Estrogen-induced Growth Research Articles

Morphometric analysis of the rat ventral prostate and seminal vesicles during prepubertal development: effects of neonatal treatment with estrogen.

In a morphometric study on the ventral prostate and seminal vesicles in the rat, we investigated the changes in fibromuscular stroma, glandular epithelium, and glandular lumen. Animals were studied at 15, 30 and 45 days of age. The rapid prepubertal growth started earlier in the ventral prostate than in seminal vesicles. In addition, the effects of neonatal administration of estrogens on the different tissue compartments were studied, comparing rats that had been castrated and/or treated with estrogen at birth to intact animals at 15 days of age. Estrogens caused a decrease in the volume of the glandular epithelium and increased the volume of the fibromuscular stroma in both ventral prostate and seminal vesicles. Castration partially abolished the estrogen-induced growth of the stroma, which suggests that the growth is dependent on testicular factors. The difference in proportion of the fibromuscular stroma between the two glands is evidence that the size of the whole seminal vesicles has increased whereas the size of the ventral prostate has decreased.

Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth.

The hormone 17 beta-estradiol acts through its receptor system to induce MCF-7 human breast cancer cells to form tumors in athymic mice. In vitro studies have identified the production of estrogen-induced growth factors from MCF-7 cells that may have a role in growth control. These induced growth factors were sufficient to stimulate MCF-7 tumor growth in ovariectomized athymic mice, thus partially replacing estradiol. Growth factors may act as estrogen-induced "second messengers" in estrogen-responsive growth of human breast cancer.

Estrogen-induced proteins: A new class of regulatory substances

The discovery of estrogen-induced growth factors (estromedins) identified a missing link in understanding endocrine regulation. Estromedins are probably not on in vitro mitogens or auto-/paracrine growth regulators but play an important endocrine regulatory role. A review of the literature and our own previous in vivo endocrine experiments with uterus and uterine extracts support this concept. We have also discussed the effects of some other newly discovered endocrine regulators on the synthesis/release and peripheral action of gonadotropins and lactogens. We conclude that our view on endocrine regulation is fundamentally changing. In addition to the classical endocrine axis (hypothalamus-pituitary-peripheral tissue) several new factors and conditions have to be taken into consideration to understand the regulation of an endocrine effect on a target organ.

Proliferative pattern of uterine cells from birth to adulthood in intact, neonatally castrated, and/or adrenalectomized mice, assayed by incorporation of [125I]iododeoxyuridine.

The proliferative pattern of uterine cells from birth to adulthood was investigated in mice. The uptake of 5-[125I] iodo-2'-deoxyuridine [( 125I]dUrd) by the whole uterus was used as an index of cell proliferation. Nearly parallel changes in uterine growth were found from days 0-25 after birth in both intact and neonatally castrated mice. In both groups of mice, the weight of the uterus increased (0.7-6 mg) and high [125I] IdUrd uptake values were found from days 0-15, while the weight remained nearly constant, and very low uptake values were found in the next 10 days. Additionally, we could demonstrate that adrenalectomy plus ovariectomy caused no significant effect on neonatal growth of the uterus. After day 25, the weight of uterus (6-50 mg) and [125I]IdUrd uptake increased again in the intact mice, but remained low in the neonatally castrated mice. The proliferative response of the uterine cells to exogenous 17 beta-estradiol was then examined. The injection of 17 beta-estradiol on days 0 (20 micrograms/mouse) and 10 (5 micrograms/mouse) induced significant increases in [125I]IdUrd uptake the next day. Neonatal castration had no significant effect on the responsiveness of the uterus to estrogen-induced growth in adult mice. These findings suggest that sex steroids secreted from both the ovaries and adrenals of neonatal and prepubertal mice play no significant role in the proliferation of uterine cells, and that a quiescent interval of cell proliferation occurs around day 20 after birth between the autonomous (days 0-15) and the ovary-dependent (after day 25) proliferation of mouse uterine cells.

Percutaneous Estrogen Therapy

A hydroalcoholic gel containing estradiol-17 beta (0.6 mg/g) for percutaneous application was used for estrogen replacement therapy in postmenopausal women. During treatment the serum concentrations of estrogens were significantly increased and stable. The conversion of estradiol into estrone was far less pronounced after percutaneous vis-à-vis oral therapy. In terms of FSH suppression the estrogenic potency of percutaneous estradiol-17 beta 3 mg daily was similar to that of oral estradiol-17 beta 2 mg. The serum concentrations of three estrogen-sensitive liver proteins--sex hormone binding globulin (SHBG), pregnancy zone protein (PZP) and ceruloplasmin--were unchanged during percutaneous treatment, whereas during oral therapy all three proteins showed a marked increase. The endometrial response was quantified by morphometry. The mean relative endometrial gland volume increased from 10% to 40% and was correlated to serum levels of estradiol-17 beta. Single-cell growth did not reveal the same correlation and the sequential addition of lynestrenol, 5 mg daily for ten days, did not reduce the estrogen-induced endometrial growth. No obviously harmful local effects were observed in skin samples. Topical application of estradiol-17 beta may develop into an alternative treatment for climacteric complaints and may even have some metabolic advantages over oral treatment.

Cellular morphometric analysis of the postmenopausal endometrium during treatment with percutaneous estradiol-17 beta with and without oral gestagen.

The effects of percutaneous estradiol-17 beta 3 mg daily on the postmenopausal endometrium were quantified by morphometric analysis during 6 months of cyclic replacement therapy. A marked cellular response was recorded, together with increased serum levels of estradiol-17 beta and a satisfactory therapeutic effect. Glandular epithelial cells and nuclei proved to be the most sensitive markers for the estrogenic effect, with profile areas increasing 80% and 65% respectively, whereas stromal cell nuclei showed a weaker response. In the women investigated, no correlation was found between individual cell growth and estrogen level. The increase in mean cellular profile areas was quite similar in women taking lynestrenol 5 mg daily for the last 10 days of each treatment cycle, as compared with those receiving unopposed estrogen. A 10-day gestagen supplementation was found too short to reduce the estrogen-induced growth.

Identification of estrogen-inducible growth factors (estromedins) for rat and human mammary tumor cells in culture.

The role of polypeptide growth factors (estromedins) as mediators of estrogen-responsive mammary tumor growth is studied in this report. Three possible new mechanisms were investigated that include endocrine, autocrine, and paracrine related growth factors. The first hypothesis being tested is whether estrogens interact with target tissues and cause the biosynthesis and secretion of polypeptide growth factors, which then act as mitogens for normal and neoplastic mammary tissues. Data presented suggest that this mechanism involves estrogen interaction with uterus, kidney, and pituitary gland causing production of growth factors, which then enter the general circulation and promote growth of distant target tissues. This is an endocrine type mechanism. Another type of estromedin control (autocrine control) may be exerted in an autostimulatory way in which the target tissue produces the polypeptide factors for its own growth in response to estrogen stimulation. A variation of the autocrine mechanism may be a paracrine mechanism in which some cells of an estrogen-responsive normal or neoplastic tissue produce growth factors that act on adjacent or neighboring cells. From the data available, all three possible types of growth factors could be functioning synergistically to yield the final result of continuous estrogen responsive tumor growth in vivo.

Estrogen induced growth of human breast cancer cells (MCF-7) in athymic nude mice is enhanced by secretions from a transplantable pituitary tumor

MCF-7, a human breast carcinoma cell line, was maintained s.c. in female athymic nude mice for a period of 5–6 weeks. Administration of estrogen (s.c. pellet of 17β-estradiol and estrone in drinking water, 0.5 mg/l) to these mice resulted in sustained ( P < 0.001) growth of MCF-7 tumors. Grafting of a prolactin and growth hormone secreting rat pituitary tumor to the estrogen-treated mice resulted in an increased ( P < 0.05) rate of MCF-7 tumor growth. MCF-7 did not grow in athymic nude mice grafted with rat pituitary tumor alone or in mice without hormone treatment (controls). Thus, secretions of pituitary hormones alone are not capable of promoting in vivo growth of MCF-7 although such secretions significantly enhance estrogen-induced growth of this cell line. A synergism between pituitary hormones and estrogen for in vivo growth of a human breast carcinoma has been demonstrated in this study.

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The endocrine biology of cancers originating from the ovarian epithelium was examined with respect to three sequential indicators for estrogen action: available estrogen receptor in the cytosol, total extractable estrogen receptor from the nucleus, and endogenous tissue peroxidase--a putative postnuclear marker for estrogen-induced growth in uteri of laboratory animals and in some mammary tumor models. Cancers of human ovarian epithelium were distinguished from other ovarian tumors by a higher incidence of detectable (greater than 50 fmol/g tissue wet wt) estrogen receptor in the cytosol (P less than 0.001). Approximately one-half (14/29) of the ovarian adenocarcinoma specimens had greater than 500 fmol available estrogen receptor/g tissue wet weight in their cytosols when assayed by a 2-hour incubation with 17 beta-[2,4,6,7-3H(N)]estradiol followed by treatment with dextran-coated charcoal. With a single exception, ovarian adenomas and nondiseased specimens of premenopausal and postmenopausal ovaries (n = 24) contained less than 500 fmol available estrogen receptor/g tissue wet weight in their cytosols. With respect to extractable estrogen receptor in the nucleus, 11/14 primary and 3/9 metastatic ovarian adenocarcinomas had greater than 50 fmol/g wet weight, as assayed by exchange at 30 degrees C for 5 hours after adsorption of the extracted receptor to hydroxylapatite. Endogenous peroxidase activity, measured in vitro by guaiacol oxidation, occurred in substantially higher amounts in the primary ovarian adenocarcinomas than in benign tumors and control ovaries and could be demonstrated within ovarian adenocarcinoma cells by electron microscopy.

Properties of a growth factor activity present in crude extracts of rat uterus.

We have shown previously (D. A. Sirbasku, 1978, Proc. Natl. Acad. Sci. U.S.A., 75:3786-3790) that an estrogen-inducible growth factor activity for rat mammary and rat pituitary tumor cells can be identified in extracts of rat uteri, although at the time of that report only a limited biochemical characterization of the activity was presented. In this report, we have evaluated the growth factor activity for lipid, steroid hormone or protein-like properties. Uterine growth factor activity was assayed by measure of the increased cell number of the MTW9/PL rat mammary tumor cell line established by this laboratory and described previously (D. A. Sirbasku, 1978, Cancer Res. 38:1154-1165). Studies showed the following characteristics of growth factor activity: destroyed by trypsin treatment; labile when heated at 80 degrees C; partially denatured by 6 M guanidine or 8 M urea treatment or 50% aqueous solutions of organic solvents; inactivated by extremes of pH or overnight treatment with mild acid; not dialyzable at neutral pH; of apparent molecular weight of 70,000 daltons by G-100 Sephadex chromatography; possessing an isoelectric point of 4.8 to 5.2; not chloroform/methanol extractable; and not in any way identified as either a lipid or a steroid hormone. The data available suggest that the uterine growth factor activity is a protein or polypeptide of apparent high molecular weight, and that the activity does not directly correspond to other known growth factors.

Estrogen Receptor Binding and Growth of the Reproductive Tract

It is well known that normal growth and development of the reproductive tract depends on the proper stimulation by estrogen and other sex hormones. Likewise, it has been recognized for years that estrogenic stimulation provides an environment that is conducive to the development of neoplasia.1 The interrelationships between normal and abnormal estrogenic stimulation are not well understood. However, because of recent developments in biochemical and molecular biology, the mechanism of action of estrogen is beginning to be understood. In this article, we present some of these findings and relate them to normal and abnormal estrogeninduced growth. At physiological temperatures, estrogen readily enters all cells (Fig. 1). In hormone-sensitive cells, estrogen is retained by binding to soluble macromolecules in the cytoplasm. These macromolecules are called cytosol receptors (Rc); while their exact nature in vivo is not known, they appear to be large proteins made up of two or more subunits. The binding reaction is specific for estrogens and results in the formation of receptor estrogen complexes (RcE) that undergo translocation to nuclear sites (RnE). The translocation process depletes the cytosol of Rc sites and these are subsequently replenished by mechanisms discussed below. Nuclear binding of the RnE complexes can be classified as either acceptor (A) or nonacceptor (NA) sites. Acceptor sites are generally visualized as a specific complex of chromosomal proteins, probably nonhistone proteins, that the RnE complex recognizes and binds to with a very high affinity. Nonacceptor sites are considered to be secondary sites on chromatin where the RnE complex can bind with a lower affinity.

Comparative effects of estradiol-17β and estriol on uterine RNA polymerases I, II, and III [formula omitted

The early and later effects of estradiol-17β and estriol on the RNA polymerase activities of uterine nuclei obtained from ovariectomized rats were compared. At 4 hr of hormone action both estradiol-17β and estriol stimulated the activity of polymerase I, but not the activities of polymerases II and III. At 24 hr, however, the effect of estriol had disappeared, whereas estradiol-17β stimulated all three polymerase activities. These results indicate that estrogen-induced growth of the uterus occurs in two phases, initiation and maintenance. Estriol initiates uterine growth, but does not maintain the process. Estradiol-17β, in contrast, does both. The differences in the effects of the two estrogens may reside in their different binding affinities.

Action of progesterone ans synthetic progestogens on estrogen-induced ovarian growth.

SummaryFive synthetic progestogens along with progesterone and 20a-hydroxy-pregn-4-en-3-one were compared for their ability to influence diethylstilbestrol (DES)-induced ovarian growth in the immature hypo-physectomized rat. Ovaries of DES-treated rats showed a marked increase in ovarian weight, total RNA, total DNA and the RNA/ DNA ratio. Norethindrone, norethindrone acetate, and medroxyprogesterone acetate inhibited DES-induced ovarian growth by preventing cell division as indicated by significant decreases in total DNA and RNA with no change in the ratio of RNA to DNA. Conversely, norethynodrel enhanced ovarian hyperplasia in DES-treated rats since total DNA and RNA were increased and the RNA/ DNA ratio remained unchanged. Progesterone, 20α-hydroxy-pregn-4-en-3-one, or 17α hydroxyprogesterone caproate did not alter DES-induced ovarian growth. Norethindrone was observed to have no effect on the uptake of 14C-DES by the ovary and therefore appears to antagonize the action of DES on ovarian growth rather ...

The effect of estrogen on the histology of the uterine epithelium of the mouse: V. Histochemistry of decomposing lipid granules

Two types of lipid granules are present. One type is autofluorescent and contains highly unsaturated lipids, probably phosphatides. The other type is not autofluorescent and contains less unsaturated lipids, probably glycerides. The number of the former type already shows a decrease 6 hr after an injection of estrogen, but a decrease in number of the latter type is not noted until 1 day after the injection. This might indicate that the autofluorescent, phosphatide-rich granules form a bulk of easily available material used at the early stages of the estrogen-induced growth of the cell. Acid phosphatase and indoxyl esterase activity increase after the injection of estrogen, the former preferably in the apical and the latter in the whole cytoplasm. This might indicate that these hydrolytic enzymes are active during the lipid decomposition and that the acid phosphatase works primarily with the phosphatides and the indoxyl esterase with the glycerides.

Estrogen Antagonisms: Effects of Several Steroidal Spirolactones on Estrogen-Induced Uterine Growth in Mice.

Estrogen Antagonisms: Effects of Several Steroidal Spirolactones on Estrogen-Induced Uterine Growth in Mice.

A COMPARISON OF THE BIOLOGICAL ACTION OF ALLOPREGNANE-21-OL-3,20-DIONE ACETATE AND PROGESTERONE1

THE inhibitory effect of progesterone on the estrogen-induced tissue growth response of the chick oviduct was reported by Hertz et al. (1947). Among other steroid hormones tested for inhibitory activity in the chick oviduct test, allopregnane-21-ol-3,20-dione acetate (cpd. I) proved to be a potent antagonist (Hertz, 1951). In a test for corticoid activity, Wettstein and Hunzicker (1940) reported the compound to be inactive for weight maintenance and survival in adrenalectomized rats at a daily dose of 2 mg. Since progesterone and cpd. I inhibit the estrogen-stimulated chick oviduct, further investigations were made to determine whether these compounds possessed any other common biological properties. In the present report, we present details of a comparison between progesterone and cpd. I based on certain biological actions exhibited by progesterone. MATERIALS AND METHODS (1) Oviduct inhibition test Two week old New Hampshire Red chicks were housed in electrically heated brooders under controlled lighting...

Inhibition of Estrogen-induced Growth in the Genital Tract of the Female Chick by a Purine Antagonist; Reversal by Adenine

Inhibition of Estrogen-induced Growth in the Genital Tract of the Female Chick by a Purine Antagonist; Reversal by Adenine

Inhibition of Estrogen-induced Growth in the Genital Tract of the Female Chick by a Purine Antagonist; Reversal by Adenine

Inhibition of Estrogen-induced Growth in the Genital Tract of the Female Chick by a Purine Antagonist; Reversal by Adenine

Inhibition of Estrogen-Induced Tissue Growth with Progesterone

Inhibition of Estrogen-Induced Tissue Growth with Progesterone