Progesterone inhibits glucocorticoid-dependent aromatase induction in human adipose fibroblasts.
In fibroblasts derived from human adipose tissue, aromatase induction is observed after exposure to 1 microM cortisol in the presence of serum or platelet-derived growth factor (PDGF). Progesterone suppresses this induction in a dose-dependent manner, 10 microM resulting in complete inhibition. A reduced cortisol concentration (0.1 microM) concomitantly reduces the progesterone concentration required for effective inhibition (10-100 nM). This effect of progesterone is specific, as neither the release of cellular enzymes nor aromatase induction by dibutyryl-cAMP, which acts independently from cortisol, are affected. However, the inhibitory effect of progesterone requires its presence throughout the induction period. Kinetic studies in intact cells reveal a reduced number of aromatase active sites upon progesterone treatment, whereas progesterone at near-physiological concentration (100 nM) does not inhibit aromatase activity in isolated microsomes. Semi-quantitative reverse transcriptase PCR analysis shows reduced amounts of aromatase mRNA in progesterone-treated cells, indicating specific inhibition of the glucocorticoid-dependent pathway of aromatase induction. The inhibitory effect of progesterone is not blocked by the anti-progestin ZK114043, excluding action via progesterone receptors and indicating competition for the glucocorticoid receptor. Progesterone must be considered a potential physiological inhibitor of glucocorticoid-dependent aromatase induction in adipose tissue. It is proposed that it is a suppressor of aromatase induction in adipose tissue in premenopausal women.
Schmidt
M
M
Institut für Biochemie, Genetik und Mikrobiologie, Universität Regensburg, Germany.
Renner
C
C
Löffler
G
G
D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology*; D000704:Analysis of Variance; D001141:Aromatase / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D000077214:Becaplermin; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D003864:Depression, Chemical; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D018709:Statistics, Nonparametric
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D000077214:Becaplermin; D011374:Progesterone; D003994:Bucladesine; D001141:Aromatase; D006854:Hydrocortisone