Potency and selectivity of the aromatase inhibitor R 76,713. A study in human ovarian, adipose stromal, testicular and adrenal cells.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

The effects of R 76,713 on steroidogenesis were studied in primary cultures of four different human cell types, i.e. ovarian granulosa cells, adipose stromal cells, testicular cells and adrenal cells. In human granulosa cells aromatization of [1 beta, 2 beta-3H]androstenedione (as measured by the release of tritiated water) showed a Km (Michaelis constant) of 78 nM. R 76,713 competitively inhibited aromatization with a Ki (dissociation constant of the enzyme-inhibitor complex) of 1.6 nM. In human adipose stromal cells aromatization was measured by following the conversion of androstenedione to estrone and 17 beta-estradiol. In this system a Km for aromatization of androstenedione of 10.8 nM was found. R 76,713 again showed competitive kinetics with a Ki-value of 0.14 nM. In human testicular cells the synthesis of the androgens testosterone, androstenedione and dehydroepiandrosterone was only inhibited by drug concentrations exceeding 10(-6) M. At 10(-5) M of R 76,713, steroid concentrations were lowered to 56, 64 and 81% of the control for testosterone, androstenedione and dehydroepiandrosterone respectively. Concomitantly, a slight increase in the levels of pregnenolone (138% of the control) and progesterone (133% of the control) was seen. In human adrenal cells the synthesis of cortisol and aldosterone was slightly affected by R 76,713 also at concentrations exceeding 10(-6)

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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