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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Role of Gonadotropin Pulsations in the Reversal of Hypogonadotropic Hypogonadism

Conditions
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Kallmann Syndrome, Hypogonadotropic Hypogonadism, GnRH Deficiency

Intervention / Treatment
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* Drug: gonadotropin releasing hormone (GnRH)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: off treatment<br>Subjects undergo the baseline evaluation off treatment | |
| Experimental: GnRH Treatment<br>Subjects receive long term pulsatile GnRH therapy | Drug: gonadotropin releasing hormone (GnRH)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| endogenous LH secretion pattern |  | 8 to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| testicular volume |  | up to 2 years | 
| sperm count |  | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kallmann Syndrome, Hypogonadotropic Hypogonadism, GnRH deficiency, Pulsatile GnRH