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

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ClinicalTrials.gov Identifier: NCT00392756
Recruitment Status : Recruiting
First Posted : October 26, 2006
Last Update Posted : June 16, 2020
Sponsor:
Information provided by (Responsible Party):
Stephanie B. Seminara, MD, Harvard University

Brief Summary:

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 sex hormone (testosterone, estrogen) levels and gamete (sperm, egg cell) production.

This study involves a detailed evaluation and 24-48 hours stay at the hospital.

In this study, males and females 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 or disease Intervention/treatment Phase
Kallmann Syndrome Hypogonadotropic Hypogonadism GnRH Deficiency Drug: gonadotropin releasing hormone (GnRH) Not Applicable

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 participants 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Role of Gonadotropin Pulsations in the Reversal of Hypogonadotropic Hypogonadism
Study Start Date : April 1989
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. endogenous LH secretion pattern [ Time Frame: 8 to 24 hours ]

Secondary Outcome Measures :
  1. testicular volume [ Time Frame: up to 2 years ]
  2. sperm count [ Time Frame: up to 2 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Eligibility

Ages Eligible for Study:

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

Exclusion Criteria:

  • no specific exclusion criteria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00392756


Contacts
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Contact: Ravikumar Balasubramanian, MD, PhD 617-726-5384 ReproEndoGenetics@partners.org
Contact: Kathryn Salnikov, BS 617-726-1309 ksalnikov@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114-2696
Contact: Ravikumar Balasumbramanian, MD, PhD    617-726-5384    ReproEndoGenetics@partners.org   
Contact: Kathryn Salnikov, BS    617-726-1309    ksalnikov@mgh.harvard.edu   
Principal Investigator: Stephanie Seminara, MD         
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
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Principal Investigator: Stephanie B Seminara, MD Massachusetts General Hospital
Publications of Results:

Other Publications:

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Responsible Party: Stephanie B. Seminara, MD, Professor, Harvard University
ClinicalTrials.gov Identifier: NCT00392756    
Other Study ID Numbers: U54HD028138-024
5U54HD028138 ( U.S. NIH Grant/Contract )
First Posted: October 26, 2006    Key Record Dates
Last Update Posted: June 16, 2020
Last Verified: June 2020
Keywords provided by Stephanie B. Seminara, MD, Harvard University:
Kallmann Syndrome
Hypogonadotropic Hypogonadism
GnRH deficiency
Pulsatile GnRH
Additional relevant MeSH terms:
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Kallmann Syndrome
Hypogonadism
Syndrome
Disease
Pathologic Processes
Gonadal Disorders
Endocrine System Diseases
Disorder of Sex Development, 46,XY
Disorders of Sex Development
Urogenital Abnormalities
Congenital Abnormalities
Genetic Diseases, Inborn
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs