Assessment of oestrogen and progestin effects on epithelium and stroma from pre- and postmenopausal endometria.
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Cell Division↗
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Proliferative effects of estradiol, progesterone, and two CB congeners and their metabolites on gray seal (Halichoerus grypus) uterine myocytes in vitro.
Gray seal females living in the Baltic Sea have been found to exhibit a high prevalence of uterine leiomyomas. These animals are also known to accumulate lipid-soluble PCBs in their blubber. PCBs have documented endocrine-disrupting effects; to investigate whether the PCBs could be part of the genesis of uterine smooth muscle tumors in this species, gray seal myometrial cell cultures were exposed to two CBs and their metabolites, as well as to estradiol and progesterone, after which the effects were analyzed in terms of proliferative activity by measurements of BrdU absorbance and protein content. Progesterone was found to have an inhibitory effect, whereas one CB acted as a stimulant on the myometrial cell proliferation. One of the CB metabolites also seemed to have an inhibitory effect, although this could not be statistically verified. These results suggest that some CBs have effects on uterine myometrial cell proliferation in gray seals and, thus, may also take part in the growth regulation of uterine leiomyomas.
Animals↗
[Hormonal contraceptives and arterial hypertension].
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Adult↗
Characterization of human progesterone receptor by high performance hydrophobic interaction chromatography.
High performance hydrophobic interaction chromatography has been used to separate progestin receptors (PRs) from human uterus and from the T47D human breast cancer cell line. Reproducible separations of high resolution were achieved using a TSK Phenyl-5PW column and a reverse salt gradient of 400 mM to 0 mM sodium sulfate in phosphate buffer, pH 7.4. Peaks of radioactivity exhibiting hydrophobic behaviour were isolated, as well as a smaller proportion of specific bound receptors located in the void volume fraction. No differences in retention times were observed between uterine and breast cell line samples. When the technique was used in conjunction with rapid vertical tube sucrose density gradient centrifugation, the 8S sedimenting PR from fresh, low-salt cytosol always eluted with a retention time of 24 min. The natural 4S receptor chromatographed as a single peak at 29 min while the 4S receptor species from high-salt cytosol appeared as two distinct peaks of radioactivity with retention times of 29 and 33 min. While specific binding was shown to occur in the void volume of the column, the origin of these receptors were indeterminate. These results would suggest that under these conditions the 8S receptor occurs as a single hydrophobic class of protein, whereas the data provides evidence that transformed 4S receptor may be proportioned into two unequal entities as a function of exposure to salt.
Breast Neoplasms↗
[Estrogen and progestogen cytosol receptors in human breast carcinoma (author's transl)].
The authors have studied Estrogen (RE) and Progestin (RP) cytosol receptors in 379 human breast carcinomas: 281 tumors suitable for surgery, 26 pseudo-inflammatory tumors, 52 metastases and 20 recurrences. They have used an exchange technique with estradiol for RE and a synthetic compound, R 5020, for RP. The results point out that high rates of RE correlate with post-menopausal women and high rates of RP with pre-menopausal women. Tumours are considered receptor-positive when the binding sites concentration exceeds 100 fmoles/g tissue. Using this as a base 32% of the tumors are RE and RP negative. Considering only the positive tumors, 54% contain both receptors, 31% only RE and 15% only RP. The percentages are also given in terms of the hormonal state of the patients. The results are discussed in terms of McGuire's hypothesis that both receptors are necessary to obtain a positive response to hormonal therapy. Correlation between histology and receptors is also discussed.
Breast Neoplasms↗
L-histidine/medroxyprogesterone acetate interaction modulates human breast cancer cell growth and progestin receptor expression in vitro.
The effect of different L-histidine concentrations on human mammary tumour cell (CG5) proliferation was studied to test the hypothesis of a role of histidine in modulating sex steroid-regulated cell proliferation. Cell growth was only possible in the 10(-5) M and 10(-2) M range, while its inhibition by medroxyprogesterone acetate was confined to the 10(-4) M and 10(-3) M range. 10(-3) M L-histidine enhanced the effect of medroxyprogesterone acetate in reducing the number of cells in the S phase. The results show also that 10(-3) M L-histidine favours progestin diffusion into cells and increases progestin receptors density. The present data are in line with previous observations of the effect of histidine on the growth of experimental animal tumours, add evidence that histidine concentration influences the control of cell proliferation by sex steroids, and suggest a possible use of histidine in association with progestational drugs in the treatment of human neoplasia.
Breast Neoplasms↗
[Hormones in gynecologic oncology].
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Antineoplastic Agents↗
Distribution of cytoplasmic estrogen and progesterone receptors in human endometrium.
Unoccupied estrogen receptors and progesterone receptors were measured in the cytoplasm of five sections along the length of endometrium obtained from noncancerous, premenopausal hysterectomy specimens. The concentrations of the two receptors were measured with tritiated estradiol or R5020 (a synthetic progestin), the latter two having been purified by high-pressure liquid chromatography, and were found to be highest in the fundus and lowest in the cervix. Progesterone receptor levels, ranging from 50 to 3,500 fmoles of R5020 bound per milligram of protein, were generally much higher in each section of the endometrium than estrogen receptor levels, which ranged from 0 to 500 fmoles of estradiol bound per milligram of protein. Near ovulation it seemed that the distribution profiles of both receptors became very steep, with more than a tenfold difference in the receptor levels being found between the fundus and the cervix. Receptor levels measured in endometrial samples obtained by curettage or aspiration should be interpreted with caution.
Chromatography, High Pressure Liquid↗
Acute adolescent menorrhagia.
Acute menorrhagia in adolescence is a much underestimated clinical problem, often requiring urgent medical intervention. In a 9-year case review between January, 1971, and January, 1980, we looked at all admissions to a children's hospital for acute menorrhagia, where genital tract pathology had been excluded. A primary coagulation disorder was found in almost 20% of these 59 patients. One quarter of those with severe menorrhagia (hemoglobin less than 10 gm/100 ml), one third of those requiring transfusion, and one half of those presenting at menarche had such an underlying disorder. Therefore, proper screening and therapy are essential in all girls with menorrhagia. Conventional methods of hormonal control are only partially effective in these special cases.
Adolescent↗
Endolymphatic stromal myosis in two patients on progestagen therapy.
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Adult↗
[3H]DU41165: a high affinity ligand and novel photoaffinity labeling reagent for the progesterone receptor.
17 alpha-Acetoxy-6-fluoro-16-methylene-(9 beta, 10 alpha)pregna-4,6-dien- 3,20-dione (DU41165), a retroprogestin (9 beta, 10 alpha) embodying a fluorine-substituted dienone system, has been prepared in high specific activity tritium-labeled form (4 Ci/mmol) and shown to be a high affinity ligand for the progesterone receptor (PgR) and a highly selective photoaffinity labeling reagent for PgR. The radiosynthesis involved conversion of DU41231 (the 17 alpha-hydroxy analog of DU41165) to DU41165 by treatment with tritium-labeled acetic anhydride. The binding affinity of DU41165 for PgR was determined by both a competitive binding assay and a direct binding assay (Scatchard analysis) to be 1.6-2.2-times higher than that of the high affinity synthetic progestin promegestone (R5020). In unlabeled form, DU41165 demonstrates photoinactivation of PgR to the extent of 60% at 60 min. In radiolabeled form [3H]DU41165 demonstrates specific covalent attachment with an efficiency of 5-7%. SDS-polyacrylamide gel electrophoresis of photoattached [3H]DU41165 confirms that there is covalent labeling of both the B subunit (Mr = 118,000), and the A subunit (Mr = 88,000) of PgR in a molar ratio of approximately 1:3.
Affinity Labels↗
Assay for estrogen and progesterone receptors of breast cancer cell lines in monolayer culture.
A whole-cell assay for measuring estrogen (ER) and progesterone (PgR) receptors in monolayer culture of human breast cancer cell lines is described. It is based on the measurement of incorporated tritiated ligands during 50 min of incubation (i.e. [3H]estradiol for ER, [3H]ORG-2058 for PgR). The assay fulfills all criteria of specificity as shown by competitive studies and measurements of the dissociation constants of the binding reactions. Moreover, a subcellular fractionation of MCF-7 labeled cells revealed that the majority of incorporated steroids was associated with the nuclear fraction. This finding is consistent with the concept of nuclear location of steroid-receptor complexes. Cultures in the presence of 10(-8) M estradiol indicated that the methodology is adequate for detecting the well-known estrogenic induction of PgR synthesis. The assay proved suitable for the quantitative assessment of the receptor content of various neoplastic (MCF-7; ZR-75-1, Cama-1, Evsa-T) and non-neoplastic (HBL-100) cell lines. The methodology has the other advantages of being simple and rapid, of requiring small amounts of cells and of allowing histological examination of the latter before, during and after biochemical analysis.
Binding, Competitive↗
Progestins inhibit FSH-stimulated steroidogenesis in cultured rat granulosa cells.
It has been hypothesized that progesterone (P) exerts a direct inhibitory effect on ovarian follicular development, an effect which could be mediated by P receptors located in granulosa cells. We tested this hypothesis by examining the effect of several progestins on FSH-stimulated estrogen (E), P, and 20 alpha-dihydroprogesterone (DHP) production by cultured rat granulosa cells, and correlated the results with the ability of the progestins to bind to the granulosa cell P receptor. Granulosa cells from immature hypophysectomized DES-treated rat produced 9 ng/ml E, 21 ng/ml P and 29 ng/ml DHP during a 2-day incubation in McCoy's 5a medium containing 10(-7) M androstenedione and 10 ng/ml of FSH. The FSH-induced increase in E production was inhibited by 50 and 95% following concomitant treatment with 3 x 10(-6) and 10(-5) M resp. of R5020, a potent synthetic progestin. Added R5020 at these concentrations also significantly inhibited P and DHP production. R5020 had no effect on granulosa cell viability or plating efficiency, and the inhibitory action of R50920 on E production was reversible. In studies of the specificity of the progestin inhibitory action, the relative abilities of various progestins to inhibit E production were R5020 > P > DHP > 17 alpha-hydroxyprogesterone (17OHP). The relative abilities of these progestins to bind to the ovary P receptor were also: R5020 > P > DHP > 17OHP. These results indicate that exogenous progestins directly inhibit the FSH-stimulation of granulosa cell steroidogenesis in vitro and suggest that the progestin effect may be mediated by the P receptor. Such results offer a possible mechanism whereby progesterone could exert a direct but reversible inhibitory action on ovarian follicular development.
20-alpha-Dihydroprogesterone↗
Reduced levels of cathepsin D associated with tamoxifen resistance and estrogen independence in the ZR-75-1 human breast cancer cell line.
The expression and secretion of cathepsin D by ZR-75-1 human breast cancer cells, and tamoxifen-resistant (ZR-75-9a1) and estrogen-independent (ZR-PR-LT) variants was examined by electrophoresis of labeled proteins and Western blotting. Secreted proteins of 160 kDa, 52 kDa and 34 kDa were identified, and in ZR-75-1 cells, they were shown to be estrogen-inducible. Treatment of ZR-75-9a1 cells with 17 beta-estradiol (E2) and the progestin ORG 2058 increased secretion of the 52 kDa protein; ZR-PR-LT cells were unaffected. Western blotting showed that each cell line expressed high levels of the 52 kDa and 34 kDa forms of cathepsin D but that relatively little was being secreted. Each cell line secreted 52 kDa procathepsin D, but 34 kDa mature-cathepsin D was not detected as a secreted protein. ZR-75-1 cells expressed and secreted the highest levels of cathepsin D while ZR-75-9a1 cells expressed and secreted the least.
Breast Neoplasms↗
Progesterone receptors in human oestrogen target tissues.
The levels of specific oestrogen and progesterone receptors have been measured in myometrial, endometrial and vaginal tissues obtained from 18 women between the ages of 28-73 yr. High speed cytosols of the three tissues were incubated at four different concentrations of specific ligands: E2 for the oestrogen receptor (ERc) and Org-2058 for the progesterone receptor (PgRc). Separation of bound and free hormones was done by dextran-coated charcoal; data were analysed according to Scatchard. In the myometrium and endometrium both PgRc and ERc were found. In the vaginal tissues obtained from the same patients only ERc was present. There was no evidence of specific progesterone receptors in the vagina. Both clinical and histological findings indicate that the vagina is an oestrogen-sensitive organ. Therefore, it is surprising that progesterone receptors, which are considered to be a specific response of oestrogen target tissue, are absent in the human vagina. This finding suggests that the induction of the progesterone receptors is not a specific response to oestrogen stimulation in the human vagina.
Adult↗
Basis of norgestomet action as a progestogen in cattle.
Norgestomet is the progestational component present in Syncro-Mate-B, which is used to synchronize estrus in cattle. In post-partum cows, luteal phases anticipated to be short following first ovulation are of normal length when cows are pretreated with norgestomet. Because Syncro-Mate-B is used experimentally as a progestogen to affect uterine function, these studies were conducted to investigate how norgestomet acts at the level of the uterus. Receptor binding assays and a sensitive estrogen bioassay in tissue culture were used to address the possibility that some effects of norgestomet might be mediated through interaction of this compound with steroid hormone receptors other than the progesterone receptor (rP). The source of receptors was high-speed cytosol, prepared from bovine uterine endometrium, which was obtained from cyclic cows. Results of single-point and complete competition analyses comparing norgestomet and progesterone indicated that norgestomet competed even more effectively than did progesterone for specific binding of [3H]progesterone to rP. Results of similar studies, which compared the abilities of norgestomet and diethylstilbestrol to compete with [3H]estradiol for binding by uterine endometrial estrogen receptors (rE), provided no evidence for norgestomet competitive binding to rE. In MCF-7 breast cancer cell bioassays, norgestomet showed weak estrogenic activity, but only at concentrations greater than 1 micromolar. Finally, norgestomet did not compete with [3H]triamcinolone acetonide when present in an 100-fold excess, and only competed with [3H]dexamethasone for binding by endometrial glucocorticoid receptors (rG) when present in the micromolar range. We conclude that, at the concentrations used in synchronizing estrus, norgestomet interacts with bovine endometrium as a progestogen and that its biological actions occur through binding of this compound to rP present in target tissues.
Animals↗
Mechanisms of hormonal and antihormonal action of contraceptive progestins at the molecular level.
19-Nor synthetic progestins undergo extensive metabolism at the target cells. The resulting metabolic conversion products interact with putative steroid receptors within the cells, and through those interactions, they may exert either agonistic, synergistic and antagonistic hormonal effects. Studies conducted in our laboratories have disclosed that norethisterone (NET) and D-(1) norgestrel (LNG), two widely used contraceptive progestins, are biotransformed to several A-ring reduced (dihydro and tetrahydro) derivatives. The resulting metabolites 5 alpha-dihydro NET (5 alpha-NET) and 5 alpha-dihydro LNG bind with relative high affinity to the progesterone and androgen receptors. To gain insight into the underlying molecular events mediating the mode of action of NET and its neutral metabolites, we have examined the expression of their biological effects at target organs by using the rabbit uteroglobin gene model and the beta-glucuronidase activity of the mouse kidney. The results of a series of experiments seem to indicate that the enzyme-mediated formation of the 5 alpha (trans A/B ring junction) NET derivative results in a significant diminution of its progestational and androgenic potencies. Furthermore, 5 alpha-NET acquire a potent anti-progestational/contragestational effect as assessed in the female rabbit. These results demonstrated that 5 alpha-reduction of 19-nor progestins exerts a paradoxical effect, at least in terms of their hormone-like effects. The overall data are in line with the concept that metabolism of synthetic progestins at hormone-sensitive organs modulates their mechanisms of action.
Animals↗
Progestagen nuclear binding sites in the male genital tract of the mouse, studied by autoradiography.
Autoradiograms were prepared after injection of 125I progestagen (sp. act. 2200 Ci/mmol) to prepubertal and young adult mice. Nuclear concentration of radioactivity was found in smooth muscle cells at the beginning and the end of the deferent duct and in fibroblasts around the fusion of the deferent duct with the urethra. Nuclear labeling was enhanced in adult animals pretreated with oestradiol-valerate. In prepubertal mice nuclear labeling was more abundant than in adult mice and found in all smooth muscle cells of the deferent duct. No nuclear labeling was observed in other accessory sex organs. Nuclear labeling was prevented by injection of excess of unlabeled R5020. The presence of progestin receptors in smooth muscle cells of the deferent duct suggests a regulatory effect of progestin on contractions in analogy to progestin effects on oviductal and uteral smooth muscle cells. The presence of nuclear progestin receptors in the periurethral region may indicate an involvement of progestins in the etiology and regulation of benign prostate hyperplasia.
Animals↗