Genetic influence of an ACTH receptor promoter polymorphism on adrenal androgen secretion.
OBJECTIVE
Adrenocorticotropic hormone (ACTH) is the primary secretagogue stimulating secretion of adrenal androgens (AA). Yet, genetic and environmental factors are assumed to play a determining role in the regulation of their biosynthesis and thus might explain the high variability of AA levels. Here we investigate the influence of an ACTH receptor promoter polymorphism affecting ACTH receptor gene transcription on ACTH-dependent dehydroepiandrosterone (DHEA) secretion.


METHODS
We recently reported a polymorphism within the transcription initiation site of the ACTH receptor gene promoter that alters the consensus sequence from CTC to CCC at -2 bp. This results in lower promoter activity in vitro and is associated with impaired cortisol response to ACTH stimulation in vivo. We now studied 14 normal, lean volunteers aged 20-35 years (eight CTC/CTC and six CCC/CCC carriers) in a 6-h ACTH stimulation test.


METHODS
After overnight dexamethasone suppression, ACTH1-24 was administered continuously in each subject with hourly increasing doses (120-3840 ng/m2 body surface area/h) within a 6-h period. On a separate day, baseline DHEA samples were collected.


RESULTS
In the 6-h ACTH stimulation test, CTC/CTC carriers showed a significantly higher DHEA response than CCC/CCC carriers (area under the curve: 19 367 +/- 2919 vs 11 098 +/- 1241 nmol/l per min; P < 0.04, Mann-Whitney U-test). In contrast, baseline DHEA concentrations did not differ between groups.


CONCLUSIONS
These data demonstrate that genetic variations within the ACTH receptor promoter result in decreased DHEA secretion. Thus, we might have identified one of the genetic factors responsible for variation in ACTH-dependent DHEA secretion.
Reisch
Nicole
N
Division of Endocrinology, Department of Medicine Innenstadt, University Hospital Munich, Germany.
Slawik
Marc
M
Zwermann
Oliver
O
Beuschlein
Felix
F
Reincke
Martin
M
D000311:Adrenal Glands / Q000378:metabolism*; D000328:Adult; D003366:Cosyntropin / Q000008:administration & dosage; D003687:Dehydroepiandrosterone / Q000097:blood / Q000378:metabolism*; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D004334:Drug Administration Schedule; D006801:Humans; D009994:Osmolar Concentration; D011110:Polymorphism, Genetic / Q000502:physiology*; D018043:Receptors, Corticotropin / Q000235:genetics*
D018043:Receptors, Corticotropin; D003366:Cosyntropin; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate