Studies on the effects of estrogen fatty acid esters on mammary cell growth and carcinogenesis in female rats

The naturally occurring estrogen fatty acid esters are a unique group of estrogen derivatives that are formed from the enzymatic esterification of E₂ (at the C-17 position) using various fatty acyl-CoAs as cofactors. These lipophilic estrogen derivatives cannot bind to the estrogen receptor, rather their hormonal activity results from the slow enzymatic release of the parent hormone. Because of their high lipophilicity, estrogen fatty acid esters are found at higher concentrations in the fat than in the blood. Therefore, it is possible that the mammary adipocytes may serve as a storage site for the lipoidal estrogen fatty acid esters.; It was hypothesized that the estrogen fatty acid esters are a group of mammary selective hormones that are especially important for stimulating cell growth and inducing tumor formation in the fat-rich mammary tissues when compared to the uterus and pituitary. Data showed that chronic administration of 0.5 or 5 nmol/day of E₂-17β-stearate (a representative estrogen fatty acid ester) to ovariectomized Sprague-Dawley rats for 10 or 23 days had a markedly stronger stimulatory effect on mammary glandular cell growth than did E₂ at equimolar doses, while E₂ showed a preferential growth stimulatory effect in the uterus of these animals.{09}In addition, it was shown that the chronic administration of an E₂-17β-fatty acid ester preparation to ACI rats preferentially induced the development of mammary tumors while chronic administration of E₂ resulted in the preferential formation of pituitary tumors.{09}This is the first report demonstrating that chronic administration of an estrogen fatty acid ester selectively induces the development of mammary tumors in this animal model.; It would be of great interest to advance our knowledge on the biological effects of other naturally occurring estrogen-fatty acid ester derivatives. However, very few estrogen fatty acid esters are sold commercially. Therefore, a facile method for the chemical synthesis of large amounts of 4-hydroxyestradiol-17β-stearate, a representative fatty acid ester of the strongly procarcinogenic estrogen metabolite 4-hydroxyestradiol, was developed. The availability of large amounts of chemically synthesized 4-hydroxyestradiol-17β-fatty acid esters makes it possible for future studies to characterize their hormonal and carcinogenic potency in animals and humans.