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

Mass General Brigham

Status and phase

Completed

Phase 1

Conditions

Kallmann Syndrome

Hypogonadotropic Hypogonadism

GnRH Deficiency

Treatments

Drug: gonadotropin releasing hormone (GnRH)

Study type

Interventional

Funder types

Other

Identifiers

NCT00392756

5U54HD028138 (U.S. NIH Grant/Contract)

U54HD028138-024

Details and patient eligibility

About

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.

Full 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.

Enrollment

624 patients

Sex

All

Ages

16+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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: