Consequence of Lifetime Isolated Growth Hormone Deficiency
Condition: Growth Hormone Deficiency
MeSH terms: Dwarfism, Pituitary; Endocrine System Diseases
Study type: Interventional

Summary: 
      Growth hormone (GH) deficiency (GHD) in adulthood has been associated with changes in body
      composition (e.g. increased abdominal obesity, and reduced muscle mass), in organ functions
      (e.g. reduced cardiac systolic function), in metabolic parameters linked to increased risk of
      cardiovascular disease (e.g. increased serum total and LDL cholesterol, C reactive protein,
      and plasma fibrinogen), and with reduced bone density. These observations have been used to
      define the "adult GHD syndrome" and to advocate GH replacement therapy in GHD adults.
      However, most of the studies have been performed in patients who have had hypothalamic or
      pituitary diseases, and/or have undergone brain irradiation. Such patients are often
      chronically sick, and commonly lack other pituitary hormones, whose replacement therapies may
      not fully restore the physiological functions of the under-active glands. Reliable data on
      the existence of the AGHD syndrome and its response to GH therapy can be only obtained by
      studying patients that are otherwise healthy. However, isolated GH deficiency (IGHD) is a
      rare disease. In addition, up to 50% of patients who have been diagnosed with IGHD in
      childhood are no longer GH deficient as adults, making such study difficult to perform due to
      the scarcity of patients population. We have identified a very large homogeneous population
      of patients who have IGHD due to a homozygous mutation in the GHRH-receptor (GHRHR) gene that
      resides in a rural area of Brazil. None of the adult dwarf patients has ever been treated
      with hGH replacement. This population represents a unique model to study the effect of
      isolated lifetime lack of GH. We propose studies of physiological and metabolic parameters in
      subjects who are homozygous for this mutation and compare them with normal subjects residing
      in the same community.

      The primary goal of this proposal is to determine the consequences of life-long lack of GH on
      body composition, muscle strength, cardiovascular status, cardiovascular risk factors,
      thyroid status and bone density and metabolism, and to test which of these parameters are
      reversed by a 6-month course of GH replacement therapy. In addition, we want to test the
      hypothesis that heterozygosity for this GHRHR mutation causes a phenotype that may be
      intermediate between the one present in homozygous normal subjects and in homozygous affected
      GHD patients. This is relevant because inactivating mutations in the GHRHR are being
      described with increasing frequency in populations of different genetic background,
      suggesting that individuals with faulty single GHRHR alleles may be present in significant
      numbers in the general population.
    

Detailed description: 
      SPECIFIC AIM 1: To study anthropometric parameters, cardiovascular and metabolic status and
      cardiovascular risk profile, including inflammatory markers of cardiovascular relevance,
      muscle strength, bone density and bone metabolism, and thyroid status of twenty GH-naïve
      adult GHD subjects who are homozygous for a null GHRHR mutation and to compare them with
      twenty age- and sex- matched normal controls from the same population.

      SPECIFIC AIM 2: To observe the changes in all the above parameters that occur in GHD subjects
      after a 6-months treatment with hGH replacement, and their reversibility after a 6-months
      washout period.

      SPECIFIC AIM 3: To determine effect of heterozygosity for the GHRHR mutation. To this end, we
      propose to genotype a large number of apparently normal members of the Itabaianinha community
      with the goal of separating subjects homozygous for the wild-type allele from subjects
      heterozygous for the GHRHR mutation, and to compare their phenotype with the one observed in
      subjects homozygous for the wild type allele residing in the same geographical area.

      Together, these studies will determine the effect of lifetime absence of GH on multiple organ
      functions and their response to hGH therapy, and will tell if heterozygosity for mutations in
      the GHRHR gene is associated with a detectable phenotype.
    

Intervention name(s): growth hormone administration for 6 months
Intervention type(s): Drug
Intervention description(s): depot GH (Nutropin depot) 13.4 mg every 14 days
Other intervention name(s): Nuropin depot
Intervention MeSH terms: Hormones
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Growth hormone; Deficiency; Cardiovascular risk; Body composition