Mestranol

Groups of 24 virgin female C57L mice (MTV-) received 7 or 70 ug of a mixture of mestranol:norethynodrel (1:50) in oil by gavage, 5 times per week, commencing when the animals were 13 weeks of age. Pituitary tumors were found at autopsy in 7/7 mice given the higher dose that lived 84-89 weeks and in 6/11 mice given the lower dose, compared with 2/15 controls that lived 90 weeks. In this, and in a concurrent experiment with norethisterone:ethinyloestradiol (50:1), hepatomas were found in 10/96 treated mice, but the distribution within the different treatment groups was not reported. No hepatomas occurred among 48 control mice.

Intact male (C3H x RIII)Fl mice (MTV+) given 3 mg/kg (ppm) Ovulen (90% ethynodiol diacetate and 10% mestranol) mixed into the diet (intake, 7.5-10.0 ug/mouse per day) showed an increased incidence of mammary tumors, from 0/76 to 14/25; in castrated males, the incidence was increased from 10/61 to 21/28. The high spontaneous incidence (161/167) and short latent period of tumor induction (30-33 weeks) in intact females were not altered (37/38). In ovariectomized females the tumor incidence was not altered by Ovulen (28/34 in controls as compared with 20/26), but the latent period was reduced in both ovariectomized females (from 49 to 26 weeks) and castrated males (from 82 to 43 weeks).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2.2X10+4(SRC), determined from a structure estimation method(2), indicates that mestranol is expected to be immobile in soil(SRC). Volatilization of mestranol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.5X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Mestranol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Mestranol was greater than 90% removed in the sewage treatment process; however, 99.80% attributed to sludge adsorbance(5) indicating that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2.2X10+4(SRC), determined from a structure estimation method(2), indicates that mestranol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.5X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 500(SRC), from a log Kow of 4.61(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Mestranol was greater than 90% removed in the sewage treatment process; however, 99.80% attributed to sludge adsorbance(6), indicating that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), mestranol, which has an estimated vapor pressure of 9.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase mestranol may be removed from the air by wet or dry deposition(SRC). Mestranol absorbs at wavelengths of 287.5 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

Patients who are fully breast-feeding should not take Norinyl-1 tablets since, in common with other combined oral contraceptives, the estrogen component may reduce the amount of milk produced. In addition, active ingredients or their metabolites have been detected in the milk of mothers taking oral contraceptives.

Mestranol is the 3-methyl ether of ethinylestradiol. Ethinylestradiol, is a synthetic derivative of estradiol. Ethinylestradiol is orally bio-active and the estrogen used in almost all modern formulations of combined oral contraceptive pills. It binds to (and activates) the estrogen receptor. Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylated in the liver with a conversion efficiency of 70%. Estrogens diffuse into their target cells and interact with a protein receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. The combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH).

For mestranol, a concentration range of 0.50 to 1.94 ug/L was reported as a result of analysis of raw sewage entering 14 representative sewage plants within a 50-mile radius of Cincinnati, OH; the average concentration was 1.21 ug/L. The treated effluent concentration range was 0.40 to 1.90 ug/L, average 1.05 ug/L(1). Mestranol was detected in 3 of 38 German municipal sewage treatment plant effluents from below the limit of quantification to a maximum of 0.004 ug/L(2). Detected in 3 of 18 sewage treatment plant effluents in Baden-Wuerttemberg, southeastern Germany with a maximum concentration of 2.7 ng/L reported; sampling took place between August 1998 and December 1999 and the detection limit was 0.6 ng/L(3). Mestranol was detected, not quantified in influent samples to the Piera and Igualada sewage treatment plants, respectively, on the Anoia tributary in the vicinity of Barcelona, Spain, sampled from April to June, 1999; detected (method detection limits = 50-100 ng/L)(4). The compound was detected at concentrations of <2.0 (July 2003), <2.0 (Sept 2003, and <2.0 ng/L (Feb 2004) in effluent from the Eysines Sewage Treatment Plant (northern suburbs, Bordeaux, France) and runs through agricultural and residential areas(5).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of mestranol can be estimated to be 2.2X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that mestranol is expected to be immobile in soil. Mestranol exhibited a sorption coefficient (log Kd) of 2.26 using Blackwater estuary sediments and Thames River sediments, UK(3). The compound was not detected in the effluent of a 23-day column drainage study using Mahall-Laveen sandy loam soil from an area northwest of Phoenix, AZ and 200 L of treated effluent from a municipal waste treatment facility; reporting limit = 0.005 ug/L(4), suggesting adsorption to soil in the column(SRC). A log Koc of 5.85 was measured in a sewage treatment process, corresponding to a Koc of 707,397. Mestranol was greater than 90% removed in the sewage treatment process, with 99.80% attributed to sludge adsorbance(5).

/SIGNS AND SYMPTOMS/ Overdosage may be manifested by nausea, vomiting, breast enlargement and vaginal bleeding. There is no specific antidote and treatment should be symptomatic...

/EPIDEMIOLOGY STUDIES/ There is some evidence from epidemiologic studies that use of oral contraceptives may be associated with an increased risk of cervical carcinoma. In one study, the incidence of biopsy-proven cervical neoplasia (ie, dysplasia, carcinoma in situ, or invasive carcinoma) was increased in long-term oral contraceptive users compared with women who used an intrauterine contraceptive device (IUD)...

/EPIDEMIOLOGY STUDIES/ Although a causal relationship to the drugs could not be excluded, data from a population-based (Costa Rican women), case-control study suggest that the increased risk of carcinoma in situ associated with oral contraceptive use may have resulted from a detection bias secondary to more frequent use of Papanicolaou tests in oral contraceptive users. These data revealed no evidence of increased risk of invasive cervical cancer in users compared with nonusers.

/EPIDEMIOLOGY STUDIES/ Several retrospective case-controlled studies have shown an increased relative risk of endometrial carcinoma in postmenopausal women who received prolonged estrogen replacement therapy for relief of menopausal symptoms. Although an increased risk of adenocarcinoma of the endometrium has been associated with sequential oral contraceptive use (sequential oral contraceptives are no longer available in the US), no association between increased risk of endometrial cancer and use of currently available estrogen-progestin combination preparations or progestin-only preparations has been shown, although individual cases have been reported. The Cancer and Steroid Hormone Study of the US Centers for Disease Control and Prevention (CDC) and the National Institute of Child Health and Human Development (NICHHD) showed that women who used estrogen-progestin oral contraceptives had decreased relative risk of epithelial endometrial cancer (ie, adenocarcinoma, adenoacanthoma, and adenosquamous cancers) compared with nonusers; the protective effect occurred in women who had used combination oral contraceptives for at least 12 months, and it persisted for at least 15 years after discontinuance of oral contraceptives. This decreased risk of endometrial cancer was not evident in women who had used oral contraceptives for less than 12 months.

For more Human Toxicity Excerpts (Complete) data for MESTRANOL (24 total), please visit the HSDB record page.

AEROBIC: Mestranol was rapidly degraded in batch experiments using activated sludge, forming 17alpha-ethynylestradiol by demethylation(1).Mestranol was greater than 90% removed in the sewage treatment process; however, 99.80% attributed to sludge adsorbance(2).

An estimated BCF of 500 was calculated in fish for mestranol(SRC), using a log Kow of 4.61(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for mestranol is estimated as 4.5X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that mestranol is expected to be essentially nonvolatile from water and moist soil surfaces(2). Mestranol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.7X10-9 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including mestranol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

For Mestranol (USEPA/OPP PC Code: 115401) there are 0 labels match. /SRP: Not registered for current use in the U.S./

...synthetic steriodal estrogen...

THERAPEUTIC CATEGORY: Estrogen; in combination with progestogen as an oral contraceptive

Mestranol was used as one of the first oral contraceptives.

Estrone is converted to its 3-methoxy analog by reaction with methyl sulfate. The ethynyl group may then be introduced at position 17 either through reaction with sodium acetylide in liquid ammonia followed by hydrolysis of the sodoxy compound, or through grignardization with ethynyl bromide.

Mestranol is commercially available as a component of combination tablets with chlormadinone acetate, ethynodiol diacetate, levonorgestrel, lynestrenol or norethisterone and formerly with norethynodrel.

ENOVID 5 MG CONTAINS 5 MG NORETHYNODREL & 0.075 MG MESTRANOL; ENOVID-E CONTAINS 2.5 MG NORETHYNODREL & 0.10 MG MESTRANOL.