Adrenocorticotropic Hormone (ACTH) Stimulation and G Protein

Overview

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.

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.