Molecular Basis of Inherited Reproductive Disorders Study

Study Background

The key initiating factors for reproductive development remain among the great mysteries of pediatric and reproductive endocrinology. The onset of puberty is initiated by pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The neuroendocrine events leading to increased GnRH secretion and the resultant onset of puberty remain largely unknown. Isolated deficiency of GnRH results in the rare clinical syndrome of idiopathic hypogonadotropic hypogonadism (IHH), where decreased secretion of GnRH results in impaired gonadotropin secretion. The resultant hypogonadism presents with delayed, incomplete, or absent sexual maturation. Human and animal models have identified a number of genes responsible for IHH, but more than half of patients with clinical evidence of the disorder do not have a detectable mutation. In addition, there is significant clinical heterogeneity among affected individuals, including members of the same family harboring the same mutations. Careful human phenotyping of such patients and families has expanded our understanding of this spectrum of disorders to include oligo-digenic inheritance, as well as reversibility of the condition, and has provided insight into developmental pathways involved in the ontogeny of GnRH neurons. In particular, hypogonadotropic hypogonadism (HH) exists along a genetic and phenotypic spectrum that includes milder forms of GnRH dysregulation, precocious and delayed puberty, and onset of reproductive dysfunction after puberty.

Genetic analysis of subjects with unknown mutations is likely to yield important insights into additional pathways involved in the regulation of GnRH secretion. Here, we propose a genetic investigation of subjects with IHH to characterize further the phenotypic effects of previously described genetic variants, as well as to identify novel genes involved in congenital GnRH deficiency. We will use candidate gene and whole exome approaches, as well as linkage analysis. This protocol will utilize the disease model of IHH to increase our understanding of the physiology of GnRH secretion, including the neuroendocrine regulation of GnRH pulsatility. Examining the genetic characteristics of subjects with isolated GnRH deficiency will reveal insights into the mechanisms underlying the reawakening of the hypothalamic-pituitary-gonadal axis at puberty, providing opportunities for new diagnostic capabilities and therapeutic interventions for disorders of puberty and fertility.

Inclusion Criteria

1. Failure to go through a normal, age-appropriate, spontaneous puberty and low sex steroid levels in the setting of low/normal gonadotropins (due to substantial variability among patient presentations, this will be based on the clinical judgement of the Investigator).
2. Abnormally early development of puberty.
3. Normal puberty with subsequent development of low gonadotropin levels.
4. Pre-pubertal individuals with features suggestive of hypogonadotropic hypogonadism.
5. Loss of reproductive activity after puberty.
6. Family members: both affected and unaffected family members are strongly encouraged to participate.

Principal Investigator

Natalie D. Shaw, M.D., MMSc.
Principal Investigator

Tel 984-287-3716
natalie.shaw@nih.gov

Curriculum Vitae Natalie D. Shaw (152KB)
NIH Intramural Profile

P.O. Box 12233

Mail Drop D3-02

Durham, N.C. 27709

Delivery Instructions

Co-investigator

Janet E. Hall, M.D., M.S.
Clinical Director and Senior Investigator;
Chair - Clinical Advisory Committee (CAC)

Tel 984-287-3647
janet.hall@nih.gov

Curriculum Vitae Janet Hall (731KB)

P.O. Box 12233

Mail Drop A2-03

Durham, N.C. 27709

Delivery Instructions

Skand Shekhar, M.D., M.H.Sc.
Assistant Research Physician

Tel 301-451-1866
skand.shekhar@nih.gov

Curriculum Vitae (389KB)

111 Tw Alexander Dr
Clinical Research Unit / Modular Clinic
Research Triangle Park, NC 27709

Delivery Instructions