Large Doses Of Estrogen Research Articles

Cambios endometriales anormales producidos en la rata por estrógenos y hormona coriónica

La administración de hormona coriónica humana y estrógeno, a ratas normales, produce un cuadro histológico endometrial atípico, caracterizado por presencia simultánea de cambios proliferativos y secretorios. El núcleo de las células epiteliales muestra en general un aspecto más vesicular que lo normal y ocasionalmente alcanza gran tamaño. El cuadro anormal no puede ser inducido tratando a las ratas normales con estrógenos u hormonas coriónicas aisladamente o administrando ambas a animales castrados. Una alteración similar se ve, sin embargo, cuando ratas ooforectomizadas son tratadas con grandes dosis de estrógenos y progesterona. Se discute brevemente la patogenia y la posible relación de esta alteración con ciertos cambios endometriales observados en seres humanos.

Cambios endometriales anormales producidos en la rata por estrógenos y hormona criónica

La administración de hormona coríónica humana y estrógeno a ratas normales, produce un cuadro histológico endometrial atípico caracterizado por presencia simultánea de cambios proliferativos y secretorios. El núcleo de las células epiteliales muestra en general un aspecto más vesicular que lo normal y ocasionalmente alcanza gran tamaño. El cuadro anormal no puede ser inducido tratando a las ratas normales con estróqenos u hormones coriónicos aisladamente o administrando ambas a animales castrados. Una alteración similar se ve, sin embargo; cuando ratas ooforectomizadas son tratadas con grandes dosis de estrógenos y progesterona. Se discute brevemente la patogenia y la posible relacíón de esta alteración con ciertos cambios endometriales observados en seres humanos.

The effect of oestrogen on megakaryocyte differentiation and platelet counts in vivo

Background Oestrogen alters megakaryocyte number in humans and mice. In mice, high-dose oestrogen stimulates an initial increase in megakaryocyte number followed by a decrease. However, the cellular action, effect of physiologically circulating and smaller supra-physiological oestrogen doses and whether changes in megakaryocyte number alter platelet counts have not been studied. Methods To further examine oestrogen's effect on megakaryocytes and platelets we administered intact or ovariectomised mice various doses of oestrogen and measured megakaryocyte and platelet counts. To determine the cellular mechanism by which oestrogen influences megakaryocytopoesis we also examined its effect on markers of megakaryocytic differentiation (CD41, CD61, CD34). Results We found that large doses of oestrogen (500 μg/kg) increased mature CD41+ megakaryocyte number within 2 days, and this was associated with an increase in circulating platelets. Smaller supra-physiological doses (100 μg/kg) lacked this anabolic effect, but still suppressed megakaryocyte and platelet number by day 10 in intact and ovariectomised mice. This was preceded by a reduction in the number of CD61+ megakaryoblasts and CD34+ precursors available to form mature megakaryocytes. In contrast, ovariectomy had no effect on megakaryocyte or platelet number, indicating that circulating oestrogen concentrations do not influence megakaryocyte differentiation or activity. Conclusions Our data suggest that in mice at least platelet counts reflect changes in megakaryocyte number, and while both are independent of physiological hormone concentrations, they are sensitive to even small supra-physiological doses of oestrogen. Therefore, to ovoid disrupting platelet homeostasis the dose of oestrogen given should be no more than replacement.

Oral contraceptives decrease hepatic cholesterol independent of the LDL receptor in nonhuman primates.

Pharmacological doses of estrogens have been reported to increase hepatic catabolism of low-density lipoprotein (LDL) by the LDL receptor (LDL-R) pathway and to increase the concentration of mRNA for the LDL receptor. The induction of LDL-Rs by large doses of estrogen may not be relevant to the role of estrogens under physiological conditions. Furthermore, the mechanisms by which oral contraceptives, a combination of synthetic estrogen and progestin, may modulate LDL metabolism remain largely unexplored. Adult female cynomolgus monkeys were given combination ethinyl estradiol/norgestrel preparations (n = 16) for 16 weeks and were compared with a control group that did not receive exogenous sex hormones (n = 7). All animals consumed a diet containing 0.25 mg cholesterol/kcal with 40% of calories from saturated fats. After 16 weeks of treatment there was no significant difference in LDL cholesterol (LDL-C) and hepatic LDL-R mRNA concentration between oral contraceptive-treated animals (LDL-C, 242 +/- 113 mg/dL; LDL-R mRNA, 0.60 +/- 0.31 pg/microgram RNA) and control animals (LDL-C, 277 +/- 100 mg/dL; LDL-R mRNA, 0.51 +/- 0.21 pg/microgram RNA). In contrast, the hepatic cholesteryl ester concentration was significantly lower in the oral contraceptive-treated animals (7.28 +/- 3.59 mg/g liver) compared with the control animals (16.07 +/- 11.86 mg/g liver; P = .01) with no significant difference in hepatic free cholesterol concentration between the groups. Thus, oral contraceptives decrease hepatic cholesterol concentration independent of LDL-R expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose/response study of the effects of oestrogens on tumour growth and morphology in the Dunning R3327 prostatic adenocarcinoma

The present study was undertaken to investigate to what extent the oestrogen-induced effects on growth and morphology of the Dunning R3327 rat prostatic adenocarcinoma are dose-dependent. Castrated and testosterone-supplemented rats were used in order to study effects of increasing doses of oestrogens on the tumour. It was found that the lowest dose of oestradiol-17 beta that reduced the overall growth, the volume density of the epithelium and epithelial cell area in Dunning R3327 prostatic tumours is 10 micrograms given as daily injections. Higher oestrogen doses (50 micrograms, 200 micrograms, and 500 micrograms), in addition to reducing the volume of tumour epithelium, also induced an increase of the volume density of tumour stroma. The area of stroma cell nuclei was increased by 50 micrograms and 200 micrograms oestradiol-17 beta. These observation, may indicate that the lowest effective oestrogen dose is different in the epithelium and stroma of Dunning tumours and that large doses of oestrogen stimulate the stromal compartment. This stimulatory effect did not influence the inhibitory effects seen on the overall growth of the tumour and on the tumor epithelium.

Megestrol acetate in breast cancer--a panel discussion.

Physicians have been using hormonal manipulation to treat advanced breast cancer for almost a century. Surgical ablation of the ovaries, adrenals, and pituitary glands has achieved remarkable tumor regression in sensitive patients. Alternatively, large doses of estrogens, progestins, and androgens have achieved similar results. More recently, the emergence of new therapies, such as antiestrogens, LHRH agonists, and chemical blockade of adrenal steroid biosynthesis offer additional choices. Within limits, all of these therapies are equally effective in sensitive patients. The trend at the present time is to select a therapy that will produce a good response with minimal toxicity. Here the participating physicians will discuss one such therapy-Megace (megestrol acetate). They will consider the role of Megace in the treatment of advanced breast cancer along with issues such as toxicity, dose response, etc.

Estrogen-Induced Prolactinoma in a Man

Prolactinomas can be induced in rats by large doses of estrogens. Whether prolactinomas can be induced in humans by estrogens, however, is not known. This report describes the development of a prolactinoma in a man with previously normal plasma PRL levels after the administration of pharmacological doses of estrogen. The patient, a 26-yr-old male to female transsexual, took cyproterone acetate (100 mg/day, orally) and ethinyl estradiol (100 μg/day, orally) for 10 months and (surreptitiously) estradiol-17-undecanoate (100 mg, twice weekly, im) for about 6 of the 10 months. Plasma PRL levels rose from 0.05 to 5.20 U/L within 10 months (normal, 0.05–0.30 U/L). A computed tomographic scan showed a pituitary mass with suprasellar extension. After all estrogen therapy was discontinued, his plasma estradiol levels gradually declined from 2.8 to 0.77 nmol/L (normal, 0.04–0.12 nmol/L), but PRL levels rose further to 6.2 U/L. Bromocriptine treatment (2.5 mg twice daily) then was given. Plasma PRL fell gradually to ...

Hormonal control of female sexual behavior in the Japanese quail

Four experiments were carried out to study the hormonal control of female receptivity and proceptivity in Japanese quail. Both aspects of reproductive behavior can be activated in a dose-dependent manner by injections of estradiol benzoate (EB). Progesterone (P) given in addition to suboptimal doses of EB has little additional stimulatory effect. Other aspects of the reproductive physiology such as enlargement of the cloacal diameter and growth of the oviduct also seem to be controlled primarily by estrogens with little or no additive effect of P. These conclusions were confirmed by injecting egg-laying females with an antiestrogen, tamoxifen, or an antiprogestin, RU38486. Only the former had marked effects on sexual receptivity, cloacal diameter, and oviduct weight. The inhibiting effects of tamoxifen could easily be reversed by injecting females with large doses of estrogen, which demonstrates that tamoxifen acts on an estrogen-dependent mechanism and not through nonspecific effects.

Postcoital IUD insertion, a review

Following the development of hormonal interception after coitus the post-coital insertion of an intrauterine contraceptive device was proposed by Tatum . The advantage of this treatment is the avoidance of the ingestion of large doses of estrogen which causes much nausea and vomiting although it is a very effective post-coital method of contraception. The recently proposed alternative administration of 200 micrograms Ethynol Estradiol combined with 2 mg of DL norgesterol in 2 equal doses at 12 hour intervals has the same disadvantage of a high percentage of side effects. The post-coital insertion of an intrauterine contraceptive device is the first method which is effective up to five days following unprotected intercourse which is three days longer than treatment by estrogen. In addition the method can be offered to women who would want to continue to wear the intrauterine contraceptive device for long term contraception. The disadvantage of the post-coital insertion of an intrauterine contraceptive device is the ability of serious complications if the patient has a vaginal or venereal infection or an asymptomatic cervicitis or salpingitis. Following appropriate physical examination women who present themselves for post-coital treatment are selected. Cases of rape are usually not suitable for treatment with intrauterine contraceptives devices. However, when cases of rape are seen early enough the appropriate investigations may be done and the treatment with the intrauterine device started within five days. The potential risk of future infertility must be considered since salpingitis is 7 times more common in nulliparous wearers of intrauterine devices than in nulliparous non-wearers. Young sexually active nulliparous women especially of lower socio economic background are patients with a high risk. Over 70% of the women who present themselves for interception treatment are nulliparous.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen Treatment of Tall Girls: Risk of Thrombosis?

In 34 girls who were treated with large doses of ethinylestradiol because of expected excessive tall stature, antithrombin activity in the blood was followed before, during, and after treatment. All girls showed lower levels of antithrombin during treatment than before or after estrogen administration; the mean concentration during treatment was at or below the lower limit of control values (-2 SD). In three girls, the antithrombin levels were so low that the medication was withdrawn. There was no difference between the mean levels of antithrombin activity in the three groups treated with 0.25, 0.50, or 1.0 mg of ethinylestradiol. Deficiency of antithrombin is known to be associated with an increased risk of thrombosis. Therefore, antithrombin concentrations in blood should be determined before and during treatment with large doses of estrogens.

Kidney tubule cell injury of male rats after estrogen treatment

Ultrastructural changes in the tubular epithelium of the rat kidney following a large dose of estrogen (300 micrograms per week for 20 weeks) were studied by means of electron microscopy. The ultrastructural changes in estrogen-treated rats were confined to the proximal tubule. The changes consisted of intracytoplasmic vacuoles and dilatation of the intracellular space between adjacent tubule cells. The cisternae of the endoplasmic reticulum exhibited some degree of vesiculation characterized by club-like formations. In addition, large masses of collagen could be observed within the peritubular capillaries. In contrast to the controls the tubular cells of estrogen-treated rats exhibited large areas or granules with dense inclusions and membranous, filamentous material in a process of being transformed into an autolysosome and residual body. The results are discussed in the light of those of other authors.

UTERINE OESTROGEN AND PROGESTERONE RECEPTORS IN THE OVARIECTOMIZED RAT

The effect was studied of repeated injections of oestradiol-17 beta (5, 10, 25, 50 micrograms) given for various lengths of time (3, 5, 9 days) on total cell content of oestrogen receptors and cytosol progesterone receptors in the uteri of ovariectomized rats. An additional group of rats was injected daily with 50 micrograms oestradiol benzoate (OB) for 9 days in order to achieve a more sustained concentration of oestradiol in the blood. Injections were begun 24h after ovariectomy and the rats were killed 24h after the last injection. Daily administration of 5 micrograms oestradiol prevented the initial transient rise in oestrogen receptors which was observed in the uteri of untreated rats after ovariectomy. Repeated injections of 10 micrograms oestrogen produced an initial lowering in oestrogen receptors after 3 days of treatment which was followed by a prompt rise at 5 and 9 days when treatment was continued. A significant reduction in oestrogen receptors occurred at all times studied when rats were injected daily with 25 and 50 micrograms oestradiol. A more profound reduction in oestrogen receptors was observed in the group of rats treated for 9 days with 50 micrograms OB. Synthesis of progesterone receptors was stimulated by all doses of oestrogen studied. Concentrations of progesterone receptors were significantly higher after 3 and 5 days of treatment with 25 and 50 micrograms oestrogen. After 9 days of treatment, however, concentrations of progesterone receptors were virtually identical in all treated groups, including the group treated with OB. We have concluded that large doses of oestrogen significantly decrease oestrogen receptor content in the rat uterus, especially when OB is used. The degree of reduction, however, is only moderate under these experimental conditions and is insufficient to inhibit synthesis of progesterone receptors.

The therapeutic effect of concurrent administration of 5-fluorouracil and allylestrenol or hexestrol in small doses on prostatic carcinoma.

A trial to reduce the dosage of estrogen or to substitute it by other agents was done as a treatment of prostatic carcinoma. Either the combination of 5-FU (200 mg/day) and allylestrenol (50 mg/day), or 5-FU and hexestrol (20 mg/day) was given to 24 cases of prostatic carcinoma, 4 of whom were relapsed hormonal-resistant cases, 14 cases were controlled by large doses of estrogen and 6 were newly treated cases. No progressions were observed following 3 months of therapy. In 5 cases, progression was observed after 6 months. Deteriorated cases increased to 6 cases after 12 months. The effective rate, according to the "vital score," which is proposed as a parameter of the physical condition of patients with prostatic carcinoma, was calculated to be 100% at 3 months, 77% at 6 months, and 71% at 12 months.

Effects of 17 alpha-ethinyl estradiol on the serum lipoproteins of cholesterol-fed diabetic rats.

Large doses of 17 alpha-ethinyl estradiol were administered to rats made diabetic by administration of streptozotocin and fed a diet containing 2% cholesterol and 1% cholic acid. Before estrogen treatment, these rats were severely hypercholesterolemic and had high concentrations of lipoproteins of d < 1.006 g/ml (very low density lipoproteins, VLDL), d = 1.006 to 1.03 g/ml (intermediate density lipoproteins, IDL), and d = 1.03 to 1.063 g/ml (low density lipoproteins, LDL), and low concentrations of lipoproteins of d = 1.063 to 1.21 g/ml (high density lipoproteins, HDL). The VLDL contained two populations of particles with a mean diameter of 1150 and 350 A, respectively. The IDL contains only the latter particles. These particles are unusual in that they contain apolipoprotein A-I in addition to their usual complement of apolipoproteins. After estrogen treatment, the concentrations of both large and smaller particles in VLDL were greatly decreased as were the concentrations of IDL and LDL; apo A-I was no longer present in the residual VLDL and IDL. HDL phospholipid, protein, and cholesterol increased 7-fold, 4-fold, and 2-fold, respectively. Studies by others have shown that large doses of estrogen enhance uptake of LDL by the liver and this is associated with an increase in the saturable binding sites for LDL on liver membranes. The present studies suggest that these binding sites recognize lipoproteins other than LDL. Furthermore, the enhanced uptake of these lipoproteins appears to result in transfer of their surface components to HDL.

Effects of ethinylestradiol on enzymes catalyzing bile acid conjugation and sulfation

Administration of large doses of estrogens has been shown to result in decreased conjugation and increased sulfation of bile acids as well as cholestasis. There have been no previous studies on the effects of low doses of estrogens on these parameters of bile acid metabolism. Therefore, rats were given ethinylestradiol, 0.06 to 600 micrograms/kg/day subcutaneously for up to 21 days and the in vitro activity of the hepatic conjugation and sulfation enzymes was measured. Conjugating enzyme activity was unchanged at doses below 600 micrograms/kg/day. In contrast, hepatic sulfation of conjugated bile acids increased significantly after 21 days treatment with 0.6 micrograms/kg/day. The magnitude of the increase was both time- and dose-dependent. Increased sulfotransferase activity was noted only in the liver and was specific for conjugated bile acids; there was no change in the rate of sulfation of the unconjugated bile acids or in renal sulfotransferase activity. Increased hepatic bile acid sulfotransferase activity occurred in the presence of normal bile flow and bile acid secretion. These data indicate that treatment with doses of ethinylestradiol comparable to those present in oral contraceptives may lead to readily detectable time- and dose-dependent changes in bile acid sulfation without producing cholestasis. The data also suggest that there may be significant differences in the enzymatic sulfation of conjugated and unconjugated bile acids in the liver.

Estrogen Therapy for Severe Persistent Depressions in Women

Positive results are reported from a double-blind study of estrogen therapy administered to severely depressed, inpatient women who had failed to respond to various conventional treatments of depression. Large doses of oral conjugated estrogen were administered for a three-month period to 23 premenopausal and postmenopausal inpatient women. Placebos were administered for a comparable period to 17 similar patients. The posttreatment Hamilton ratings of depression were significantly reduced in the estrogen-treated group, but not in the placebo group. Possible physiological mechanisms are discussed. The risk-benefit ratio for estrogen therapy of depression in these patients was judged to be favorable. However, periodic endometrial biopsies are required to monitor the endometrial response of women receiving high doses of estrogens.

Influence of estrogens on intraocular tension in the eyeballs of rabbits.

Iridocorneal angles from the eyes of female rabbits subjected to large doses of estrogens were examined under an electron scanning microscope. A temporary rise in intraocular tension was noted lasting up to 24 h after injection of estrogens, followed by a slow return to normal conditions. Histostructural changes of the iridicorneal angle were observed as widening of the marginal sector, enlarging of the dimple-shaped depressions and also increased number and narrowing of the micropores in the central part of the iridocorneal field. The authors postulate that estrogens affect the histostructure of the iridocorneal field and also stimulate the circulation of the aqueous fluid.

Prevention of Body Fluid Retention by Furosemide During Estrogen Therapy of Prostatic Cancer

The usefulness of prophylactic diuretic therapy with furosemide was investigated in 6 patients with stages III and IV prostatic cancer who were undergoing diethylstilbestrol therapy. A significant increase was noted in sodium and water excretion, whereas outputs of chloride and potassium, and serum electrolyte concentrations, blood volume, blood pressure and body weight remained unchanged. The results demonstrate the value of diuretics in preventing fluid retention whenever large doses of estrogen are to be used in the treatment of prostatic cancer.

Testosterone 5alpha-reduction in the skin of normal subjects and of patients with abnormal sex development.

Human pubic skin was obtained from normal subjects and patients with abnormal sex differentiation. Skin samples (200 mg) supplemented with NADPH, were incubated for 1 h with labelled testosterone. The conversion of testosterone to dihydrotestosterone, 3alpha- and 3beta-androstanediol was calculated. This conversion averaged 14.9 plus or minus 3.4% (SE) in 11 normal men and 3.6 plus or minus 1.4% (SE) in 8 normal women. In 4 children as in 4 young hypogonadotrophic hypogonadal men, the conversion rate of testosterone to 5alpha-reduced metabolites was low (0.8 to 3.5%) and increased at puberty (13.5 to 19.2%). After administration of HCG for 3 months to 1 of the hypogonadal men, it reached 30.2%. Inversely, the formation of dihydrotestosterone and androstanediols from testosterone was suppressed in 2 men treated with large doses of oestrogen. In 3 subjects with an incomplete form of testicular feminization syndrome, the conversion rate of testosterone to 5alpha-reduced metabolites was in the normal male range (6.4 to 18.3%), whereas it was low in one case of the complete form of the syndrome (1.5%). In 9 women with idiopathic hirsutism the rate of 5alpha-reduced metabolites recovered from testosterone was close to that of normal men (13.5 plus or minus 5.5% (SE). From these results, it is postulated that in human subjects, there is a good correlation between hair growth in skin from a sexual area and the extent of testosterone 5alpha-reduction in this tissue. Such an enzymatic activity might be induced by active androgens; this latter hypothesis is in good agreement with the increase of 5alpha-reduction activity observed at puberty or after treatment of young hypogonadal males. In addition, it is pointed out that a positive correlation is observed between the 5alpha-reductase activity present in each skin sample studied and the urinary 3alpha-androstanediol found for the same individual. This confirms our previous findings suggesting that the determination of urinary 3alpha-androstanediol might prove of clinical interest in the evaluation of the androgenic status in human subjects.

THE EFFECT OF LARGE DOSES OF ESTROGENS POST COITUM IN 2000 WOMEN

Abstract The administration of large doses of estrogens to 2000 women during the first 5 days after unprotected intercourse was found to be effective in reducing the incidence of pregnancy to a very low level. We personally prescribe only the maximum dosage of 5 mg ethinylestradiol or 50 mg diethylstilbestrol starting within 24–36 hours post coitum, under which regimen we have not observed a single pregnancy thus far. The basal temperature curve showed a decrease in temperature to preovulatory values. Implantation of the ovum in the uterus is probably prevented by accelerated expulsion of the ovum and/or endometrial changes. Impairment of the production and/or the release of progesterone from the corpus luteum could also play a role. Side effects such as nausea and vomiting can be reduced by administration of an antiemetic. Subsequent unprotected intercourse during the same cycle should be discouraged. The fact that pregnant women excrete large amounts of estrogens indicates the theoretical likelyhood that the period during which estrogens can be effective, will be relatively short. As vaginal cancer has been described in children of about 15 years old of mothers who used diethylstilbestrol in large quantities during their pregnancy we recently decided to prescribe only 5 mg ethinylestradiol for 5 days.