Estrogen activity and novel tissue selectivity of Delta(8,9)-dehydroestrone sulfate in postmenopausal women

Recent basic and clinical advances have consolidated the concept of tissue- selective estrogens, i.e. molecules that express different degrees of parti al agonist, full agonist or antagonist activity in different tissues or cel ls. Delta(8,9)-Dehydroestrone sulfate (Delta(8,9)-DHES) is a conjugated est rogen and a component of conjugated equine estrogens (CEE). It is metaboliz ed in the human in at least a 1:1 ratio to its 17 beta form, 17 beta-Delta( 8,9)-DHES. To evaluate its activity in different clinical and biochemical p arameters, a clinical research study was conducted with Delta(8,9)-DHES and estrone sulfate as a comparator in postmenopausal women. Delta(8,9)-DHES w as given orally at a daily dose of 0.125 mg for 12 weeks in a group of 10 w omen. Two additional groups of women received either estrone sulfate alone (1.25 mg/day) or the combination of Delta(8,9)-DHES and estrone sulfate at the previously specified doses. A significant and consistent suppression of hot flushes (number, severity, and total score) was observed with Delta(8, 9)-DHES, reaching more than 95% suppression in all parameters of vasomotor symptoms. This level of activity was equal to that obtained with the much h igher dose of estrone sulfate, and it was sustained for the duration of the treatment period (12 weeks). Measurements of a bone resorption marker. i.e . urinary excretion of N-telopeptide, demonstrated that Delta(8,9)-DHES at 8 weeks produced a degree of suppression (40%) similar to that observed wit h the higher dose of estrone sulfate. Gonadotropin secretion (FSH and LH) w as significantly suppressed in women receiving Delta(8,9)-DHES, similar to that observed with estrone sulfate alone or with the combination of the two . Other parameters, such as total cholesterol, low density lipoprotein chol esterol and high density lipoprotein cholesterol were not modified signific antly, whereas serum globulins (sex hormone-binding globulin and corticoste roid-binding globulin) showed only marginal increases after Delta(8,9)-DHES administration. Taken together with preclinical data, it is found that Delta(8,9)-DHES is a n active estrogen with a distinct pharmacological profile that results in s ignificant clinical activity in vasomotor, neuroendocrine (gonadotropin and PRL) and bone preservation parameters, whereas displaying little or no eff icacy, at the dose tested, on other peripheral parameters normally affected by estrogens, Collectively, this information supports the concept that Del ta(8,9)-DHES is an integral component of GEE, with distinct tissue selectiv ity contributing to the CEE's overall clinical activity, and places this es trogen as a distinct member of a novel class of centrally active molecules with unique peripheral tissue selectivity.