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.

01 Jul 1995·Journal of Cellular PhysiologyQ2 · BIOLOGY

Antiprogestins inhibit growth and stimulate differentiation in the normal mammary gland

Q2 · BIOLOGY

Article

Author: Minglin Li ; Eva Spitzer ; Richard Grosse ; Bert Binas ; Wolfgang Zschiesche ; Karsten Parczyk

AbstractAntiprogestins possess a potent antitumor activity in hormone‐dependent experimental breast cancer models. Though the underlying mechanism is not clear, induction of functional differentiation seems to be a major event. This study attempts to test directly for antiproliferative and differentiation promoting activities of antiprogestins on the normal mammary gland. To this end, whole organ cultures of mammary glands from estradiol/progesterone‐primed virgin mice maintained in a serum‐free medium with aldosterone, prolactin, insulin, and hydrocortisone were exposed to the antiprogestin ZK114043. A 4‐day treatment of organ cultures led to a strong inhibition of epithelial DNA synthesis. In parallel, ZK114043 caused alveolar cells to acquire a more differentiated phenotype distinguished by secretory active alveoli composed of single cell layers with increased fat droplet accumulation and enhanced expression of the milk proteins b̃‐casein and whey acidic protein (WAP). Particularly strong effects were found on the expression of mammary‐derived growth inhibitor (MDGI). Both half‐maximal inhibition of epithelial DNA synthesis and stimulation of MDGI mRNA expression were found at about 5 ng/ml of ZK114043. Presence in the medium of 5 m̈g/ml hydrocortisone rendered antiglucocorticoid effects of ZK114043 highly unlikely. Furthermore, prevention of action of ZK114043 by the progesterone agonist R5020 and ZK114043 stimulated expression of b̃‐casein and MDGI mRNA in cultured glands of 10‐week‐old unprimed virgin mice suggest a progesterone receptor‐mediated mechanism of antiprogestin action. Two other antiprogestins, Mifepristone and Onapristone, likewise stimulated MDGI expression. The data provide direct evidence that antiprogestins act like a differentiation factor in the normal mammary gland. © 1995 Wiley‐Liss, Inc.

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Indication	Highest Phase	Country/Location	Organization	Date
Carcinoma	Discovery	DE	Bayer Schering Pharma AG	-
Contraception	Discovery	DE	Bayer Schering Pharma AG	-

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