摘要:

This paper contains: A review of the features implicated in estrogen action on uterine cells: metabolism, transport, entry, cytosol receptor, and first effects. (2) New results concerning the interaction of several estrogens and antiestrogens with the receptor. Binding of radioactive estrogens: at equilibrium at 0 °C, KD (in nM) of estradiol 0.2–0.5, estrone 2.0, and estriol 1.3. Inhibition constant at equilibrium measured by competition with nonradioactive compounds of natural and synthetic steroid and nonsteroidal estrogens, new stilbene derivatives, phytoestrogens, etc. (28 compounds). Kinetic studies. Same dissociation rate constant for estradiol, estrone and estriol and association rate constant greater for estradiol. Formation of the neonuclear steroid receptor complex by estrone and estriol, implicating that estradiol is not unique for promoting the cytosol receptor translocation to the nucleus. (3) A review of possible mechanisms for antiestrogen action.

ISSN:0378-7346    

DOI:10.1159/000301742

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

This presentation covers three areas in relation with the mechanism of oestrogen action on the central nervous system. The ability of the uterus, vagina, anterior pituitary and anterior hypophysis to take up and retain oestradiol has been proposed as a distinctive character for the oestrogenic target organs. Although no specific protein receptors have been isolated in the neocortex, the administration of oestradiol was able to increase the incorporation of cytidine to RNA, and the protein synthesis. Those findings, together with the fact that oestradiol is concentrated and retained in the nuclei of the cerebral cortex, forced us to review the concept of target organs. The presence of very small quantities of oestradiol in the central nervous system cell nuclei may reflect the amounts that the tissue requires, and the emphasis that has always been put on quantity should be placed on there-sholds for oestrogen action in different tissues. The capacity of progestagens to compete with oestradiol binding was evaluated by organotypic culture of the hypothalamus. In a group of experiments, progestagens were added before oestradiol and, in the other group, both progestagens and oestradiol were added simultaneously to the medium. Oestradiol binding was significantly inhibited when either of the progestagens derived from 17α-hydroxyprogesterone (chlormadinone acetate (CA) and medroxyprogesterone acetate (MPA) was added simultaneously. When added previously to oestradiol, progestagens behaved differently. MPA diminished the oestradiol binding significantly; CA, on the contrary, increased it. RO4–8347, a compound derived from retroprogesterone, diminished the oestradiol binding when added previously, but not when added simultaneously. Lynestrenol and norgestrel, both 19-norsteroids, inhibited the oestradiol binding when added simultaneously, but not when added previously. Catecholamines and oestrogens participate in the control of ovulation and it was thought worthwhile to investigate their relationships in the hypothalamus and the uterus. The simultaneous administration of epinephrine and labelled 17β-oestradiol injected i.p. produced a significant increase in the uptake of oestradiol by the anterior hypothalamus and a diminution in the uterus. When norepinephrine and 17β-oestradiol were simultaneously injected, the uptake of oestradiol was increased in the uterus and not modified in the hypothalamus. As the concentration of histamine is higher in the hypothalamus than in any brain region, it seemed interesting to us to study the effect of histamine on the uptake of oestradiol and testosterone. Histamine increased the uptake of labelled oestradiol by the uterus and the hypothalamus. When histamine effects were studied in relation with testosterone uptake, it increased the hypothalamic, but not the uterine uptake. Even knowing that the mammalian pineal gland has an inhibitory effect on gonadal function, little attention has been paid to the role of gonadal hormones on pineal activity. In view of the contradictory results concerning the action of oestradiol on the pineal gland, we have studied in our laboratory the uptake of labelled oestradiol by this gland and the hydroxyindole-O-methyl transferase (HIOMT) modifications produced by oestradiol and/or norepinephrine administration. Our results demonstrate that the pineal ability to take up oestradiol was significantly higher than that of the uterus. Besides, the administration of oestradiol to spayed female rats inhibited the pineal HIOMT activity, this effect being reversed by norepinephrine, which when injected alone modifies neither the uptake of oestradiol nor HIOMT activity.

ISSN:0378-7346    

DOI:10.1159/000301743

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

Synthetic and natural antiuterotrophic and uterotrophic compounds were tested invitro in their ability to bind to the uterine cytosol receptor for estradiol (Rc) and to favor the formation of the nuclear receptor. These compounds were compared to estradiol in their capacity to decrease the number of specifically bound estradiol in cytosol and increase those in nuclear extracts when incubated with uteri invitro. For each compound, a ‘nuclear transfer activity’ was defined and compared on the one hand to its binding affinity for Rc and on the other hand to its invivo uterotrophic activity. For estrogens devoided of antiestrogenic activity, estradiol and estrone, the nuclear transfer activity was parallel to the affinity for Re and the biological activity. The antiestrogen nafoxidine (U11,100) when added to the cytosol was found to be a reversible and competitive inhibitor of estradiol for Re with an affinity about 30-fold less than estradiol (Ki 7 nM). A complete inhibition could be obtained both before and after the dissociation of Rc by KCl. However, these binding properties of nafoxidine were not in agreement with its partial nuclear transfer activity and its partial uterotrophic activity. The androgens do not bind to Rc; however, they were shown to activate the transfer of the estrogen Rc to the nucleus whereas progesterone did not. These results are discussed in relation to the mechanism of action of uterotrophic and antiuterotrophic compounds.

ISSN:0378-7346    

DOI:10.1159/000301744

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

Recent advances in these laboratories in analysis of mechanisms of steroid hormone-induced growth have identified lysosomal function in the triggering of the coupled events leading from selective accumulation of the active agent at the cell periphery, to its rapid, cyclic AMP-dependent traversal of the nuclear envelope, and eventual genie activation of the cellular target. Capture of trophic steroid hormone leads to site-specific labilization of the lysosomal bounding membrane, associated with graded extrusion of characteristic hydrolases and acidic glycolipoprotein matrix. In uterus and preputial gland of the ovariectomized rat, these closely-linked phenomena result in the cascading secondary metabolic responses characteristic of estrogen stimulation. The demonstrated antagonistic effects of glucocorticoids upon estrogen action are paralleled to a striking degree by their capacity, likewise, to accumulate in lysosomal fractions where, in optimal concentrations, they and certain other anti-inflammatory agents produce membrane stabilization. Biochemical and cytomorphologic data have been presented which reveal that the counteractive influence of specific glucocorticoids and estrogens upon relative stability of lysosomal membranes is concordant with the long-recognized antagonistic and competitive interaction of these classes of steroid hormones at membranous interfaces. Conversely, estrogen hyperactivity correlated with exaggerated lytic susceptibility of target-specific lysosomal preparations are observed following exposure to estradiol-17β invivo in the absence of adrenocortical function. The β-adrenergic blocking-drug, propranolol, which shares the membrane-stabilizing properties of the glucocorticoids, is also capable of inhibiting estrogen-induced structural labilization of target-specific lyso-somes, as well as certain additional estrogenic functions. DOC and the α-adrenergic blocking agent, phentolamine, are inert under the same conditions. Thus, it is demonstrated that the counterpoised influence which estrogens and certain membrane-stabilizing agents, respectively, exert upon lysosomo:plasma membrane complex of specific cellular targets is a decisive regulatory factor in the ultimate growth response. The new findings provide a rational integrative approach to numerous unresolved questions on the mechanisms underlying steroid hormone action and its blockade.

ISSN:0378-7346    

DOI:10.1159/000301745

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

Most so-called antiestrogens are ‘estrogenic’ in the mouse uterine growth test and in the Allen-Doisy test (in mice or rats). With regard to their uterotrophic effects, they were classified as giving normal (cis- and trans-clomiphene, ICI-46,474 and U-11,555A); impeded (estriol, DMS and ent-estradiol); partial (U-11100A and CN- 55,945) or practically no response (MER-25). A similar classification was obtained in a modified Allen-Doisy test in mice. As antiestrogens, the impeded estrogens are fairly inactive, while compounds such as U-11100A, CN-55,945 and MER-25 are more effective. This difference could be traced back to differences in interaction with estradiol-17β at the uterine level: the impeded estrogens have rather high affinities for estrogen receptors but are easily lost to the circulation while the other compounds have lower affinities but still remain on the receptors for a longer period of time. Compounds U-11,555A, U-11100A, MER-25, ICI-46,474 and 66/179 produced an estrogen-like ultrastructural picture of the luminal epithelium of the rat uterus. However, when given before a standard dose of estradiol-17β to a progesterone-treated rat, all except U-11,555A, which was inactive, were antiestrogenic, i. e., inhibited the so-called attachment reaction which is believed to be a prerequisite for implantation of the ovum. Two compounds, R2323 and 66/179 which have been described as antiprogestational, could not selectively counteract the effects of progesterone on rat uterine epithelial ultrastructure. Closer analysis of the ultrastructural effects of MER-25 revealed that at doses which are negative in conventional tests for estrogenicity the whole uterus looked atrophic except the uterine luminal epithelium which showed marked estrogen-like stimulation.

ISSN:0378-7346    

DOI:10.1159/000301746

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

Certain antiuterotrophic agents, such as ethamoxytriphetol, nafoxidine, clomiphene and Parke-Davis CI-628, act by preventing the association of estrogenic hormones with the extranuclear receptor protein of target tissues. These agents have proved of considerable value in estrogen receptor studies by permitting the distinction between specific hormone-receptor interaction and artifacts of nonspecific binding. Examples include evidence that estrogen-receptor interaction plays a role in uterine growth induction, the first indication of a relation between cytosol and nuclear binding, the relation between steroid structure and specific uterine binding invitro and the prediction of response of human breast cancers to adrenalectomy orhypophysectomy.

ISSN:0378-7346    

DOI:10.1159/000301747

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

Treatment of pregnant rats with small amounts of non-specific estrogen antibodies did not inhibit pregnancy but increased the percent males in the litter. Administration of specific antibodies to estradiol immediately following mating prevented pregnancy in all animals, while administration at mid-pregnancy caused only some reduction in the number of pregnant animals. Administration of specific estriol antibody had no effect following mating but caused nearly total resorption of fetuses at mid gestation.

ISSN:0378-7346    

DOI:10.1159/000301748

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

The experiments dealed with the regulatory action of clomiphene citrate on the FSH and LH serum levels in women of different endocrine state. The radioimmunologically obtained data can be summarized as follows: (1) In adult women with an eugonadotropic ovarian insufficiencyclomiphene stimulates the FSH- and LH-secretion during treatment, which is followed by a plasma profile comparable to that of normal cycles. This effect probably is due to the antioestrogenic property of the substance. In postmenopausal women with the typical high gonadotropin and low oestrogen levels, clomiphene displays – independent of the treatment schedule and the dose given – only an oestrogenic action, recognizable by the suppression of the FSH- and LH-plasma values. The finding of a plasma gondotropin increase after clomiphene administration in some postmenopausal women with unusual oestrogen excretion indicates that the regulatory effect of the substance mainly depends on the endogenous oestrogen level. Finally a model is given for the possible mode of action of clomiphene in stimulated ovulatory cycles.

ISSN:0378-7346    

DOI:10.1159/000301749

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

The anti-oestrogenic and oestrogen-like potencies of clomiphene citrate are presumably mainly responsible for the mode of action of this synthetic compound in different organs of the female endocrine system. The investigations described in this paper should give more informations about these properties of clomiphene. Therefore the in vivo effect of cis- or trans-clomiphene on some metabolic pathways of the uterine tissue was tested. Studying the influence of cis- or trans-clomiphene on the 3H-oestradiol uptake into uterine tissue in vivo, the cis-isomer indicated the higher anti-oestrogenic effectiveness. In contrast to this observation both isomers were able to imitate biochemical effects of natural oestrogens in the uterus, i.e. the stimulation of the protein- and RNA-synthesizing activity of this organ. These biochemical alterations however, appeared some hours later as compared with 17β-oestradiol. On the base of these results and of experimental data obtained from the literature a model for the mode of action of clomiphene in the female reproductive system is proposed

ISSN:0378-7346    

DOI:10.1159/000301750

出版商:S. Karger AG    

年代:1972

数据来源: Karger

摘要:

(1) The ‘true antiestrogens’ are estrogenic and are competitive inhibitors of estrogen action at the estrogen-sensitive target organs. The estrogenicity of a compound needs to be specified with reference to (a) the target tissue, (b) parameter used, (c) route of administration, (d) dose of the compound, (e) time sequence of action. The degree of antiestrogenicity is directly proportional to the, estrogenicity of the compound. The antiestrogenic action of a compound is related to its affinity with the receptor sites in the target organ: (a) compounds which are bound to the receptors for brief periods are weakly estrogenic (DMS, cis-clomiphene), (b) compounds which have greater binding affinity with the receptors in the target organ are strongly estrogenic and antiestrogenic (CN 55, 945–27; trans-clomiphene, DES, MER-25 at high doses). The duration of antiestrogenic action of a compound is related to the duration of its binding with the receptor in the target organ.

ISSN:0378-7346    

DOI:10.1159/000301751

出版商:S. Karger AG    

年代:1972

数据来源: Karger