Weak Estrogenic Activity Research Articles

Effects of tibolone, lynestrenol, ethylestrenol, and desogestrel on autoimmune disorders in [formula omitted] mice

The effects of two progestagens—lynestrenol, desogestrel—an anabolic steroid—ethylestrenol—and a compound with weak progestational, anabolic, androgenic, and estrogenic activities—tibolone—on the development of systemic lupus erythematosus and Sjögren's syndrome-like disorders were studied in the NZB W mouse. All four compounds inhibited the expression of autoimmune disease. Tibolone was 10–40 times more potent—depending on the parameter used—in preventing symptoms of autoimmunity than the second most effective compound lynestrenol. Ethylestrenol was the third effective compound and desogestrel the least effective compound in this series. Combined with literature data, these results show that steroids with different endocrine profiles can prevent the development of autoimmunity in the NZB W mice. Since the NZB W mouse is a good animal model for human systemic lupus erythematosus and Sjögren's syndrome and since tibolone, lynestrenol, and ethylestrenol have endocrinological profiles which are not prohibitive for treatment of male and female patients, investigation whether these compounds have a value in the treatment of human autoimmune diseases seems warranted.

Effects of desogestrel, levonorgestrel and lynestrenol on serum sex hormone binding globulin, cortisol binding globulin, ceruloplasmin and HDL-cholesterol

The effects of 0.125 mg daily doses of the new progestagen, desogestrel, 0.125 mg of levonorgestrel or 5 mg of lynestrenol on serum sex hormone binding globulin (SHBG), cortisol binding globulin (CBG). ceruloplasmin and HDL-cholesterol were studied in 30 healthy female volunteers to compare the possible androgenic and oestrogenic effects of these contraceptive steroids in vivo. All the progestagens in the applied dosages decreased SHBG and HDL-cholesterol concentrations, suggesting some androgenicity. Lynestrenol increased ceruloplasmin and CBG concentrations, indicating weak oestrogenic effects of the steroid. During desogestrel treatments, CBG and ceruloplasmin concentrations remained unchanged. After 30 days treatment with levonorgestrel there was a slight decrease ( P < 0.05) in ceruloplasmin concentrations. Thirty days after finishing the progestagen treatments serum protein concentrations were normal. In conclusion, at the doses used and under the present test conditions the progestagens studied had a weak androgen-like effect and lynestrenol also showed weak oestrogenic activity, as determined by their effects on serum proteins.

Antagonism of the actions of estrogens, androgens and progesterone by anordrin (2α,17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol dipropionate)

Anordrin, an antifertility agent that is an antiestrogen with weak estrogenic activity, has been studied to further characterize its hormonal activities. A dose of 2.0 μg/mouse·day for 7 days did not increase the uterine content of protein, but it did inhibit to a small extent the effect of administered estradiol-17β on uterine protein content and more significantly the effect of estradiol-17β on the uterine content of progesterone receptors. Anordrin also decreased serum corticosteroid-binding globulin levels. Administration of an average daily dose of 160 μg/day of anordrin to intact male mice had no effect on weights of kidney, testis, or seminal vesicle after 10 days, but seminal vesicle weight was significantly decreased after 30 days at a slightly lower dose. Similarly, anordrin inhibited the increase in seminal vesicle weight induced by testosterone propionate treatment of castrated mice. In female mice anordrin failed to maintain deciduomata and blocked the ability of progesterone (2.0 mg/mouse·day) to do so. However, anordrin did not compete with the androgen [ 3H]R1881 for binding in kidney cytosol or with the progestin [ 3H]R5020 for uterine receptor sites. Anordrin also did not compete with [ 3H]corticosterone for binding to serum proteins.

Weak estrogenic activity of lindane in rats.

Administration of lindane (20 mg/kg . d) for 30 d to ovariectomized rats caused no significant change in the weight of the uterus, cervix, or vagina. Histological changes in these organs were comparable to those in ovariectomized control rats. Treatment with estradiol dipropionate alone and in combination with lindane induced a significant increase in the weights of these organs. Microscopically, these organs appeared normal. Lindane induced a significant increase in the glycogen content of the uterus, cervix, and vagina of ovariectomized rats compared to ovariectomized control rats, whereas a two- to fourfold increase in glycogen was observed in ovariectomized rats treated with estradiol dipropionate or estradiol dipropionate plus lindane. There was a significant increase in total erythrocytes and hemoglobin in ovariectomized rats treated with lindane, estradiol dipropionate, or lindane plus estradiol dipropionate. An increase in neutrophils with a corresponding decrease in lymphocytes was also observed in rats treated with lindane or lindane plus estradiol dipropionate.

Uterotrophic activity of polychlorinated biphenyls (PCB) and induction of precocious reproductive aging in neonatally treated female rats

Polychlorinated biphenyls (PCBs) have been found to contaminate the ecosystem and reach both prenatal and postnatal individuals via the placental circulation and milk, respectively. Some PCBs also possess weak estrogenic activity. Experiments were devised to examine the estrogenic activity of Aroclors (Monsanto Co.) and their capacity to induce a permanently altered pattern of neuroendocrine reproductive function in female rats treated only during neonatal development. Aroclor 1221 at a dose of 1000 μg/kg body weight produced significant uterine growth 24 hr after treatment in weanling rats. This estrogenic PCB given to pups only on the second and third days of life induced precocious puberty, persistent vaginal estrus (PVE), and anovulation by 6 months of age; the latter end points are signs of reproductive again and do not normally occur in rats until later in life. Aroclors 1242, 1254, and 1260 did not produce a uterotrophic response in weanling rats at the doses tested nor did they induce the PVE syndrome when given to neonates. It is concluded that there is an association between the estrogenic activity of a PCB and its effectiveness in altering neuroendocrine differentiation and inducing premature reproductive aging.

Competition of delta 9-tetrahydrocannabinol with estrogen in rat uterine estrogen receptor binding.

Direct competition experiments with delta 9 -tetrahydrocannibinol (delta 9-THC) and estradiol in binding assays with rat uterine cytosol estrogen receptors showed that delta 9-THC was a weak, but nevertheless significant, competitor for binding to cytoplasmic estrogen receptors. These data support, at the molecular level, the observations that delta 9-THC has a weak estrogenic activity (at least the ability to bind to estrogen receptors). Moreover, estrogen-like binding suggests that delta 9-THC, acting at the level of estrogen receptor, causes a primary estrogenic effect rather than an indirect or secondary phenomenon.

Tamoxifen is a potent "pure" anti-oestrogen in chick oviduct.

OESTROGEN responsive cells contain a specific proteinaceous macromolecule—one receptor—capable of recognising physiologically active oestrogens as well as a number of synthetic oestrogen agonists and antagonists1,2. In the nonstimulated state, the majority of receptors are located in the cytoplasmic fraction of responsive cells3,4, including the chick oviduct5. When oestrogen reaches the target cell, it binds to the cytoplasmic receptor causing its ‘activation’ and the translocation of the hormone–receptor complex to the nucleus. The interaction of receptor with chromatin is thought to facilitate gene transcription and the synthesis of proteins implicated in the changes characteristic of the oestrogenic response6,7. Receptor is retained in the nucleus for varying periods of time depending on the concentration and nature of the oestrogen. In the rat uterus, the length of time that receptor is retained in the nucleus correlates well with a number of parameters of the hormonal response8. The initial translocation of receptor to the nucleus is followed by a period of cytoplasmic receptor replenishment3–5,9. This process is very important as it has been implicated in the ability of cells to respond to subsequent oestrogenic stimulation10,11. Anti-oestrogens prevent oestrogens from expressing their full effects on oestrogen target tissues. Recent studies have indicated that some non-steroidal anti-oestrogens (CI-628, nafoxidine and clomiphene) bind to cytoplasmic oestrogen receptor, induce the translocation of the antagonist–receptor complex to the nucleus, but fail to stimulate subsequent cytoplasmic receptor replenishment12–14. Oestrogen antagonism would be primarily due to inhibition of cytoplasmic receptor replenishment12. Further, such a hypothesis could explain the weak oestrogenic activity of these compounds following a single injection when cytoplasmic receptor is translocated to the nucleus, and their subsequent potent anti-oestrogenic activity after serial injections when the low cytoplasmic receptor level is the limiting factor in receptor translocation15. We present here results which illustrate that this theory of anti-oestrogenic action does not hold for tamoxifen (ICI 46,474) in the chicken oviduct.

In vivo effect of anti-estrogens on the localisation and replenishment of estrogen receptor

Interactions between estrogen receptors and triaryl ethylene anti-estrogens (U-11100A, MER 25 and CI 628) were tested on immature rat uteri. The accessible and the total (accessible and occupied) estrogen receptor sites were assayed in the cytosol and nuclear extracts using charcoal adsorption. After in vivo administration of anti-estrogens, the estradiol receptor sites were occupied and subsequently transferred to the nuclear compartment. The nuclear localisation of the receptor induced by the antagonist lasted for several days, during which replenishment of the cytosol receptor occurred. The nuclear receptors transferred by antiestrogens and labelled in vitro with [ 3H]estradiol, were similar to the nuclear receptor-estradiol complex formed in vivo as far as their sedimentation constants and extractability from nuclei were concerned. Although these anti-estrogens are capable to translocate the estrogen receptor to the nucleus and to induce the replenishment of the cytosol receptor, the mechanism of their antagonism and of their weak estrogenic activity is still not clear.

Anti-inflammatory and some other pharmacological effects of 3,4-trans-2,2-dimethyl-3-phenyl-4-(p-(beta-pyrrolidinoethoxy)-phenyl)-7-methoxy-chroman (Centchroman).

1. Anti-inflammatory, analgesic, antipyretic and other pharmacological activities of a new chroman derivative, Centchroman, have been described.2. Centchroman was found to possess significant anti-inflammatory action in the carrageenin-induced oedema test in mice and rats. It inhibited granuloma formation in the cotton pellet test. The anti-arthritic activity was also evident in formaldehyde-induced arthritis and adjuvant-induced arthritis in rats.3. Centchroman had a lower ulcerogenic index than phenylbutazone.4. The mechanism of the anti-inflammatory action of Centchroman seemed to be independent of endogenous adrenocortical hormones or of its weak oestrogenic activity.5. Centchroman antagonized phenylquinone writhing and bradykinin-induced bronchospasm but was devoid of any antipyretic activity.

INHIBITORY EFFECTS OF ESTRIOL-16,17-DISODIUM SUCCINATE ON LOCAL HAEMORRHAGES INDUCED BY SNAKE VENOM IN CANINE HEART-LUNG PREPARATIONS.

ABSTRACT In heart-lung preparations of dogs, the effect of estriol-16,17-disodium succinate** was studied on circumscribed pulmonary haemorrhages induced by the local application of cobra venom on to the lung surface. Aqueous solutions of estriol-16,17-disodium succinate were either applied topically at the site of exposure to the venom, or added to the perfusing blood. Irrespective of the route of administration, estriol-16,17-disodium succinate delayed the appearance and diminished the intensity of the haemorrhages. The weak estrogenic activity of estriol-16,17-disodium succinate, the use of an isolated organ system and the rapidity with which it develops all suggest that the antihaemorrhagic effect and the conventional estrogenic effects occur independently. The use of heparinized dogs and defibrinated blood both favour the view that the antihaemorrhagic effect observed was of vascular origin. Some possibilities regarding more detailed aspects of the mechanism of this effect are discussed.

Suppression of pituitary gonadotropins by 17-ethynyl-19-nortestosterone in patients with metastatic carcinoma of the breast.

ABSTRACT 17-Ethynyl-19-nortcstosterone was found to be effective in suppressing pituitary gonadotropin excretion in 4 cases of metastatic mammary carcinoma. The mean 24-hour excretion of gonadotropin fell from 34.5 μg. to 7.7 μg. by the fourth week and to 5.7 μg. by the sixth week of injection, and remained low when the steroid was administered by mouth for an additional sixteen weeks. It is suggested that the effect might result from the weak estrogenic activity of the compound. THERE is evidence that certain types of mammary carcinoma are stimulated by estrogens (1). A compound suppressing the gonadotropin output of the pituitary might obviate the use of oophorectomy and hypophysectomy in such cases. A report is given of the urinary gonadotropin excretion in 5 cases of metastatic carcinoma of the breast treated with 17-ethynyl-19-nortestosterone over a period of six months. MATERIALS AND METHODS Two complete 24-hour specimens of urine were collected from each subject prior to treatment. After treatment ...

Inhibitory activity of some alpha, beta, beta-triarylethylenes toward anterior pituitary secretions

An investigation has been made of the inhibitory effects on the secretions of the anterior pituitary of four α,β,β-triarylethylenes with weak oestrogenic activity. These substances have been found to vary in the degree to which they inhibit each of the secretions investigated.

Biological properties of a highly purified preparation of 17-alpha estradiol.

1 The anabolic. The estrogenic and the pituitary gonadotrophin inhibiting actions table of a highly purified sample of α-estradiol have been studied in experimental animals. 2. It appears that α-estradiol has not significant anabolic action and that the weak estrogenic and gonadotrophin inhibiting activities might be due to contamination with a very small amount of the potent β-epimer. 3. If the activity found in this preparation is truly due to α-estradiol has one-two hundred fiftieth the gonadotrophin inhibiting activity of β-estradiol and approximately one-three hundred fiftieth the estrogenic activigy.

ESTROGENIC ACTIVITY OF MONOBENZYL ETHER OF STILBESTROL IN THE HUMAN

The monobenzyl ether of stilbestrol has been found to have a strong pituitary potentiating capacity in laboratory animals, but to exhibit a very weak estrogenic activity. According to the data in the literature, it has 1/10 to 1/5 the ovulation-inducing capacity of stilbestrol, but only 1/300 the estrogenic activity (1). Its effectiveness as a nonestrogenic stimulator of ovulation in humans has been reported (1). This communication is to report a preliminary effort to establish its relative estrogenic effect on the human vagina, plans for a more complete definition of its human estrogenic activity having been interrupted by a call to active duty in the Armed Forces. The method used for assay was that of Brown and Bradbury (2). Three groups of menopausal women were given priming doses of ethinyl estradiol, 0.05 mg. daily for ten days. When the effect on the vaginal smears had worn off, each group received 3.0 mg. of monobenzyl ether of stilbestrol daily for ten days. The vaginal-smear response of each of these groups of women (14 to 23 patients per group) is presented graphically in Figure 1. For comparison, Figure 2 reproduces a similar assay of stilbestrol.

Metabolic and toxicity studies on parahydroxypropiophenone.

INTEREST was recently aroused concerning the pharmacology of parahydroxypropiophenone (PHP) by reports of Buu-Hoi and associates (1950). This well-known compound was believed to exert a number of actions on the endocrine system which if true might have therapeutic value. In fact, early clinical trials by Perrault et al. (1949) indicated that such was the case. Earlier work with PHP, which is a precursor of stilbestrol, had indicated that the former was essentially actionless except for a weak estrogenic activity (Emmens, 1941). The following report deals with toxicologic, metabolic, and fertility studies in experimental animals in an attempt to verify the findings of the French workers. EXPERIMENTAL STUDIES 1. Chemical properties The PHP employed was a purified preparation obtained from the Sumner Chemical Company Inc. It is a white crystalline compound relatively insoluble in water and slightly soluble in alcohol and ether.