Mestranol

 ( Ethynyl Compounds ) 

Mestranol, sold under the brand names Enovid, Norinyl, and Ortho-Novum among others, is an estrogen medication which has been used in birth control pills, menopausal hormone therapy, and the treatment of menstrual disorders. It is formulated in combination with a progestin and is not available alone. It is taken by mouth.

of mestranol include nausea, breast tension, edema, and breakthrough bleeding among others.

It is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.

(2007). 9781597451505, Springer Science & Business Media. . ISBN 9781597451505

Mestranol is a prodrug of ethinylestradiol in the body.

Mestranol was discovered in 1956 and was introduced for medical use in 1957. It was the estrogen component in the first birth control pill. In 1969, mestranol was replaced by ethinylestradiol in most birth control pills, although mestranol continues to be used in a few birth control pills even today. Mestranol remains available only in a few countries, including the United States, United Kingdom, Japan, and Chile.

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Medical uses

Mestranol was employed as the estrogen component in many of the first oral contraceptives, such as mestranol/noretynodrel (brand name Enovid) and mestranol/norethisterone (brand names Ortho-Novum, Norinyl), and is still in use today.

(2025). 9780300167917, Yale University Press. . ISBN 9780300167917

(2013). 9781483277387, Elsevier Science. . ISBN 9781483277387

In addition to its use as an oral contraceptive, mestranol has been used as a component of menopausal hormone therapy for the treatment of menopause .

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Side effects

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Pharmacology

Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylation in the liver (via O-Dealkylation) with a conversion efficiency of 70% (50 μg of mestranol is bioequivalent to 35 μg of ethinylestradiol).

(1998). 9780443047060, Churchill Livingstone. ISBN 9780443047060

(2025). 9780323033091, Elsevier Health Sciences. . ISBN 9780323033091

It has been found to possess 0.1 to 2.3% of the relative binding affinity of estradiol (100%) for the estrogen receptor, compared to 75 to 190% for ethinylestradiol.

(2025). 9780471266945, Wiley. ISBN 9780471266945

The elimination half-life of mestranol has been reported to be 50 minutes.

(2013). 9783662076354, Springer-Verlag. . ISBN 9783662076354

The elimination half-life of the active form of mestranol, ethinylestradiol, is 7 to 36 hours.

(2016). 9783319274492, Humana Press. . ISBN 9783319274492

(1986). 9789401083393, Springer. ISBN 9789401083393

The effective ovulation-inhibiting dosage of mestranol has been studied in women.

(2013). 9781483270883, Elsevier. . ISBN 9781483270883

(1966). 9780397590100, Lippincott. . ISBN 9780397590100

It has been reported to be about 98% effective at inhibiting ovulation at a dosage of 75 or 80 μg/day.

(1972). 9783540059592 ISBN 9783540059592

(1970). 9783642495069, Springer. ISBN 9783642495069

In another study, the ovulation rate was 15.4% at 50 μg/day, 5.7% at 80 μg/day, and 1.1% at 100 μg/day.

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Chemistry

Mestranol, also known as ethinylestradiol 3-methyl ether (EEME) or as 17α-ethynyl-3-methoxyestra-1,3,5(10)-trien-17β-ol, is a synthetic estrane steroid and a derivative of estradiol.

(2012). 9783642961588, Springer Science & Business Media. . ISBN 9783642961588

It is specifically a derivative of ethinylestradiol (17α-ethynylestradiol) with a methyl group ether at the C3 position.

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History

In April 1956, noretynodrel was investigated, in Puerto Rico, in the first large-scale clinical trial of a progestogen as an oral contraceptive.

(2005). 9780471899792, John Wiley & Sons. . ISBN 9780471899792

(2025). 9780323069861, Elsevier Health Sciences. . ISBN 9780323069861

The trial was conducted in Puerto Rico due to the high birth rate in the country and concerns of moral censure in the United States.

(2013). 9781483163666, Elsevier Science. . ISBN 9781483163666

It was discovered early into the study that the initial chemical syntheses of noretynodrel had been contaminated with small amounts (1–2%) of the 3-methyl ether of ethinylestradiol (noretynodrel having been synthesized from ethinylestradiol). When this impurity was removed, higher rates of breakthrough bleeding occurred. As a result, mestranol, that same year (1956), was developed and serendipitously identified as a very potent synthetic estrogen (and eventually as a prodrug of ethinylestradiol), given its name, and added back to the formulation. This resulted in Enovid by G. D. Searle & Company, the first oral contraceptive and a combination of 9.85 mg noretynodrel and 150 μg mestranol per pill.

Around 1969, mestranol was replaced by ethinylestradiol in most combined oral contraceptives due to widespread panic about the recently uncovered increased risk of venous thromboembolism with estrogen-containing oral contraceptives.

(2009). 9780080932927, Elsevier. . ISBN 9780080932927

The rationale was that ethinylestradiol was approximately twice as potent by weight as mestranol and hence that the dose could be halved, which it was thought might result in a lower incidence of venous thromboembolism. Whether this actually did result in a lower incidence of venous thromboembolism has never been assessed.

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Society and culture

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Generic names

Mestranol is the generic term of the drug and its , , , , , and , while mestranolo is its .

(2014). 9781475720853, Springer. . ISBN 9781475720853

(2025). 9783887630751, Taylor & Francis. . ISBN 9783887630751

(2012). 9789401144391, Springer Science & Business Media. . ISBN 9789401144391

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Brand names

Mestranol has been marketed under a variety of brand names, mostly or exclusively in combination with progestins, including Devocin, Enavid, Enovid, Femigen, Mestranol, Norbiogest, Ortho-Novin, Ortho-Novum, Ovastol, and Tranel among others.

(2013). 9780815518563, Elsevier. . ISBN 9780815518563

Today, it continues to be sold in combination with progestins under brand names including Lutedion, Necon, Norinyl, Ortho-Novum, and Sophia.

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Availability

Mestranol remains available only in the United States, the United Kingdom, Japan, and Chile. It is only marketed in combination with , such as norethisterone.

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Research

Mestranol has been studied as a male contraceptive and was found to be highly effective.

(1999). 9783642601071, Springer Science & Business Media. ISBN 9783642601071

At a dosage of 0.45 mg/day, it suppressed gonadotropin levels, reduced sperm count to zero within 4 to 6 weeks, and decreased libido, erectile function, and testicular size. Gynecomastia occurred in all of the men. These findings contributed to the conclusion that estrogens would be unacceptable as contraceptives for men.

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Environmental presence

In 2021, mestranol was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were collectively associated with estrogenic activity in in vitro.

Categories: Ethynyl Compounds, Estranes, Estrogen Ethers, Hormonal Contraception, Prodrugs, Synthetic Estrogens

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