Modulation of androgen metabolism by estradiol-17beta and progesterone, alone and in combination, in human gingival fibroblasts in culture.
BACKGROUND
Androgens, particularly 5alpha-dihydrotestosterone (DHT), have anabolic effects on connective tissues and bone with implications on periodontal healing. This can be enhanced by estradiol-17beta (E-17beta), in synergy with androgen action. The effects of progesterone (P) contribute to plaque-induced inflammatory changes. The aim of this investigation was to study the modulation of androgen metabolism by E-17beta and P, alone and in combination.


METHODS
Human gingival fibroblasts were established in monolayer culture and duplicate incubations were performed in Eagle's MEM for 24 hours with either 14C-testosterone (14C-T) or 14C-4-androstenedione (14C-4-A) as substrate and serial concentrations of E-17beta, P and E-17beta + P. The medium was solvent extracted for steroid metabolites, analyzed, and quantified using a radioisotope scanner. The androgen substrates were converted mainly to DHT and 4-androstenedione/testosterone from 14C-T and 14C-4-A respectively.


RESULTS
At concentrations of 0.1 and 0.5 microg/ml, E-17beta stimulated DHT synthesis from 14C-T by 18% and 12%, respectively, decreasing to control values at 0.1 microg/ml. While the effect of similar concentrations of P on the same substrates was inhibitory by 18, 70, and 82% (n = 4; P <0.01). E-17beta + P showed a 12% increase in DHT synthesis over controls at 0.1 microg/ml, similar to that of E-17beta alone, despite the inhibitory effects of P (n = 4; P <0.01) with 12% and 77% decreases at 0.5 and 1 microg/ml (n = 4; P <0.01). The inhibitory effect of P on DHT synthesis was less apparent when E-17beta was present in combination. The formation of 4-androstenedione from 14C-T was stimulated by E-17beta (12.5%), inhibited by P (50%) and showed an intermediate response with E + P (33% stimulation). At the concentrations used, E-17beta stimulated DHT synthesis from 14C-4-A by 3.6-, 3- and 2.6-fold. P also stimulated this conversion from the same substrate by 16%, 2-fold, and 1.6-fold increases, partly due to the low yields at baseline. The combination of E + P stimulated the synthesis of DHT from 14C-4-A by 4-fold at 0.1 and 0.5 microg/ml and a 2.3-fold increase at 1 microg/ml. The formation of T from 14C-4-A was stimulated by E-17beta (50%) and inhibited by P (40%), with 93% stimulation by E + P at 0.1 microg/ml.


CONCLUSIONS
The modulatory effects of estradiol-17beta and progesterone on androgen metabolism may influence disease presentation and the progress of healing responses in the inflamed periodontium.
Tilakaratne
A
A
Department of Periodontology, University of Sri-Lanka, Peradeniya Campus.
Soory
M
M
D000328:Adult; D000735:Androstenedione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002250:Carbon Radioisotopes; D004338:Drug Combinations; D019275:Radiopharmaceuticals; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D011374:Progesterone; D004958:Estradiol