Progesterone inhibits glucocorticoid-dependent aromatase induction in human adipose fibroblasts

Abstract

In fibroblasts derived from human adipose tissue, aromatase induction is observed after exposure to 1 µM cortisol in the presence of serum or platelet-derived growth factor (PDGF). Progesterone suppresses this induction in a dose-dependent manner, 10 µM resulting in complete inhibition. A reduced cortisol concentration (0·1 µM) 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 dibutyrylcAMP, 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 glucocorticoiddependent aromatase induction in adipose tissue. It is proposed that it is a suppressor of aromatase induction in adipose tissue in premenopausal women.

Sex-change and gonadal steroids in sequentially-hermaphroditic teleost fish

“…However, if P inhibits aromatase transcription (as it does in humans: Schmidt et al, 1998), then GtH-II would be expected to exert a negative effect on aromatase activity (and thus protandrous sex-change), because GtH-II is generally considered to have a positive influence on the abundance of progestogens (Nagahama, 1997). Alternatively, aromatase expression may be under the dual control of alternative GtH types, thereby enabling differential GtH secretion from the pituitary gland to regulate sex-change (Devlin and Nagahama, 2002;Wong and Zohar, 2003).…”

“…Thus, in this situation, 'saturation' of 11bH and 11bHSD enzymes by cortisol would inhibit 11KT synthesis and simultaneously increase the availability of aromatase substrates (T) for E 2 production. Furthermore, if corticosteroids are agonists of aromatase, as they are in humans (Schmidt et al, 1998;McTernan et al, 2002), then cortisol may further inhibit protogynous sexchange by promoting ovarian development (Perry and Grober, 2003). On the other hand, removing the effects of (male) suppressive dominance from a female fish would result in the clearance of cortisol, the 'release' of 11bH and 11bHSD enzymes, and finally, sex-change via the synthesis of 11KT or other androgens.…”

Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages

“…For RT-PCR, 1 µg total RNA was reverse transcribed (1 h at 37 C) using 200 U M-MLV reverse transcriptase (Amersham, Braunschweig, Germany) and subsequently amplified with 2·5 U Taq DNA-polymerase (Boehringer, Mannheim, Germany) for 26 cycles (1 min at 94 C, 1 min at 64 C, 30 s at 74 C) using the oligonucleotides 5 -TTATGAGGAGCATGCGGTACC (forward) and 5 -TAGTGTTCCAGACACCTGTC (reverse) in the presence of 1·5 m MgCl 2 . This protocol leads to amplification of a single 432 bp cDNA-fragment covering parts of exons 9 and 10 of the aromatase gene as shown previously (Schmidt et al 1998). For routine analysis, 10 µl of the reaction mixture were dot-blotted according to standard protocols (Sambrook et al 1989).…”

Regulation of aromatase and 5α-reductase by 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D3, dexamethasone and progesterone in prostate cancer cells

“…Progesterone has been reported to inhibit aromatase enzyme activity in the stroma of endometrium and in breast cancer cells [22]. It has also been reported to reduce the action of cortisol in inducing aromatase enzyme activity in adipose fibroblasts [23].…”