J Natl Cancer Inst Monogr. 2000;(27):95-112.
Tissue-specific synthesis and oxidative metabolism of estrogens.
Jefcoate CR, Liehr JG, Santen RJ, Sutter TR, Yager JD, Yue W, Santner SJ, Tekmal R, Demers L, Pauley R, Naftolin F, Mor G, Berstein L.
Estrogen exposure represents the major known risk factor for development of breast cancer in women and is implicated in the development of prostate cancer in men. Human breast tissue has been shown to be a site of oxidative metabolism of estrogen due to the presence of specific cytochrome P450 enzymes. The oxidative metabolism of 17beta-estradiol (E2) to E2-3,4-quinone metabolites by an E2-4-hydroxylase in breast tissue provides a rational hypothesis to explain the mammary carcinogenic effects of estrogen in women because this metabolite is directly genotoxic and can undergo redox cycling to form genotoxic reactive oxygen species. In this chapter, evidence in support of this hypothesis and of the role of P4501B1 as the 4-hydroxylase expressed in human breast tissue is reviewed. However, the plausibility of this hypothesis has been questioned on the grounds that insufficient E2 is present in breast tissue to be converted to biologically significant amounts of metabolite. This critique is based on the assumption that plasma and tissue E2 levels are concordant. However, breast cancer tissue E2 levels are 10-fold to 50-fold higher in postmenopausal women than predicted from plasma levels. Consequently, factors must be present to alter breast tissue E2 levels independently of plasma concentrations. One such factor may be the local production of E2 in breast tissue through the enzyme aromatase, and the evidence supporting the expression of aromatase in breast tissue is also reviewed in this chapter. If correct, mutations or environmental factors enhancing aromatase activity might result in high tissue concentrations of E2 that would likely be sufficient to serve as substrates for CYP1B1, given its high affinity for E2. This concept, if verified experimentally, would provide plausibility to the hypothesis that sufficient E2 may be present in tissue for formation of catechol metabolites that are estrogenic and which, upon further oxidative metabolism, form genotoxic species at levels that may contribute to estrogen carcinogenesis.
Contraception. 1981 Apr;23(4):447-55.
Comparison of plasma and myometrial tissue concentrations of estradiol-17 beta and progesterone in nonpregnant women.
Akerlund M, Batra S, Helm G.
Plasma and myometrial tissue concentrations of estradiol (E2) and progesterone (P) were measured by radioimmunoassay techniques in samples obtained from women with regular menstrual cycles and from women in pre- or postmenopausal age. In women with regular cycles, the tissue concentration of E2 ranged from 0.13 to 1.06 ng/g wet weight, with significantly higher levels around ovulation than in follicular or luteal phases of the cycle. The tissue concentration of P ranged from 2.06 to 14.85 ng/g wet weight with significantly higher level in luteal phase than in follicular phase. The tissue/plasma ratio of E2 ranged from 1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal phase. The ratio for P ranged from 0.54 to 23.7 and was significantly lower in the luteal phase than in other phases of the cycle. One woman in premenopausal age with an ovarian cyst was the only case with a tissue/plasma ratio of E2 Less Than 1, since her plasma E2 levels were exceptionally high. In postmenopausal women, the tissue concentration of E2 was not significantly lower than in menstruating women in follicular phase, and the tissue concentration of P was not significantly lower than in fertile women in any of the phases. Neither in these women nor in menstruating women was there a close correlation between tissue and plasma levels. The present data indicate that the myometrial uptake capacity for ovarian steroids may be saturated, and also that a certain amount of these steroids is bound to tissue even if plasma levels are low.
Clin Endocrinol (Oxf). 1979 Dec;11(6):603-10.
Interrelations between plasma and tissue concentrations of 17 beta-oestradiol and progesterone during human pregnancy.
Batra S, Bengtsson LP, Sjöberg NO.
Oestradiol and progesterone concentration in plasma, decidua, myometrium and placenta obtained from women undergoing Caesarian section at term and abortion at weeks 16-22 of pregnancy were determined. There was a significant increase in oestradiol concentration (per g wet wt) both in placenta, decidua and myometrium from mid-term to term. Both at mid-term and term oestradiol concentrations in decidua and myometrium were much smaller than those in the plasma (per ml). Progesterone concentration in placenta and in myometrium did not increase from mid-term to term where it increased significantly in decidua. Decidual and myometrial progesterone concentrations at mid-term were 2-3 times higher than those in plasma, but at term the concentrations in both these tissues were lower than in plasma. The ratio progesterone/oestradiol in plasma, decidua, myometrium and placenta at mid-term was 8.7, 112.2, 61.4 and 370.0, respectively, and it decreased significantly in the myometrium and placenta but was nearly unchanged in plasma and decidua at term. The general conclusion to be drawn from the present study is the lack of correspondence between the plasma concentrations and the tissue concentrations of female sex steroids during pregnancy.
J Steroid Biochem. 1984 Nov;21(5):607-12.
The endogenous concentration of estradiol and estrone in normal human postmenopausal endometrium.
Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman J, Thijssen JH.
The endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were measured in 54 postmenopausal, atrophic endometria and compared with the E1 and E2 levels in plasma (pg/ml). The results from the tissue levels of both steroids showed large variations and there was no significant correlation with their plasma levels. The mean E2 concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270 pg/g was 9 times higher. The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being 0.3. We conclude that normal postmenopausal atrophic endometria contain relatively high concentrations of estradiol and somewhat lower estrone levels. These tissue levels do not lead to histological effects.
Ann N Y Acad Sci. 1986;464:106-16.
Uptake and concentration of steroid hormones in mammary tissues.
Thijssen JH, van Landeghem AA, Poortman J.
In order to exert their biological effects, steroid hormones must enter the cells of target tissues and after binding to specific receptor molecules must remain for a prolonged period of time in the nucleus. Therefore the endogenous levels and the subcellular distribution of estradiol, estrone, DHEAS, DHEA ad 5-Adiol were measured in normal breast tissues and in malignant and nonmalignant breast tumors from pre- and postmenopausal women. For estradiol the highest tissue levels were found in the malignant samples. No differences were seen in these levels between pre- and postmenopausal women despite the largely different peripheral blood levels. For estrone no differences were found between the tissues studied. Although the estradiol concentration was higher in the estradiol-receptor-positive than in the receptor-negative tumors, no correlation was calculated between the estradiol and the receptor consent. Striking differences were seen between the breast and uterine tissues for the total tissue concentration of estradiol, the ratio between estradiol and estrone, and the subcellular distribution of both estrogens. At similar receptor concentrations in the tissues these differences cannot easily be explained. Regarding the androgens, the tissue/plasma gradient was higher for DHEA than for 5-Adiol, and for DHEAS there was very probably a much lower tissue gradient. The highly significant correlation between the androgens suggests an intracellular metabolism of DHEAS to DHEA and 5-Adiol. Lower concentrations of DHEAS and DHEA were observed in the malignant tissues compared with the normal ones and the benign lesions. For 5-Adiol no differences were found and therefore these data do not support our original hypothesis on the role of this androgen in the etiology of breast abnormalities. Hence the way in which adrenal androgens express their influence on the breast cells remains unclear.
