The –2 basepair initiation start site ACTH receptor polymorphism influences ACTH induced adrenal androgen secretion

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the most abundant steroids in human circulation. Adrenocorticotropic hormone (ACTH) is the primary secretagogue stimulating adrenal androgens (AA) secretion. Yet, genetic and environmental factors are assumed to play a determinant role in the regulation of their biosynthesis and, thus, might explain the high variability of AA levels. We recently reported a polymorphism within the transcription initiation site of the ACTH receptor promoter gene altering the consensus sequence from CTC to CCC at –2bp which results in lower promoter activity in vitro and is associated with impaired cortisol response to ACTH stimulation in vivo. Here we show that this polymorphism also affects ACTH dependent AA secretion. We studied 14 normal volunteers: 6 CCC/CCC carriers and 8 CTC/CTC carriers of the ACTH receptor polymorphism. Baseline DHEA concentrations did not differ between groups. However, in a 6 hour ACTH stimulation test with increasing ACTH1–24 doses (120 to 3860 ng/m^{body surface area/h}), CCC/CCC carriers showed a significantly lower DHEA response compared to CTC/CTC carriers (area under the curve: 3201±358 vs. 5586±842µg/ml*min, P<0.04). Thus, we might have identified one of the genetic factors responsible for highly intersubject differences of DHEA concentrations.