  Purpose

The purpose of the study is to examine how Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) affect reproductive hormones. These disorders are caused by a defect in Gonadotropin Releasing Hormone (GnRH) secretion. GnRH is a hormone released by a small gland in the brain called the hypothalamus. When GnRH is released, it signals another gland in the brain, the pituitary, to secrete the reproductive hormones that influence testosterone levels and sperm production.

This study involves a detailed evaluation and 8-24 hours stay at the hospital.

In this study, males ages 16 and older with IHH have a detailed evaluation which involves an overnight study at the hospital. Some men (18 years and older) may continue on to receive treatment with pulsatile GnRH. This treatment replaces the hormone which is absent in IHH and results in normalized testosterone and typically is effective in developing fertility.


Condition Intervention
Kallmann Syndrome
Hypogonadotropic Hypogonadism
GnRH Deficiency
Drug: gonadotropin releasing hormone (GnRH)

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Role of Gonadotropin Pulsations in the Reversal of Hypogonadotropic Hypogonadism

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:
  • endogenous LH secretion pattern [ Time Frame: 8 to 24 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • testicular volume [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]
  • sperm count [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 800
Study Start Date: April 1989
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: off treatment
Subjects undergo the baseline evaluation off treatment
Experimental: GnRH Treatment
Subjects receive long term pulsatile GnRH therapy
Drug: gonadotropin releasing hormone (GnRH)
pulsatile GnRH is delivered to adult men (18+ yrs) via portable microinfusion pump. A small dose (30 microliters) is delivered subcutaneously every 120 minutes. The initial dose is 25 ng/Kg which is increased until normal serum testosterone levels are achieved.

Detailed Description:

The specific aims of this study are:

  • To identify men and women with hypogonadotropic hypogonadism and to define the spectrum of abnormalities in GnRH secretion in these patients.
  • To study the physiology and control of the reproductive system in the human male and female.
  • To determine the relationship between glucose metabolism and testosterone levels in men with hypogonadotropic hypogonadism.
  • To characterize the neuroendocrine and metabolic phenotype of subjects with IHH and use this information to make genotype-phenotype correlations.

Despite variability in the triggers, timing, and pace of sexual maturity between species, all species utilize the final pathway of hypothalamic secretion of GnRH to initiate and maintain the reproductive axis. Thus, GnRH is required for reproductive competence in the human. The classic studies of Knobil and his colleagues in the 1970s clearly demonstrated that pulsatile release of GnRH from the hypothalamus is a prerequisite for physiologic gonadotrope function, with continuous stimulation resulting in a paradoxical decrease in gonadotrope responsiveness.

Absence, decreased frequency or decreased amplitude of pulsatile GnRH release results in the clinical syndrome of hypogonadotropic hypogonadism (HH). Deficient GnRH secretion may occur in isolation (idiopathic hypogonadotropic hypogonadism [IHH]), in association with anosmia (Kallmann syndrome [KS]) or as a result of a variety of structural and functional lesions of the hypothalamic-pituitary axis. The phenotypic expression of GnRH deficiency in the human demonstrates considerable heterogeneity, suggesting that patients with IHH and KS may represent part of a spectrum of isolated GnRH deficiency as opposed to representing discrete diagnostic subsets.

Defining the physiology of GnRH is critical to understanding the clinical heterogeneity of isolated GnRH deficiency. This protocol will utilize the disease model of HH to increase our understanding of the physiology of GnRH secretion. Examining the baseline characteristics of patients with isolated GnRH deficiency allows the determination of the normal requirements for endogenous GnRH secretion in the human.

Recent studies have revealed an association between hyperinsulinemia and low testosterone levels in men. This finding has been demonstrated in normal physiological conditions as well as in insulin resistant states. However, the causal nature and directionality of this relationship is not yet understood. Specifically, do lower testosterone levels cause insulin resistance resulting in hyperinsulinemia or vice versa. Because insulin resistance is an important risk factor for cardiovascular disease as well as type 2 diabetes, it is important to investigate this relationship for the implications it may have for prevention of and therapeutic interventions for these disorders.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Eligibility

Ages Eligible for Study:

  • Adolescent boys (16-17yrs)
  • Adults (18 years and older)

    • Genders Eligible for Study:
  • Male and Female

    • Accepts Healthy Volunteers:
  • No

Criteria

Inclusion Criteria:

  • adolescent boys (age 16-17 years) and adult male individuals (age 18 years and older) with a single serum sample demonstrating low testosterone in association with low or inappropriately normal gonadotropin levels
  • suitable male and adult female hypogonadotropic hypogonadal subjects

Exclusion Criteria:

  • no specific exclusion criteria
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00392756

Contacts
Contact: Ravikumar Balasubramanian, MD, PhD 617-726-8432 RBALASUBRAMANIAN@mgh.harvard.edu
Contact: Nirav Patel, BA 617-726-1896 npatel34@mgh.harvard.edu

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114-2696
Contact: Ravikumar Balasumbramanian, MD, PhD    617-726-8432    RBALASUBRAMANIAN@mgh.harvard.edu   
Contact: Nirav Patel, BA    617-726-1896    npatel34@mgh.harvard.edu   
Principal Investigator: William Crowley, MD         
Sponsors and Collaborators
Investigators
Principal Investigator: William F Crowley, Jr., MD Massachusetts General Hospital
  More Information

Additional Information:
Publications:

Responsible Party: William Crowley, Daniel K. Podolsky Professor of Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT00392756     History of Changes
Other Study ID Numbers: U54HD028138-024, 5U54 HD028138
Study First Received: October 25, 2006
Last Updated: May 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
Kallmann Syndrome
Hypogonadotropic Hypogonadism
GnRH deficiency
Pulsatile GnRH

Additional relevant MeSH terms:
Syndrome
Hypogonadism
Kallmann Syndrome
Disease
Pathologic Processes
Gonadal Disorders
Endocrine System Diseases
46, XY Disorders of Sex Development
Disorders of Sex Development
Urogenital Abnormalities
Congenital Abnormalities
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on September 18, 2014