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

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.

Eligibility

Ages Eligible for Study:

- Adolescents (16-17yrs)

- Adults (18 years and older)

- Genders Eligible for Study:

- Male and Female

- Accepts Healthy Volunteers:

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