Crystalline Estrogen Research Articles

The effect of estrogen supplementation on cell proliferation and expression of c‐kit positive cells in the rat prostate

Benign prostatic hyperplasia (BPH) is associated with the proliferation of prostate tissue and an increase in smooth muscle tone. However, the way in which the hormonal environment affects cell proliferation and prostatic interstitial cells (PIC) responsible for the maintenance of the smooth muscle tone is not clear. The present study investigated the effect of estrogen supplementation on cell proliferation, androgen/estrogen ratio, and expression and/or distribution of PIC. Male Sprague-Dawley rats were anesthetized with isoflurane/oxygen breathing mixture and subcutaneously implanted with silastic capsules. These capsules were either empty or filled with a 10 or 20 mg of crystalline estrogen. Estrogen exerted a potent effect on ventral prostate weight, which was manifested as a significant decrease between controls and the E(10)- and E(20)-treated rats. Active cell proliferation detected as Ki67-positive nuclei was observed in the stromal and epithelial cells of the ventral prostatic lobes from estrogen-treated rats and controls. Estrogen supplementation caused a significant and dose-dependent increase in prostatic estradiol and 5alpha-dihydrotestosterone (DHT) concentration but the ratios of either DHT/E(2) or E(2)/DHT were not significantly affected. PIC were observed in the region between the fibromuscular stroma and the glandular epithelium in all three experimental groups. E(20)-treated rats showed a higher expression of PIC than controls and E(10)-treated rats. The present study provides novel information regarding the synergistic role of estrogens and androgens in the prostate: estrogen may prevent prostatic hyperplasia via mechanisms other than affecting cell proliferation or DHT/estrogen ratio.

Changes in Lipoproteins with Various Sex Steroids

Menopausal symptoms are a consequence of the decline in sex hormone production, and hormone replacement therapy aims not only to relieve these symptoms but also to prevent the development of diseases of old age such as osteoporosis. The general opinion taken from a wide variety of publications is that the serum lipid concentrations change during hormone replacement therapy with estrogen, progesterone, and testosterone, or when oral contraceptives are administered. The intolerance of many women to oral contraceptives and the many side effects developed from the birth control pill lead us to suggest that pure crystalline estrogen pellets for subcutaneous implantation are an excellent method of contraception, adding beneficial influence upon lipid metabolism by increasing HDL concentration. The use of progestogens (nortestosterone or hydroxysteroid derivatives) in order to induce withdrawal periods and to avoid endometrial hyperplasia is recommended. But it is important to note that the nortestosterone derivatives (norgestrel and norethindrone acetate) differ markedly from the nonadrogenic 17-alpha hydroxyprogesterone derivative in that the former lowers HDL levels noticeably more than the latter.

Positive feedback sites of estrogen in the brain on ovulation: possible role of the bed nucleus of stria terminalis and the amygdala.

Direct effects of estrogen on the brain inducing ovulation have been studied on the late night of diestrus II in 4-day cyclic rats. Injection of 3mg of progesterone on the evening of diestrus II (23:00) delayed ovulation. However, the inhibitory effect of progesterone was restored by the simultaneous injection of estradiol benzoate (8/10) or bilateral implantation of crystalline estrogen into the medial amygdala (8/12). Implantation of estrogen into the medial preoptic area, the bed nucleus of the stria terminalis and the lateral amygdala resulted in making ovulated rats fewer such as, 1/8, 3/8 and 1/6, respectively. Positive feedback effect of implanted estrogen into the medial amygdal a blocked by chronical transection of the surrounding area of the bed nucleus of the stria terminalis (0/5). Estrogen implantation to the medial amygdala and the bed nucleus of the stria terminalis on the night of diestrus II overcame the inhibitory effect of progesterone on LH release during the critical period of proestrus, while estrogen implantation to the medial preoptic area was relatively ineffective. Thus, estrogen appears to feed back to the medial amygdala and the bed nucleus of the stria terminalis inducing the release of ovulatory hormone.

Isolation of a crystalline estrogen from urine and the follicular hormone from ovaries

The history of the isolation of a crystalline estrogen from urine and the follicular hormone from ovaries is presented. In 1927 Aschheim and Zondek reported the presence of a large amount of estrogen in the urine of pregnant women. The 1st crystalline estrogen (estrone) was isolated on July 13 1929. The isolation of estriol was reported in 1930 by Marrian and a few years later estradiol-17beta was isolated from sow ovaries by Doisy et al. These estrogens were then called theelin theelol and dihydrotheelin which are now universally estrone estriol and estradiol-17beta respectively.

The metabolism of radioestrone in the rat.

DURING the period of twenty-five years since the isolation of the first crystalline estrogen many experiments on the metabolism of estrogens have been reported. Since a number of reviews (Doisy et al., 1942; Heard, 1949; Lieberman and Teich, 1953) have considered this subject, only a few points which are closely relevant to the experiments reported in this paper will be mentioned. Most investigators studied the excretion of estrogens in urine, but the low recoveries (5–20%) of administered estrogenic activity led others to search for the unaccounted for estrogen. The recovery of some additional estrogenic activity in feces (Siebke and Schuschania, 1930; Levin, 1945; Dingemanse and Laqueur, 1937; Dorfman, 1937), led to the examination of bile (Longwell and McKee, 1942; Cantarow et al., 1942; Pearlman et al., 1948). However, the amounts detected in dog bile were still insufficient to account for the missing estrogen (Longwell and McKee, 1942; Pearlman et al., 1948).

The Photofluorometric Estimation of Estrogens

A satisfactory photofluorometric method for the estimation of certain crystalline estrogens is described. This method was successfully adapted to the assay of commercial preparations of estrone in oil, aqueous suspensions of estrone, and estradiol tablets.

Treatment of surgical menopause by implantation of crystalline estrogens: Pineda, R.: An. Catedra de clin. ginec. 2: 156–204, 1943

Treatment of surgical menopause by implantation of crystalline estrogens: Pineda, R.: An. Catedra de clin. ginec. 2: 156–204, 1943

STUDIES ON INACTIVATION OF ESTRADIOL BY THE LIVER1

IT IS generally believed that estrogens are rapidly inactivated by the liver, this belief being based largely upon data obtained from four types of observation, a) Liver tissue (dog, rat, mouse, rabbit, guinea-pig, frog) and cell-free extracts of liver have been found to inactivate estrogens in vitro (Silberstein, et al., 1933; Zondek, 1934; Engel and Navratel, 1937; Heller, et al, 1939; Heller, 1940; Engel, 1941; Heller and Heller, 1943). b) It was reported (Israel, et al., 1937) that estrone s i not inactivated when perfused through a heart-lung preparation (dog) but is rapidly (within 15 minutes) inactivated when perfused through a heart-lung-liver preparation, c) Ovaries transplanted to the mesentery (Golden and Sevringhaus, 1942) or pellets of crystalline estrogen implanted in the spleen (Biskind and Mark, 1939; Biskind, 1940, 1941) exert little or no estrogenic effect as comparedwith their characteristic action when implanted subcutaneously.

METABOLISM OF ESTROGENS: EFFECT OF PREGNANCY UPON METABOLISM IK VITRO OF ESTRONE, ESTRADIOL AND ESTRIOL12

WHEN KNOWN AMOUNTS of crystalline estrogens were incubated with tissue slices in a buffered medium and the mixture was subsequently assayed biologically (I), the following observations were made: a)αcestradiol was completely inactivated by liver tissue, partially inactivated by kidney and not at all by the other tissues tested, b) Estrone was completely inactivated by rabbit liver and only partially inactivated by rabbit kidney and rat liver. Estrone increased in biologic activity, however, after incubation with endometrium, ovary, spleen, heart and lung from the rat and rabbit. This increase in biologic potency of estrone by hese tissues was ascribed to its conversion to αcestradiol by an enzymatic reduction system. The inactivation of estrone and αestradiol by liver and kidney tissue was attributed to an oxidative enzyme

EFFECT OF VITAMIN B COMPLEX DEFICIENCY ON INACTIVATION OF ESTRONE IN THE LIVER

IN A PRELIMINARY NOTE (i) we have reported that deficiency of the vitamin B complex in female rats markedly diminishes the inactivation of estrone in the liver. Further study of this phenomenon, which is the subject of the present communication, shows that the inactivation mechanism, impaired by vitamin B deficiency, may be restored by addition of brewers yeast to the diet. Subsequent depletion of the diet is again capable of interfering with the destruction of estrone in the liver. The flow of estrogen through this organ can thus be controlled at will, by withholding the vitamin B complex or by restoring it to the diet. Within a few years after the isolation of the first crystalline estrogen, it became apparent that this and related compounds are rapidly inactivated in the body. Much of the early literature has been reviewed elsewhere (a). Perhaps the earliest clue to the possibility that estrogen is destroyed by an organ or organs in the portal circulation was the observation by Evans and Burr in 1926 (...

GROWTH OF THE MALE GUINEA PIG MAMMARY GLAND WITH DIETHYLSTILBESTROL1,2

GROWTH OF THE MAMMARY GLAND with hormone treatment has been exten-sively studied in the guinea pig. Crude lipid extracts of placentae, ovaries and corpora lutea were reported to develop ducts or complete lobule'alveolar systems and to cause secretion in some cases in virginal, parous and castrate females and in normal, castrate and immature males (see Turner, i, for review). More recently purified and crystalline estrogens at low dosages have been shown to develop both mammary ducts and complete lobule'alveolar systems equal to that observed at the time of pregnancy (2, 3, 4). The guinea pig thus differs from other laboratory rodents in that complete mammary development can be readily obtained with estrogens in-jected for short periods of time at low dosages.

Absorption of Crystalline Estrogen from Paraffin Nodules in the Rat.

SummaryAn effective and simple method of insuring slow continuous absorption of estrogen in the rat is the incorporation of the crystalline hormone in paraffin (melting point 48°C), which after subcutaneous, intramuscular, or intraperitoneal injection in a liquid state, solidifies locally. As indicated by vaginal smear, the average time required for complete absorption and utilization of 5.0 mg estradiol dipropionate contained in 0.1 cc paraffin, introduced into animals 3 to 5 weeks of age, is 151 ± 5.9 days. In males the position and activity of the testes are comparable indicators of the utilization of the injected estrogenic hormone.

CAPACITY OF RATS LIVER TO INACTIVATE DESOXYCORTICOSTERONE ACETATE

CERTAIN CRYSTALLINE ESTROGENS AND ANDROGENS (1–7) and t h e endogenous ovarian estrogens and testicular androgens of the rat (8–12) are inactivated by the liver. Such evidence is used to explain the fact that natural estrogens and androgens are relatively ineffective when administered by mouth. Kuizenga, Nelson and Cartland (13) found that 2, of the adrenal steroids, corticoster one and dehydrocorticosterone, as well as certain adrenal cortical extracts were just as effective orally as when given subcutaneously. This indicates that these adrenal substances, unlike the gonadal hormones, are not inactivated by the liver. Desoxycorticosterone acetate, on the contrary, was found to be much less effective orally than parenterally. By transplantation experiments in the rat, Eversole, Edelmann and Gaunt (14) have shown that the endogenous adrenal hormone or hormones necessary For maintenance of life are not inactivated by the liver.

Therapeutic Use of Estrone Suspensions1

NATURAL ESTROGENS ARE READILY destroyed or inactivated by the liver, so that upon being rapidly absorbed from the site of administra tion their effect lasts only a short time. Retarding the rate of absorption results in an increased period of estrogen action which permits more desirable therapeutic effects. Absorption of estrogens into the blood stream may be delayed a) by chemical combination with fatty acids, b) by dissolving in a medium which one. Nevertheless, there is a certain amount of hesi tation on the part of many physicians to use this method of administering estrogens which requires a special technic. We have therefore, utilised the prin ciple of implantation of crystalline estrogens in a form which does not sacrifice the convenience or practicability of simple injections. This dosage form consists of a suspension of estrone crystals in an aqueous medium. It is postulated that is slowly absorbed, such as oil or wax, and c) by dzpositing the crystalline material directly into the tis sues. With...

THE ACTION OF VARIOUS STEROID HORMONES ON THE TESTIS

EVER SINCE Moore and Price (1) formulated the hypothesis that the hormones of the sex glands cause atrophy of the gonads because they inhibit the gonadotropic hormone secretion of the pituitary, numerous investigators published experiments showing that androgens and estrogens produce atrophy of the gonads in both sexes. Since gonadal atrophy is one of the most readily developing consequences of non-specific damage (2), the first observations in which impure and often toxic organ or urine extracts were used, are inconclusive. However, it has now definitely been proven that even pure crystalline sex hormones are capable of producing gonad atrophy. As regards the relevant literature dealing with the action of such substances on the mammalian testis, the subject under consideration in this paper, it will be recalled that testis atrophy had been produced with crystalline estrogens in the rat (3–6)the rabbit (7) and several other species.