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PubMed2000

Induction of estrogen receptor-alpha and -beta activities by synthetic progestins.

The cellular action of steroid hormones is mediated by specific receptors. Recently, two different estrogen receptors (ER), alpha and beta, have been cloned with a specific tissue distribution. Active estrogen as well as active progestin are compounds of oral hormonal contraceptives and hormone replacement therapy. To examine the regulation of ER-alpha and -beta activities after treatment with synthetic progestins and synthetic and natural estrogens, COS 7 cells were transfected with the vector expressing ER-alpha and -beta in combination with a luciferase reporter vector. ER-alpha activity was upregulated in the presence of synthetic progestins in a dose-dependent manner. Norethisterone, norethynodrel and desogestrel proved to be the most potent stimulatory agents of ER-alpha expression. On the other hand, not all progestins exhibited a stimulatory action on ER-beta activity. Only norgestrel, levonorgestrel, norethynodrel and norethisterone induced ER-beta-activating functions in a dose-dependent manner. Luciferase activity due to estrogen stimulation served as a positive control. Our results indicate that progestins have different effects on the activities of ER-alpha and -beta.

Animals↗
PubMed1992

Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation.

Most oral contraceptives (OC) contain a progestin in combination with an estrogen, and the progestin component in OC includes one of the following 19-nortestosterone derivatives: norethynodrel; norethindrone; or norgestrel (levonorgestrel). It is well known that estrogens promote the growth of breast cancer. However, progestins have recently also been implicated in the development of breast cancer. We have compared and contrasted the ability of synthetic progestins to stimulate the proliferation of cultured human breast cancer cells and examined their possible mechanism of action. We found that some progestins used in OC were able to stimulate the growth of estrogen receptor-positive (ER+) MCF-7 and T47DA18 human breast cancer cells but not ER- MDA-MB-231, BT-20, and T47DC4 human breast cancer cells. However, two other progestins, MPA and R5020, which are not used in OC, were either not able to stimulate or only slightly stimulated growth. The potency of norethynodrel [median effective dose (EC50) = 4 x 10(-8) M] and norethindrone (EC50 = 3 x 10(-8) M) was greater than norgestrel (EC50 = 2 x 10(-7) M) in MCF-7 cells. E2 (EC50 = 8 x 10(-13) M) was an even more potent stimulator of growth. More importantly, the progestin-induced growth stimulation was blocked by the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)-estra-4, 9-dien-3-one (RU486). To determine whether the proliferative action of progestins was mediated through the ER, cells were transfected with a chloramphenicol acetyltransferase reporter gene containing an estrogen response element derived from vitellogenin 2A gene. The progestins which stimulated the growth of breast cancer cells also increased chloramphenicol acetyltransferase activity. The induction of chloramphenicol acetyltransferase activity was blocked by the addition of the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin RU486. This study provides direct evidence that the 19-nortestosterone derivatives in OC have estrogenic properties and suggests that activation of ER, but not progesterone receptor, is the growth-stimulatory mechanism for these synthetic progestins. Our results may help to explain the conflicting evidence linking OC and breast cancer risk. A rigorous evaluation of the "total" estrogenic potential of OC might produce a better correlation with breast cancer risk.

Amino Acid Sequence↗
PubMed1978

Intravenous glucose tolerance after 18 months on progestogen or combination-type oral contraceptive.

The effect of long-term use of different oral contraceptives compounds was evaluated in two groups of 36 normal women on the basis of blood glucose and plasma insulin changes measured during i.v. glucose tolerance tests. Progestogen (ethynodiol diacetate) alone or a combination-type steroid compound (norethynodrel-mestranol) were used. After 18 months of ethynodiol diacetate therapy, a mild though obvious diabetogenic effect similar to that seen with norethynodrel-mestranol was observed.

Adult↗
PubMed1977

Collaborative study of an assay for progestational steroids in individual contraceptive tablets.

A single tablet assay method has been developed for determining norethindrone, norethynodrel, and norgestrel in commercial contraceptive tablets. The steroid is separated from the tablet constituents on a diatomaceous earth column, the chloroform eluate is reacted with isonicotinic acid hydrazide, and the steroid is determined by colorimetry. Norethynodrel is isomerized to a conjugated ketosteroid before the colorimetric determination. Fourteen laboratories collaboratively tested the method. The average recoveries in 3 brands of tablets were as follows: 102.6% for the sample labeled as containing 0.35 mg norethindrone/tablet, 99.4% for the 2.5 mg norethynodrel/tablet, and 98.2% for the 0.5 mg norgestrel/tablet. The assay method has been adopted as official first action.

Contraceptives, Oral, Combined↗
PubMed1994

Estrogenic and progestagenic activities coexisting in steroidal drugs: quantitative evaluation by in vitro bioassays with human cells.

The progestin-specific stimulation of alkaline phosphatase (AP) activity in cells of the T47D human breast cancer line was applied to the development of a sensitive microtiter plate bioassay for the quantitative evaluation of progestagenic and antiprogestagenic potencies of natural and synthetic compounds. Some of the steroids tested (viz. progesterone, medroxyprogesterone acetate, norethynodrel) behaved as full-agonists, capable of inducing AP activities to the same maximal levels (equal efficacy), while others (norethindrone, gestrinone, R5020, norgestrel, Org OD 14 and its 4-ene metabolite) behaved as partial agonists, eliciting lower maximal effects. Efficacy, EC50 values (concentrations at which they induce one-half of the maximal response) and "slope factors" serve to characterize agonistic effects. Relative progestagenic potencies among the full-agonists were evaluated by comparing EC50 concentrations. Several 19-nor synthetic progestins (norethynodrel, norethindrone, Org OD 14 and its 4-ene isomer, dl-norgestrel, levo-norgestrel, RU2323), but none of the tested progestins with the pregnane structure, showed intrinsic estrogenic activity, as evaluated by using a similar in vitro bioassay based on a previously reported estrogen-specific induction of AP in human endometrial adenocarcinoma cells of the Ishikawa Var-1 line. Maximal estrogenic effects of all the tested progestins with dual activity were as high as those of estradiol. However, these compounds widely varied in their EC50 values for estrogenic activity. Consequently, the in vitro bioassays can reveal differences in the ratio of progestagenic and estrogenic activities intrinsic to these compounds. The reduced capability of the partial agonists to exert progestagenic or estrogenic effects on AP expression may reflect an impeded, receptor-mediated action, a mechanism that would also account for their inhibitory effects on the induction of AP activity by full agonists. Partial progestagenic agonists were able to reduce the efficacy of a full agonist to their own partial maximal activity.

Alkaline Phosphatase↗
PubMed1976

Lack of influence of the phase of estrus cycle or treatment with steroid contraceptive drugs on cholinergic parameters in mouse and rat brain.

Acetylcholine and choline levels were found not to fluctuate with the phase of the estrus cycle in the cerebral hemispheres, deincephalon and mesencephalon in the rat and mouse. Choline acetyltransferase activity was not altered in these brain areas in the mouse while in the rat there was a small but significant decrease in the cerebral hemispheres during proestrus (p less than 0.01), and in the mesencephalon during estrus (p less than 0.05), both with respect to diestrus. Chronic 30-day treatment with steroid contraceptive drug combinations (lynestrenol, 5 mg/kg+ mestranol, 0.3 mg/kg; lynestrenol, 2.5 mg/kg+ mestranol, 0.15 mg/kg; norethindrone, 4 mg/kg+ mestranol, 0.2 mg/kg; norethynodrel, 4 mg/kg+ mestranol, 0.06 mg/kg) did not alter cholinergic parameters in the brain areas of these two species except for minor changes in rare instances.

Acetylcholine↗
PubMed1975

Oral contraceptives: effects on plasma insulin response to glucose and on the response to insulin and 2-deoxyglucose uptake by peripheral tissue.

Oral contraceptive steroids, norethynodrel and mestranol, were fed to 11-wk-old female Sprague-Dawley rats, in combination and in quantities proportional to those used by women for contraceptive purposes. Three experiments were performed. The first experiment, demonstrated that 10 wk of treatment, impaired the animal's glucose tolerance, but not its insulin response to glucose. The second experiment demonstrated that 6 wk of steroid feeding, decreased the in vivo conversion of blood U-14C-labeled glucose into adipose tissue fatty acids and into diaphragm glycogen, although the effect on the diaphragm was not statistically significant. In the third experiment, it was found that the uptake of 2-deoxyglucose-1-14C by the adipose tissue removed from rats after 6 wk of treatment, was not different from that of control tissue, but the uptake by the hemidiaphragms was slightly lower.

Adipose Tissue↗
PubMed1975

Investigation of the serum level of pregnancy-associated alpha2-globulin during contraceptive treatment by means of radial immunodiffusion method.

The serum level of pregnancy-associated alpha2-globulin was studied in 70 healthy women taking three different types of oral contraceptives [40 Bisecurin: containing 1.0 mg of Ethynodiol diaceticum +0.05 mg Ethynilestradiol; 20 Infecundin: containing 2.5 mg of Norethynodrel +0.1 mg of Mestranol; 10 Cervicundin: containing of 0.5 mg Ethynodiol diaceticum]. Elevated amounts of serum level of pregnancy associated alpha2-globulin could be detected in 37 of the 40 women taking Bisecurin and in all 20 taking Infecundin. Cervicundin however, failed to induce any change in the serum protein pattern of the 10 subjects studied. Serum levels of pregnancy-associated alpha2-globulin were higher in the Infecundin-taking (53 mg %), than in the Bisecurin-taking group (29 mg %). This shows the oestrogen dependency of the pregnancy-associated alpha2-globulin and points to a possible implication of this globulin in the immunosuppressive processes.

Alpha-Globulins↗
PubMed1977

Effect of ethynodiol diacetate and a combination-type oral contraceptive compound on carbohydrate metabolism. II. One year intravenous glucose tolerance study.

Blood glucose and plasma insulin levels were measured in two groups of women, following one year of oral contraceptive therapy of different types. There were no significant differences from pretreatment glucose and insulin values in the first group of women (on ethynodiol diacetate). In the second group (on norethynodrel and mestranol), there was a significant elevation of mean blood glucose levels in the fasting state and at all times of an i.v. glucose tolerance test. Furthermore, a statistically significant alteration in plasma insulin was observed at all times of the test (except at 120 min). Patients participating in this study will continue this treatment, and results of carbohydrate metabolism monitoring will be reported after 2 years of therapy.

Adult↗
PubMed1980

Treatment of endometriosis: a study of medical management.

Fifty patients with endometriosis were treated with hormones: 27 with danazol and 23 with Enavid (mestranol 75 micrograms and norethynodrel 5 mg). Side effects were more common and potentially more serious in the group treated with Enavid. Fewer women completed treatment with Enavid and their physical signs showed little improvement. Danazol was better tolerated and the results of treatment, as judged by improvement of symptoms or signs and in future fertility rates, were superior to those recorded in the Enavid treated group. Patients with large endometriotic cysts or severe fibrosis did not benefit from medical treatment. Danazol treatment appeared helpful for women who had mild or moderate endometriotic disease. It may be used alone or as a complimentary treatment after conservative surgical operations.

Adult↗
PubMed1976

Modifications of striatal dopamine levels by steroid contraceptive drugs in mice and rats.

The effect of steroid contraceptive drugs (SCDs) on the concentration of dopamine (DA) in the striatum was studied in mice and rats. Mestranol was combined with each one of the three progestins, lynestrenol, norethindrone and norethynodrel. Treatments were given daily for 1, 4 or 30 days; animals were sacrificed 1 or 18 h after the last administration. In all groups, with the exception of the animals sacrificed 1 h after an acute treatment, striatal DA was significantly lower than in controls.

Animals↗
PubMed1975

Studies on the mechanism of the ovulation-inhibiting effect of 19-norsteroids in cyclic rats.

Experiments performed in cyclic female rats demonstrated an equal ovulation-inhibiting activity of the 19-norgestagens norethynodrel, lynestrenol and norethisterone acetate after injection in oestrus and metoestrus, and after daily administration from oestrus to pro-oestrus. The results furthermore show that, after application of the minimal ovulation-inhibiting doses during oestrus and metoestrus, these substances 1. induce an increase in prolactin secretion, 2., with the exception of norethisterone acetate, possess a hypophysial site of action, 3. are able to induce deciduoma formation following traumatization of the uterus, and 4. maintain the reactivity of the cyclic corpora lutea to the injection of prolactin. The findings suggest that the prolactin-releasing and luteotrophic action of the progestagens studied may form an essential part of the mechanisms that are responsible for the inhibition of ovulation observed in rats after administration over one cycle.

Animals↗
PubMed1964

THE FERN REACTION OF CERVICAL MUCUS.

The fern reaction of endocervical mucus was tested in 100 non-pregnant and 200 pregnant women with a view to establishing the relationship of this fern pattern to normal ovarian cyclical changes and normal pregnancy. The fern appeared at day 7-9 of the cycle and disappeared at day 18-20. Twenty-eight of 100 pregnancies before 10 weeks yielded positive fern reactions; two of 100 pregnancies after 10 weeks yielded positive fern reactions. In the presence of a positive fern reaction, the administration of 10 mg. of norethynodrel (Enovid) daily for seven days led to prompt withdrawal bleeding in the absence of pregnancy. With a negative fern reaction, a spontaneous period ensues within 12 days in the absence of pregnancy. Two hundred women were tested for early pregnancy on this premise; in 198, a correct diagnosis was obtained.

Cervix Mucus↗
PubMed1975

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). An electron microscopic study of the vascular lesions before and after therapy with hormones.

Eight patients with hereditary hemorrhagic telangiectasia and severe epistaxis were treated with norethynodrel with mestranol (Enovid). Biopsy specimens of typical lesions from two patients were taken for electron microscopy before and after several months of therapy. Characteristic endothelial cell damage and nectosis were noted in the dilated venules of patients before treatment but not after. Unlined channels of blood were found in connective tissue before treatment but not after. These are thought to arise from leaks in the affected venules, and it is suggested that later indothelial ingrowth gives rise to the propagation of lesions that are known to develop with age. Reduplicated basal laminae and regenerating endothelial cells were found both before and after treatment.

Biopsy↗
PubMed1975

Estrogen potency of oral contraceptive pills.

The estrogen potencies of 9 oral contraceptive pills, Enovid-E, Enovid-5, Ovulen, Demulen, Norinyl+80, Norinyl+50, Ovral, Norlestrin 1 mg. and Norlestrin 2.5 mg., were determined by bioassay. Relative estrogen potency was determined by analysis of variance. Enovid-5, the most estrogenic compound, had a potency of 4.88 compared to ethinyl estradiol, 50 mcg. equal 1.00; Ovral, the least estrogenic compound, had a potency of 0.81, a sixfold difference. Estrogen potencies at a fractional dose of 0.00155 correlate with reports of the incidence of minor side effects and thromboembolic disease. The effect of progestins on estrogen potency was purely additive (norgestrel and norethynodrel), purely antagonistic, or additive at low concentrations and antagonistic at high concentrations (norethindrone, norethindrone acetate, and ethynodiol diacetate). These results suggest that pills with a greater margin of safety might be developed by utilizing greater ratios of progestin to estrogen. In addition, differences in relative estrogen potency of oral contraceptive pills may be used as a basis for better clinical selection.

Animals↗
PubMed1981

Increased synthesis of aortic collagen and elastin in experimental atherosclerosis. Inhibition by contraceptive steroids.

Rabbits were fed an atherogenic or normal control diet for 3 months; half of each group were treated with mestranol--norethynodrel (M--N) and half with cottonseed oil vehicle. At the end of the 3-month period rabbits were killed and aortic collagen and elastin synthesis determine. Collagen and elastin synthesis was increased in aortas of rabbits on an atherogenic diet, but those treated with M--N had a lower rate of collagen synthesis and less deposition of cholesterol in the aorta than those administered cottonseed oil. It is suggested that long-term administration of the contraceptive steroid combination may retard the progression of atherosclerosis through the hormone's effect on vascular connective tissue.

Animals↗
PubMed1975

A cytogenetic study in women who had used oral contraceptives and in their progeny.

A study has been made of the chromosome numbers and characteristics of leucocytes cultured from mothers (a total of 77) who had taken one or more types of oral contraceptive, and their babies (108), and compared with similar numbers of control subjects. When the total cytogenetic results from test and control mothers were compared, no significant differences in frequency or type of chromosome abnormalities was observed. However, with certain types of oral contraceptive, minor differences in the numbers of chromosome abnormalities were found between test and control groups and the significance of these findings are discussed. The only significant abnormalities observed in the babies from mothers taking oral contraceptives were slight increases in the numbers who had cells with less than 46 chromosomes and who exhibited chromosomal gaps. The number of abnormal cells was significantly higher in babies born to mothers who had been taking norethynodrel (Conovid) (4.6% abnormal cells in test babies; 2.0% in controls).

Aneuploidy↗
PubMed1983

Synthetic progestins and sweetness preference in intact female Sprague-Dawley rats.

Intact Sprague-Dawley female rats were treated with 0.25 microgram or 1.25 micrograms ethinyl-estradiol (EE) in combination with one of 3 synthetic progestins: (5 micrograms) norethindrone, norethynodrel, or norgestrel. In Experiment 1 both dosages of EE in combination with the synthetic progestins suppressed sweetness preference, with a somewhat greater effect for the 1.25 micrograms EE dosage. Norgestrel in combination with EE produced the longest suppression of sweetness preference. In Experiment 2 progestins administered in the absence of EE showed no significant effect on sweetness preference. When 1.25 micrograms EE was administered singularly, a significant decline in sweetness preference occurred, but not as great a decline as in combination with a progestin.

Analysis of Variance↗