Adrenocorticotropic Hormone (ACTH) Stimulation and G Protein
Condition: Adrenal Sufficiency
Study type: Observational

Summary: 
      Males and females may exhibit different responses to testing of adrenal function. The
      hormones responsible for controlling adrenal function are ACTH (adrenocorticotropic hormone
      or corticotropin) and CRH (corticotropin-releasing hormone). Adrenal function is tested with
      an ACTH stimulation test. ACTH stimulates the adrenal glands to produce cortisol. Cortisol
      levels are measured, and a certain peak level indicates normal adrenal gland function.
      Females may produce more cortisol in response to ACTH testing than males. This difference may
      be due to certain proteins, called G proteins. The hormones controlling adrenal function,
      ACTH and CRH, work through G proteins. Females may have more G proteins than males allowing
      for the increased cortisol response to ACTH stimulation.

      The investigators speculate that:

        1. There may be differences in adrenal responsiveness to ACTH stimulation testing between
           healthy males and females.

        2. ACTH and CRH induce their own function.

        3. Sex differences in adrenal responsiveness to ACTH stimulation testing may be related to
           sex differences in G protein expression.

      In this study, cortisol, a hormone produced by the adrenal glands, will be measured before
      and after the administration of ACTH.

      This study will also measure G proteins. G proteins are found in the white blood cells. White
      blood cells from females may have more active G proteins than white blood cells from males.
      Sex differences may be augmented after exposure to ACTH.
    

Detailed description: 
      Many nonsteroidal hormones work through G protein signal transducers. These heterotrimeric
      signal transducers couple cell surface receptors to intracellular pathways, thus conveying
      biologic effects. Most hormones that work via the stimulatory G protein, Gas, also exert
      actions through a homologous stimulatory G protein, Gaq, suggesting that these pathways
      exhibit redundancy. We have previously demonstrated sex differences in the expression of Gas
      and Gaq. We have observed that female mice and humans display significantly higher levels of
      mRNA and protein for the G protein, Gaq. We have also observed that estrogens induce
      expression of Gaq mRNA and protein in female mice. In addition, preliminary studies in mice
      demonstrate that both ACTH (adrenocorticotropic hormone or corticotropin) and CRH
      (corticotropin-releasing hormone) induce Gaq in immune cells and adrenal tissue in a sex
      restricted fashion, i.e. females only.

      ACTH and CRH are the two major hormones controlling adrenal function. Adrenal function can be
      tested using a standard 1mcg synthetic ACTH stimulation test and measuring the production of
      cortisol. We have observed that females exhibit a trend toward increased responsiveness to
      ACTH stimulation than males. We speculate that sex differences in cortisol responsiveness to
      ACTH exist, and that these differences will correlate with sex differences in the expression
      or induction of the G proteins, Gaq or Gas.

      We propose to determine whether healthy female subjects undergoing low-dose ACTH stimulation
      exhibit altered levels of Gaq or Gas mRNA and protein and cortisol levels compared with male
      subjects undergoing the same provocative testing. This study may have implications for the
      interpretation of provocative ACTH testing.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy male and female subjects (ages 6-34)
      
Keywords: Adrenal sufficiency; Low-dose ACTH stimulation; G proteins