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At least 19 recordsLinked to original sources
PubMed1988

The morphologic effects of synthetic reproductive steroids on the mammary gland of rhesus monkeys. Mestranol, ethynerone, mestranol-ethynerone, chloroethynyl norgestrel-mestranol, and anagestone acetate-mestranol combinations.

A total of 213 treated and 16 control monkeys comprising 12 experimental groups was evaluated for determination of the long-term (10 years) effects of various dosages of a variety of synthetic oral contraceptive steroids on the mammary glands of rhesus monkeys. The steroid hormones included mestranol, ethynerone, a combination of mestranol and ethynerone, chlorethynyl norgestrel plus mestranol, and anagestone acetate plus mestranol. Various degrees of physiologic lobular hyperplasia and lactational changes were observed in association with all of these steroid hormones; these changes appeared dose-dependent. Mestranol caused a proliferative atypia ranging from a minimal to a moderate degree in 8 of 34 (23%) animals, but it was not dose-related. Eleven of 15 monkeys (73%) administered ethynerone developed proliferative atypia, ranging in degree from minimal to severe, including one invasive carcinoma and 2 lesions resembling intraductal carcinoma in the human. The mestranol and ethynerone combination produced a proliferative atypia in 22 of 52 animals (42%), including five identical to intraductal carcinoma in the human and one identical to lobular neoplasia. Of the 40 monkeys administered anagestone acetate and mestranol, 20 (50%) developed proliferative atypias; the atypias ranged from mild to severe and included five resembling intraductal carcinoma in human breast. The chloroethynyl norgestrel and mestranol combination induced proliferative atypia in 25 of 52 monkeys (49%); six of these atypias were severe and indistinguishable from intraductal carcinoma of the human breast; and one, if in the human breast, would reflect a solid variant of an invasive carcinoma. Only 2 of the 16 control monkeys (12%) developed proliferative atypias, and these were of minimal to mild degree. The occurrence of severe degrees of atypia identical to intraductal carcinoma in the human breast and invasive carcinoma associated with hormone administration suggests a carcinogenic effect.

Animals↗
PubMed1979

Lumi-mestranol and epi-lumi-mestranol.

Treatment of lumi-estrone 3-methyl ether (I) with acetylene gave the C-17-epimeric compounds lumi-mestranol (3-methoxy-17 alpha-ethynyl-13 alpha-estra-1,3,5(10)-trien-17 beta-ol, III ) and epi-lumi-mestranol (3-methoxy-17 beta-ethynyl-13 alpha-estra-1,3,5(10)-trien-17 alpha-ol, IV). The structures of the two isomers were assigned on the basis of their molecular rotations and shift-reagent experiments in the NMR. The irradiation of estrone 3-methyl ether (II) to provide compound I was investigated in two solvent systems. Minor products of these reactions were the seco-steroids VII, VIII and X.

Acetylene↗
PubMed1995

[Estrogens. Replacement therapy. Mestranol 80 ug (1962) versus mestranol 20 ug (1994) in postmenopausal women. Clinical, local, and metabolic effects].

A group of 37 postmenopausal women ingested mestranol (MEE) 20 ug daily per 90 days. Cervical mucus, vaginal citology, endometrial biopsy, 17 beta estradiol (E-2) low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C), were determined in all of them before (phase I) and after such treatment (phase II). Besides, the relieve of vasomotor symptoms, fernlike cristallization and pyknotic nuclei cells, increase and 3/4 of the endometrial samples showed proliferation, in phase II. Endogenous circulating E-2 was not disturbed regardless MEE treatment and inverse relationship was attained on circulating lipoproteins, while LDL-C decrease (p = 0.01), HDL-C increase (p = 0.001), after comparing phase I vs. phase II. Chlormadinone acetate (2 mg/day/3 days) was administered at the end of the MEE treatment to avoid endometrial estrogenic persistence. Current studies should be enlarged to support the usage of new dose and regimen of mestranol replacement therapy.

Cholesterol↗
PubMed1975

Ultrastructural effects of mestranol and norethindrone on guinea pig endometrial stromal cell.

The effect of exogenous contraceptive steroids on the ultrstructural features of the endometrial stromal cells was studied in 64 guinea pigs allotted to 4 treatment groups. Four guinea pigs from each group were killed 14, 28, 56, and 84 days after treatment with mestranol (0.01 mg/day in 1 ml of oil) or with norethindrone (0.2 mg/day in 1 ml of oil) or with a combination of both (0.001 mg of mestranol/day and 0.02 mg of norethindrone/day in 1 ml of oil) or with 1 ml of vegetable oil (oil-treated controls). An additional 12 normal guinea pigs (nontreated controls) were killed during the follicular and luteal phases of the estrous cycle, and uterine specimens were immediately collected to determine base line characteristics. During estrus, the stromal cells of these 12 guinea pigs had abundant dilated rough endoplasmic reticulum. The interstitium was filled with collagen. During the luteal phase. the cytoplasm of the stromal cells of the 12 guinea pigs contained a prominent nucleus and rough endoplasmic reticulum with undilated cisterns. The interstitium contained sparse amounts of collagen. The stromal cells of the oil-treated control guinea pigs seemed similar in ultrastructure to the stromal cells of the 12 nontreated control guinea pigs at the luteal phase. Mestranol-fed guinea pigs had dilated rough endoplasmic reticulum and well-developed Golgi apparatus within 2 weeks of initial treatment. The interstitium of mestranol-treated guinea pigs had more collagen than that of the oil-treated controls and nontreated controls during the luteal phase. Prolonged treatment with mestranol caused extensive dilation of the cisternae of the endoplasmic reticulum. The interstitium was filled with abundant collagen. Pronounced alterations in the cytoplasmic organelles or extracellular connective tissue were not ovserved in guinea pigs given norethindrone alone or norethindrone in combination with mestranol for 14 days. The stromal cells closely resembled the cells of the mature animal at luteal phase. However, the dilated rough endoplasmic reticulum that occurred in cells after mestranol treatment was not seen in stromal cells after 84 days of treatment with norethindrone. Dilation of rough endoplasmic reticulum was also observed when both the contraceptive steroids were given simultaneously for 84 days. The increased and extensively dilated rough endoplasmic reticulum seen during the follicular phase and after mestranol administration or after 84 days of treatment with mestranol and norethindrone probably indicates increased protein synthesis by the endometrial stromal cells.

Animals↗
PubMed1984

Enhancement of hepatocarcinogenesis in female rats by ethinyl estradiol and mestranol but not estradiol.

The effect of dietary exposure to synthetic estrogens on hepatocarcinogenesis was evaluated. Diethylnitrosamine-initiated and 0.85% NaCl solution-treated noninitiated female Sprague-Dawley rats were transferred to semisynthetic diets containing mestranol (0, 0.1, or 0.5 ppm), ethinyl estradiol (0.5 ppm), estradiol (0.6 ppm), or mestranol plus beta-methasone (0.5 and 0.2 ppm, respectively). gamma-Glutamyl transferase (GGT)-positive transections and hematoxylin and eosin-detectable nodules and carcinomas were scored at 9 and 12 months. Quantitative stereological calculations were performed to determine GGT lesion number and size. At 9 months, in diethylnitrosamine-initiated rats, ethinyl estradiol and mestranol caused 3.5- and 4.4-fold increases, respectively, in the number of GGT lesions per liver and an increased incidence of hepatocellular carcinomas while estradiol had no enhancing effect. Addition of beta-methasone to the mestranol-containing diet caused a significant decrease in GGT lesion number but not carcinoma incidence compared to mestranol alone. At 12 months, in diethylnitrosamine-initiated rats, mestranol caused a dose-dependent increase in GGT lesion number. The hepatocellular carcinoma incidence was significantly increased at the high mestranol dose. Small increases in the numbers of larger GGT lesions were also observed in noninitiated animals treated with mestranol and ethinyl estradiol and are most probably due to promotion of spontaneously initiated hepatocytes. These results indicated that the synthetic estrogens cause dramatic increases in the number of presumptive preneoplastic GGT lesions. Carcinoma incidence is also enhanced. Thus, these results confirm and extend our previous studies which together with the results of others have shown that synthetic estrogens can act as promoters of hepatocarcinogenesis.

Animals↗
PubMed1987

Effect of mestranol on cell proliferation and angiotensinogen production in HepG2 cells: relation with the cell cycle and action of tamoxifen.

The effects of the estrogen analog mestranol and of the antiestrogen tamoxifen on cell growth and the rate of angiotensinogen production were investigated in HepG2 cells, an hepato-carcinoma cell line of human origin. After 36 h of cell contact with high concentration of mestranol, a (10(-5) M) dose increased by 2-fold the rate of proliferation of HepG2 while reducing angiotensinogen production to below control level. Mestranol at 10(-6) M preferentially stimulated angiotensinogen production 5-fold, whereas cell growth rate was slightly increased. Comparable results were obtained for thymidine uptake in the course of the cell cycle, with a maximum increase for 10(-5) M mestranol, and an increase of angiotensinogen production for 10(-6) M mestranol. At 10(-6) M, tamoxifen acted as a pure antagonist by strongly inhibiting the stimulatory effect of mestranol and reducing angiotensinogen production to below the control level within 60 h. Tamoxifen did not affect the growth rate of HepG2 cells, either when administered alone or together with an equimolar concentration of mestranol.

Angiotensinogen↗
PubMed1986

Body fluid volumes in rats with mestranol-induced hypertension.

Because estrogens have been reported to produce sodium retention, this study investigated the possibility that hypertension in rats resulting from the ingestion of an estrogen used as an oral contraceptive could be due to increases in body fluid volumes. Female rats were given feed containing mestranol for 1, 3, and 6 mo; control rats were given the feed without mestranol. The mestranol-treated rats had higher arterial pressures than the controls only after 6 mo of treatment. Plasma volume, extracellular fluid volume, and total body water were measured in each rat by the distribution volumes of radioiodinated serum albumin, 35SO4, and tritiated water, respectively. Values for blood volume, interstitial fluid volume, and intracellular fluid volume were derived from these measurements. These body fluid volumes, expressed per 100 g of body weight, were not different between the mestranol-treated rats and their controls at any of the three treatment times. Due to differences in body weight and lean body mass between the mestranol-treated and the control rats, these volumes also were expressed per 100 g of lean body mass. Again, no differences were observed between the mestranol-treated rats and the control rats for any of these body fluid compartments at any of the treatment times. These studies, therefore, were unable to provide evidence that increases in body fluid volumes contributed to the elevated arterial pressure in this rat model of oral contraceptive hypertension.

Animals↗
PubMed1983

Effects of chronic administration of mestranol on alpha and beta adrenergic responsiveness in female rats.

Several alpha and beta adrenergic responses were studied in female rats after treatment with a low dose of the synthetic estrogen, mestranol (15 micrograms i.p. biweekly), for 4 to 6 weeks and compared with untreated controls. The response of blood pressure to exogenously administered norepinephrine was measured in conscious rats by means of an indwelling catheter in the femoral artery. Basal systolic blood pressure was not different between control and treated groups, or was any difference observed in peak systolic pressure after acute i.v. administration of l-norepinephrine in concentrations of 0.0625, 0.125, 0.250 and 0.625 micrograms. In contrast, the half-time of the blood pressure response was significantly prolonged after administration of the various concentrations of norepinephrine to mestranol-treated rats. The half-time of the pressor response observed in control animals administered 0.625 micrograms of norepinephrine was elicited in mestranol-treated animals by only 0.250 micrograms of norepinephrine. Analysis of the time course of the pressor response indicates that mestranol treatment altered the duration of the blood pressure increase without an apparent change in the onset of the pressor response. No differences between groups were observed in beta adrenergic responsiveness measured in terms of the isoproterenol-induced increase in either heart rate (beta-1 response) or water intake (beta-2 response). Finally, the contractile response of aortic rings from mestranol-treated rats to both l-norepinephrine (10(-9) to 10(-5) M) and l-phenylephrine (10(-8) to 10(-4) M) was significantly less than that of aortic rings from control rats. These data indicate, therefore, that in vivo cardiovascular responsiveness to norepinephrine does not reflect the attenuated vascular reactivity of isolated aortic rings. Insofar as the dominant feature of the in vivo adrenergic response appears to be prolongation of pressor action, the present study suggests that processes involved in the inactivation of circulating norepinephrine may be altered by chronic treatment with a low-dose of mestranol.

Animals↗
PubMed1997

Biotransformation of mestranol to ethinyl estradiol in vitro: the role of cytochrome P-450 2C9 and metabolic inhibitors.

Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17 alpha-ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 mumol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 mumol/L (range, 1.8-8.3 mumol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60-91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. alpha-Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations < 2 mumol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (< 20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 mumol/L (range, 0.7-3.2 mumol/L) and an average Emax of 90% (range, 77-100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 mumol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.

Adult↗
PubMed1986

Effects of captopril and bradykinin on arterial pressure in rats with mestranol-induced hypertension.

Hypertension was produced in 20 female rats by the oral administration of mestranol for 6 months; 20 control rats were not given mestranol during this time. The i.v. infusion of the angiotensin converting enzyme inhibitor, captopril, into 10 conscious mestranol-treated rats reduced mean arterial pressure from 139 +/- 2 (SEM) to 130 +/- 2 mm Hg (P less than 0.01); mean arterial pressure in 10 conscious control rats averaged 123 +/- 3 mm Hg, and was not significantly changed during captopril infusion. Injections of bradykinin at 0.1, 0.3, and 1.0 microgram/100 gm body weight decreased mean arterial pressure significantly more in 10 mestranol-treated rats than in 10 control rats. These results suggest that the ability of captopril to lower arterial pressure in rats with mestranol-induced hypertension may be due, at least in part, to the action of captopril to enhance bradykinin.

Angiotensin I↗
PubMed1994

Pressor responsiveness in rats with hypertension induced by mestranol.

The aim of this study was to determine if pressor hyper-responsiveness is associated with the hypertension that results from the ingestion of the synthetic estrogen, mestranol. Rats were fed a diet containing mestranol for 6 months, while control rats were fed the same diet without mestranol. Catheters were then placed in the carotid artery and jugular vein of all rats, under halothane anesthesia. When the rats had recovered from the anesthesia, blood pressure was measured through the carotid catheter in conscious rats. Each rat received IV injections of norepinephrine (NE) at 2, 4, 8, and 16 ng per 100 gm body weight, and the pressor responses were recorded. The rats fed mestranol had significantly higher arterial pressures than did the control rats. However, the pressor responses to NE were significantly less in the mestranol-treated rats than in the controls, indicating that pressor hyper-responsiveness does not contribute to this form of hypertension.

Animals↗
PubMedDate not supplied

[Use of mestranol as an anabolic substance in fattening bulls].

In 5 experiments 137 fattening bulls received between 0 and 20 mg Mestranol per animal and day. In one experiment a dose of 10 mg/day reduced consumption. The cause of this effect could not be found. In three experiments Mestranol increased weight gain by 4-13%. Feed expenditure was significantly decreased in only one experiment, in which 5-10 mg were given (average of all experiments: 4%). In dependence on the amount of Mestranol the weight of skin, horn and testicles decreased, when only 5-10 mg were given, however, protein retention increased whereas fat retention decreased. When 20 mg Mestranol are given per animal and day, the anabolic effect is missing although the NEFcattle-expenditure per kJ retention including maintenance decreases. This is due to a higher fat retention, which is causally inexplicable. The ergotropic effect of Mestranol depends on its dosage and possibly the nutrients in the ration.

Animals↗
PubMed1984

Interruption of early pregnancy in the monkey with mestranol and 5-oxa-17-phenyl-18,19,20-trinor prostaglandin F1 alpha methyl ester.

Prior work has shown that 5-oxa-17-phenyl-18,19,20- trinor prostaglandin F1 alpha methyl ester (PGF-analog) inhibits luteal progesterone secretion, but does not shorten menstrual cycles in human chorionic gonadotropin (hCG)-treated, nonpregnant monkeys. This report demonstrates that a combination treatment of PGF-analog and mestranol not only reduces blood progesterone concentrations in the hCG-treated monkey, but also results in a significant shortening of menstrual cycles. The corpus luteum-inhibiting activity of PGF-analog in hCG-treated, nonpregnant monkeys was not enhanced by simultaneous administration of nonestrogenic steroids (norethisterone, oxymetholone, azastene , 17 alpha-allyl-3-methoxy-1,3,5(10)- estratrien-17 beta-ol). Most importantly, pregnancy was interrupted in 11 or 12 monkeys when PGF-analog and mestranol were administered on Day 28 of fertile menstrual cycles; this abortifacient activity of the prostaglandin-estrogen treatment was not prevented by concomitant administration of progesterone. Administration of PGF-analog and mestranol in the third trimester terminated pregnancy in only 1 of 3 monkeys. The data indicate that a combination treatment of PGF-analog and mestranol is highly effective for the termination of early pregnancy in the monkey. Although PGF-analog and mestranol clearly inhibit the monkey corpus luteum, it is unlikely that this activity is essential for the abortifacient activity of the prostaglandin-estrogen treatment.

Abortifacient Agents↗
PubMed1983

Effects of chronic mestranol and (or)norethindrone treatment on ethanol-associated decreases in hepatic benzo[a]pyrene hydroxylase activity and increases in central vein fat accumulation in the female Wistar rat.

Female Wistar rats were fed a liquid diet, Sustacal, which contained ethanol (40% of calories) or isocaloric sucrose. Mestranol and norethindrone in pharmacological doses were also administered via this diet. Hepatic microsomal benzo[a]pyrene (BP) hydroxylase, epoxide hydrase, aniline hydroxylase, and aminopyrine-N-demethylase activities were measured after 3 and 6 months treatment. In addition, hepatic histology and electron microscopic studies were carried out in an attempt to monitor ethanol-associated fat accumulation in the central vein region. Mestranol or norethindrone alone for 3 months produced an elevation of BP hydroxylase activity which was no longer present after 6 months treatment. When compared with the 3-month time period, BP hydroxylase activity was significantly decreased in livers of animals which had ingested ethanol (group 10 vs. group 2), ethanol plus mestranol (group 12 vs. group 4), and ethanol plus norethindrone (group 14 vs. group 6) for 6 months. However, in the steroid-treated groups, the ethanol associated decreases were not as large as that seen without ethanol over the 3-month time period (group 11 vs. group 3; group 13 vs. group 5). No decrease was observed in the combined steroid plus ethanol-treated groups. Ethanol treatment for 6 months increased hepatic epoxide hydrase activity in both the nonsteroid and mestranol-treated group. Aniline hydroxylase was increased by ethanol in the combined steroid-treated animals. Otherwise there were no significant changes in the enzyme activities measured. Hepatic histology studies carried out on the 6-month ethanol-treated animals provided evidence of fat accumulation in the central vein region of the liver lobule, as expected. However, the steroid- plus ethanol-treated groups exhibited less apparent fat accumulation in the central vein region. These data do not support the hypothesis that mestranol and (or) norethindrone will accentuate the inhibition of liver BP hydroxylase or the central vein fat accumulation produced by chronic ethanol ingestion in the female rat.

Animals↗
PubMed1989

Total exchangeable sodium in rats with mestranol-induced hypertension.

Rats were fed a diet containing mestranol, an orally active estrogen, while control rats were fed the same diet without mestranol. After 6 months of these diets, the rats were weighed, blood pressures were measured, and total exchangeable sodium was determined by injecting 24Na and determining the amount of 24Na in the plasma, the plasma Na concentration, and the residual 24Na in each rat. The 16 mestranol-treated rats were hypertensive (mean arterial pressure 135 +/- 3 mm Hg) when compared with the 17 controls (116 +/- 3 mm Hg). Total exchangeable sodium in the mestranol-treated rats averaged 39.94 +/- 0.49 (SEM) mEq/kg body wt, which was very similar to the value of 39.87 +/- 0.63 mEq/kg found in the control rats. Thus, no changes in total exchangeable sodium in mestranol-hypertensive rats were found in these studies.

Animals↗
PubMed1979

Interaction of mestranol with taurocholate uptake by isolated rat hepatocytes.

Cellular uptake interactions between mestranol and taurocholate at concentrations between 50 and 1000 microM in the medium were studied in isolated hepatocytes. Rat liver cells exposed to medium containing mestranol and taurocholate attained up to twice as large a concentration of mestranol as those exposed to mestranol without the presence of the bile acid in medium. In contrast, taurocholate concentration in cells exposed simultaneously to taurocholate and mestranol was one fourth of the concentration in cells exposed to taurocholate alone.

Animals↗
PubMed1978

Influence of 3-methylether of ethinylestradiol (Mestranol) on oviductal egg transport in rats.

The development of fertilized eggs and their transport through the oviduct were studied in rats treated orally with 3-methylether of ethinylestradiol (mestranol) at a single administration in different doses. The ED50 values were in the same range (0.11--0.34 mg mestranol/kg b.w.) as well in postcoital pregnancy inhibition test as in the experiments on tubal egg contents on day 3 as in implantation sites in niagara blue test on day 6. This suggests that the uniform cause of pregnancy inhibition of postcoital mestranol treatment on day 1 in rats is the acceleration of tubal egg transport. The ED50 of mestranol given on day 1 shortened the stay of eggs in tubes to 24 hours. Mestranol dosage above the ED50 reduced the tubal stay towards two days in comparison to five days in control animals. The number of eggs prematurely expelled from the tubes into the uterus was relatively high on day 2 and 3 in animals treated with mestranol in high dosage and with ligated cervix, compared with animals without ligation. But on day 4 on blastocysts were found. This result shows that the prevention of pregnancy is caused by the expulsion of blastocysts from uterus and/or the degeneration of zygotes in utero. Blastocysts or morulae recovered from treated rats in high dosage were transferred to the uteri of pseudopregnant recipients: 29% developed into normal term foetuses compared to 29 or 30% for both untreated control groups.

Animals↗