Tissue Of Postmenopausal Women Research Articles

The origin of oestrone sulphate in normal and malignant breast tissues in postmenopausal women.

Conversion of oestrone sulphate to oestrone has been suggested to make a major contribution to the level of oestrone found in breast tissues. In order to examine the ability of breast tissues to take up oestrone sulphate (E1S), 3H E1S or E1-35S was infused into postmenopausal women with advanced breast cancer. For 3 subjects infusion of 3H E1S was repeated after treatment with Danazol, a potential inhibitor of oestrone sulphatase activity. After infusion of 3H E1S significant levels of 3H E1S were detected in normal and malignant breast tissues (tissue: plasma ratios 0.14 +/- 0.13 and 0.24 +/- 0.12 respectively, mean +/- S.D., n = 5). Similar 3H E1S tissue: plasma ratios were detected after infusions of 3H E1 indicating that the 3H E1S detected in breast tissues after infusion of 3H E1S may have originated from the hydrolysis of 3H E1S in tissues other than the breast, with subsequent uptake and sulphation in breast tissues. After infusion of E1-35S no significant levels of radioactivity were detectable in normal or malignant breast tissues. Treatment with Danazol had no significant effect on tissue levels of 3H E1S or on the CRE1S E1 or MCR-E1S. It is concluded that oestrone sulphate, as such, is not taken up by breast tissues and that any contribution that oestrone sulphate makes to the oestrogen content of breast tissues will depend upon prior hydrolysis.

92110598 Increased steroid production by the ovarian stromal tissue of postmenopausal women with endometrial cancer

92110598 Increased steroid production by the ovarian stromal tissue of postmenopausal women with endometrial cancer

Increased steroid production by the ovarian stromal tissue of postmenopausal women with endometrial cancer.

An increase in ovarian steroid secretion could play a role in the pathogenesis of endometrial cancer in postmenopausal women. The present study was undertaken to investigate steroid production by isolated ovarian stromal tissues of postmenopausal women with endometrial cancer and to study the effect of LH and insulin on ovarian steroidogenesis in postmenopausal women. Ovarian stromal tissue was obtained from 10 postmenopausal women with endometrial cancer and 8 women without cancer. The stroma was incubated in either the medium alone or the medium to which was added LH (50 ng/mL) or insulin (500 ng/mL). The ovarian stroma of postmenopausal women with cancer released significantly more androstenedione (A), testosterone, and dehydroepiandrosterone than that of women without cancer. Addition of LH resulted in a significant increase in A, testosterone, dehydroepiandrosterone, and progesterone release compared to that with vehicle alone. Addition of insulin stimulated the release of A from the ovarian stroma of women with cancer, but had no effect on the normal postmenopausal ovarian stroma. These results indicate that the ovarian stroma of postmenopausal women with endometrial cancer secrete significantly greater amounts of androgens than those of women without cancer and that both LH and insulin may be important factors contributing to this increase in ovarian steroidogenesis.

Identification of 16α-hydroxy-estrone as a metabolite of estriol

During a study on the uptake and retention of estrogens by uterine tissues in postmenopausal women, evidence was obtained of the presence of a metabolite of estriol, tentatively identified as 16 alpha-hydroxy-estrone (16-OHE1). In view of the recent hypothesis concerning the role of 16-OHE1 as a risk marker for breast cancer, attempts were made to establish the identity of the metabolite. After infusions with labelled estriol, radioactive material with chromatographic properties of 16-OHE1 was observed; insufficient material was obtained for micro-recrystallization. After oral administration of estriol, myometrial tissue was extracted, then purified by chromatography and the appropriate fraction was analyzed by gas chromatography-mass spectrometry, monitored at 3 specific mass units. In the women receiving estriol the presence of 16-OHE1 could be unequivocally demonstrated, the concentrations in the myometrium being 6 and 18 ng/g tissue, whereas less than 0.2 ng/g was found in an untreated patient. This identification of 16-OHE1 does not support the hypothesis about its prominent role in human breast cancer. Additional investigations will be necessary to clarify its role in the process of stimulation of estrogen-sensitive tissues under physiological conditions and after exogenous administration of estriol.

Aromatase, 17β-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women

In a study of the origin of estrogens in patients with breast cancer, the concentrations of estrogens and their androgen precursors, and aromatase and 17β-hydroxysteroid dehydrogenase (E 2DH) activities were determined in normal glandular and cancerous breast tissue. The correlation between tissue estrogens, precursor concentrations, enzyme activities and plasma levels and/or receptor status were calculated. In both normal glandular and carcinomatous breast tissue, the concentrations of androstenedione (A), dehydroepiandrosterone (DHEA), 5 androstene-3β, 17β-diol (5-Adiol), estrone (E 1), estradiol (E 2) and progesterone (P) were significantly higher than plasma concentrations. While testosterone (T) concentrations were similar, dehydroepiandrosterone (DHCA) and estrone sulphate (E 1S) concentrations were lower in tissue than in plasma. In carcinomatous tissue androgen concentrations were lower, but estrogen concentrations were higher than in glandular breast tissue. Estradiol (E 2) concentration was positively correlated with the receptor concentration with the mean E 2 concentration corresponding to an estimated receptor occupancy of about 25%, probably sufficient for a submaximal biological response. Aromatase and E 2DH (E 2 → E 1) activities were observed in all breast cancer and glandular breast tissues, activities being higher in carcinoma than in glandular breast tissues; nevertheless, aromatase activity accounts probably only for a small fraction of tissue estrogen concentration. E 2DH, but not aromatase activity, was significantly higher in estrogen receptor positive than in estrogen receptor negative tissues and was negatively correlated with tissue dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) concentration; the latter two steroids are non competitive inhibitors of E 2DH which inactivates E 2 to E 1. This effect of DHEA (S) may constitute a mechanism by which these androgens stimulate cancer growth and a rationale (besides suppression of estrogen precursors) for medical or surgical adrenalectomy in hormone sensitive metastatic mammary cancer. E 2DH activity might constitute an additional marker of hormone dependency of mammary cancer.

Metabolism of [ 3H]oestradiol in vivo by normal breast and tumour tissue in postmenopausal women

Tumour and normal breast tissue was obtained from postmenopausal breast cancer patients following [ 3H] oestradiol infusion (50 μCi over a 12 h period). The fraction of radioactivity present as oestradiol or oestrone was measured and the results expressed both as the ratio of oestradiol-oestrone and as the percentage oestrogen present as oestrone, and the findings compared with in vitro measurements of 17β-hydroxysteroid dehydrogenase activity. Concentrations of 5-androstene-3β,17β-diol, dehydroepiandrosterone and its sulphate and testosterone were measured and related to oestradiol metabolism. The study demonstrated that tumour tissue is less able to metabolise oestradiol to oestrone than is normal breast tissue and indicated that the ability of the tissue to detoxify oestradiol may be dependent on cofactor availability. The results also supported the possibility that increased tissue concentrations of adrenal androgens inhibit oestradiol and thus increase tissue exposure to oestradiol.

Resistance of the ovary to blockade of aromatization with aminoglutethimide.

Aminoglutethimide (AG) is a potent inhibitor of aromatization in placental microsomes and in peripheral tissues in postmenopausal women. Aromatase inhibitors have been used to block estrogen production and induce breast tumor regression in rodents. To inhibit ovarian estrogen production, we administered various doses of AG and its highly potent D-stereoisomer to premenopausal women with breast carcinoma. However, at no dose level did AG consistently lower estrone and estradiol concentrations in plasma below those observed in normal menstruating women. Uniform increments in LH and FSH were also not observed. Only during the luteal phase were the levels of estradiol (but not estrone) significantly suppressed. These observations are best explained by the possibility that aromatase enzymes in the ovary, as opposed to those in the placenta and in peripheral tissues, are partially resistant to the effects of AG.