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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00392756
Recruitment Status : Recruiting
First Posted : October 26, 2006
Last Update Posted : September 1, 2017
Information provided by (Responsible Party):
William F. Crowley, Jr., M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

October 25, 2006
October 26, 2006
September 1, 2017
April 1989
March 2018   (Final data collection date for primary outcome measure)
endogenous LH secretion pattern [ Time Frame: 8 to 24 hours ]
  • Assess reproductive hormones on a weekly basis for 2 months.
  • After the first 2 months of treatment, hormones will be assessed on a monthly basis.
  • After testosterone levels are maintained at >300 ng/dL semen samples will be collected on a monthly basis to assess sperm production and fertility.
Complete list of historical versions of study NCT00392756 on Archive Site
  • testicular volume [ Time Frame: up to 2 years ]
  • sperm count [ Time Frame: up to 2 years ]
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Examination of Idiopathic Hypogonadotropic Hypogonadism (IHH)and Kallmann Syndrome (KS)
Role of Gonadotropin Pulsations in the Reversal of Hypogonadotropic Hypogonadism

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.

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.

Not Applicable
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
  • Kallmann Syndrome
  • Hypogonadotropic Hypogonadism
  • GnRH Deficiency
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.
  • No Intervention: off treatment
    Subjects undergo the baseline evaluation off treatment
  • Experimental: GnRH Treatment
    Subjects receive long term pulsatile GnRH therapy
    Intervention: Drug: gonadotropin releasing hormone (GnRH)

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
March 2019
March 2018   (Final data collection date for primary outcome measure)


Ages Eligible for Study:

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

    • Genders Eligible for Study:
  • Male and Female

    • Accepts Healthy Volunteers:


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
Sexes Eligible for Study: All
16 Years and older   (Child, Adult, Senior)
Contact: Ravikumar Balasubramanian, MD, PhD 617-726-8432
Contact: Kathryn Salnikov, BS 617-726-1309
United States
5U54HD028138 ( U.S. NIH Grant/Contract )
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William F. Crowley, Jr., M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Not Provided
Principal Investigator: William F Crowley, Jr., MD Massachusetts General Hospital
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP