title: Steroidal fatty acid esters.
abstract: Several years ago we discovered an unexpected family of steroidal metabolites, steroidal fatty acid esters. We found that fatty acid esters of 5-ene-3 beta-hydroxysteroids, pregnenolone and dehydroisoandrosterone are present in the adrenal. Subsequently, others have shown the existence of these non-polar 5-ene-3 beta-hydroxysteroidal esters in blood, brain and ovaries. Currently, almost every family of steroid hormone is known to occur in esterified form. We have studied the esters of the estrogens and glucocorticoids in some detail, and have found that these two steroidal families are esterified by separate enzymes. In a biosynthetic experiment performed simultaneously with estradiol and corticosterone, we established that the fatty acid composition of the steroidal esters is quite different. The corticoid is composed predominantly of one fatty acid, oleate, while the estradiol esters are extremely heterogeneous. Our studies have demonstrated that the estrogens are extremely long-lived hormones, that they are protected by the fatty acid from metabolism. They are extremely potent estrogens, with prolonged activity. Esterification appears to be the only form of metabolism that does not deactivate the biological effects of estradiol. We have demonstrated the biosynthesis of fatty acid esters of estriol, monoesters at both C-16 alpha and C-17 beta. They too are very potent estrogens. These fatty acid esters of the estrogens are the endogenous analogs of estrogen esters, like benzoate, cypionate, etc., which have been used for decades, pharmacologically because of their prolonged therapeutic potency. We have found that the estradiol esters are located predominantly in hydrophobic tissues, such as fat. Sequestered in these tissues, they are an obvious reservoir of estrogenic reserve, requiring only an esterase for activation. To the contrary the biological activity of the fatty acid esters of the glucocorticoid, corticosterone, is not different from that of its free parent steroid. We have shown that the rapid kinetics of its induction of gluconeogenic responses is caused by its labile C-21 ester which is rapidly hydrolyzed by esterase enzymes. While it appears that the physiological role of the estrogen esters may be related to their long-lived hormonal activity, the role of the other families of steroidal esters is not yet apparent. They, and perhaps the estrogen esters as well, must serve other purposes. Indeed they may serve important biological functions beyond those which we ordinarily associate with steroid hormones.
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: R B
authors.initials: RB
authors.lastname: Hochberg
authors.forename: S L
authors.initials: SL
authors.lastname: Pahuja
authors.forename: J E
authors.initials: JE
authors.lastname: Zielinski
authors.forename: J M
authors.initials: JM
authors.lastname: Larner
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000728:Androgens / Q000737:chemistry; D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism; D003345:Corticosterone / Q000737:chemistry; D003687:Dehydroepiandrosterone / Q000737:chemistry / Q000378:metabolism; D004952:Esters / Q000737:chemistry*; D004967:Estrogens / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry*; D011284:Pregnenolone / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012995:Solubility; D013256:Steroids / Q000737:chemistry*
chemical_list: D000728:Androgens; D002788:Cholesterol Esters; D004952:Esters; D004967:Estrogens; D005227:Fatty Acids; D013256:Steroids; D003687:Dehydroepiandrosterone; D011284:Pregnenolone; D003345:Corticosterone