16a-Hydroxyestrone

R. Bucala, J. Fishman, and A. Cerami, Formation of covalent adducts between cortisol and 16a-hydroxyestrone and protein Possible role in the pathogenesis of cortisol toxicity and systemic lupus erythematosus, Proc. Natl. Acad. Sci. USA 79 3320 (1982). 

Since the neutral molecules of steroid hormones and metabolites are not easily ionized under either APCP or ESI+/ modes, LC-MS/MS is less sensitive when used directly in either APCP or ESI+/ modes, with LOQs at ng/mL level as shown in Table 4 [20, 21, 52], It has been observed that estrone, 16a-hydroxyestrone, 2-methoxyestrone, 4-methoxyestrone, and 2-hydroxy-3-methoxyestrone are sensitive to APCI+ mode, while 2-hydroxyestrone and 4-hydroxyestrone are sensitive to APCI- mode, and even more sensitive to ESI mode [29], Estrone, estradiol, estradiol, and estriol are sensitive to ESI" mode, and testosterone is sensitive to ESP mode [76, 77], Similarly, estrone and estradiol are sensitive to APPI" mode, and testosterone is sensitive to APPI+ mode with LOQs in a range of 1.5-10 pg/mL [22], which are comparable with those steroid hormones and metabolites derivatized with hydroxylamine or dansyl chloride, and detected under ESP mode [2, 8],... 

One hypothesis on the etiology of breast cancer has been that its induction is caused by a covalent bond of 16a-hydroxyestrone (16a-OHEi), a metabolite of El, with the estradiol (E2) receptor. This receptor modification would result in permanent, uncontrolled stimulation of cell proliferation by receptor-mediated processes (B7, SI, S6). This hypothesis implies a correlation of high levels of 16a-OHEi with induction of breast cancer. Over the years, however, this hypothesis has never been substantiated. 

Swaneck, G. E., and Fishman, J., Covalent binding of the endogenous estrogen 16a-hydroxyestrone to estradiol receptor in human breast cancer cells Characterization and intranuclear localization. Proc. Natl. Acad. Sci. USA 85,7831-7835 (1988). 

In healthy postmenopausal women, addition of 5 or 10 g daily of flaxseed dose-dependently increased urinary 2-hydroxyestrogen excretion and the ratio of urinary 2-hydroxyestrogen to 16a-hydroxyestrone. There were no significant differences in urinary 16a-hydroxyestrogen excretion (Haggans et al. 1999). 

When Marrian et al. (1957a, b) had isolated 16a-hydroxyestrone, they advanced the hypothesis that 16a-hydroxyestrone and 16/3-hydroxyestrone are formed from estrone by 16a- and 16/3-hydroxylation and that they are intermediates in the hydration of estrone to estriol and 16-epiestriol, respectively. This hypothesis received support from the experiments of Brown and Marrian (1957), who found estriol in the urine of two individuals... 

CYB5A, yielding dehydroepiandrosterone (DHEA), which enters the circulation as DHEA sulfate (DHEAS), a substrate for P450 3A7 in the fetal liver below dashed line in box). In the plaeenta, steroid sulfatase removes the sulfate from 16a-hydroxyDHEAS, and 3PHSD1 oxidizes and isomerizes 16a-hydroxyDHEA, to yield 16a-hydroxyandrostenedione. Placental P450aro and 17PHSD1 catalyze the final transformations to 16a-hydroxyestrone and estriol, respectively. 

Cholestatic conditions, without impairment of other liver functions, inhibit the reduction of 16a-hydroxyestrone to estriol and the conversion of estrone to 16a-hydroxyestrone and estriol [190]. 

It is interesting to note that the reduction of the 17-keto function (for 16 -hydroxydeliyihx)epiaiLdrostcronc and IGa-hydroxyandrostcnedione) takes place after arornatization, and the transformation between 16a-hydroxyestrone and estriol is reciprocal (Doll Acqua et al., 1967a,b Reynolds et aL, 1068). 

It can be concluded that placental estriol could originate principally from three dilferent sources (1) from 16a-li3 drox3 -dc iydroepiandrostcrone. which is transformed into 16a-hydroxyandrostenedione, then into 16a-hydroxyestrone, and linally, by the reduction of tlie 17-keto function, is converted into e.striol (2) from androstenetriol which is first converted into 16a-hydroxytestosteroiic and then info estriol or (3) from 16-oxoandro-stenediol, which is converted into 18-oxotestosterone, then into 16-oxo-estradiol and finally into estriol. 

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