In vitro and in vivo studies with aromatase inhibitor 4-hydroxy-androstenedione

Studies with 4-hydroxyandrostenedione (4-OHA) are described which demonstrate inhibition of aromatase in human placentra and rat ovaries. In animal experiments, the compound was compared with aminoglutethimide (AG) for antitumor activity and effects on plasma hormone levels. 4-OHA was more effective than AG in causing regression of DMBA-induced hormone dependent tumors in the rat. Although estradiol concentrations in ovarian vein blood were reduced initially by both compounds, there is a reflex rise in LH and estradiol levels during long-term treatment with AG, whereas hormone levels in 4-OHA treated animals remained suppressed. Further studies in ovariectomized rats indicated that during long-term treatment, 4-OHA acts as a weak androgen (the compound has less than 1% the activity of testosterone) to directly inhibit the post-castrational rise in gonadotropin levels. This antigonadotropin action of the steroidal aromatase inhibitor may help maintain reduced ovarian estrogen secretion and thus contribute to the antitumor activity of 4-OHA.