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 A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural product, natural female sex hormone progesterone in the body. A progestin is a ''synthetic co ...

and is not available alone. It is taken by mouth. Side effects of mestranol include nausea,

breast tension Breast tension is a constellation of symptoms involving the breasts including: * Breast pain * Breast engorgement Breast engorgement occurs in the mammary glands due to expansion and pressure exerted by the synthesis and storage of breast m ...

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

, and

breakthrough bleeding Intermenstrual bleeding, previously known as metrorrhagia, is uterine bleeding at irregular intervals, particularly between the expected menstrual periods. It is a cause of vaginal bleeding. In some women, menstrual spotting between periods occ ...

among others. It is an estrogen, or an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the estrogen receptors, the biological target of estrogens like estradiol. Mestranol is a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

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 Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...

, and Chile.

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 Mestranol/norethisterone (brand names Norethin, Noriday, Norinyl, Norquen, Ortho-Novum, others) is a combination of the estrogen ethinylestradiol and the progestin norethisterone (norethindrone) which was introduced in 1963 and was the second co ...

(brand names ''Ortho-Novum'', ''Norinyl''), and is still in use today. In addition to its use as an oral contraceptive, mestranol has been used as a component of menopausal hormone therapy for the treatment of menopausal

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

Side effects

Pharmacology

Mestranol is a biologically inactive

of ethinylestradiol to which it is demethylated in the liver (via O-Dealkylation) with a conversion efficiency of 70% (50 μg of mestranol is

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

ally bioequivalent to 35 μg of ethinylestradiol). 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. The elimination half-life of mestranol has been reported to be 50 minutes. The elimination half-life of the active form of mestranol, ethinylestradiol, is 7 to 36 hours. The effective ovulation-inhibiting dosage of mestranol has been studied in women. It has been reported to be about 98% effective at inhibiting ovulation at a dosage of 75 or 80 μg/day. 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.

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 Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

estrane

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

and a derivative of estradiol. It is specifically a derivative of ethinylestradiol (17α-ethynylestradiol) with a

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

ether at the C3 position.

History

In April 1956, noretynodrel was investigated, in Puerto Rico, in the first large-scale clinical trial of a

progestogen Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the body. ...

as an oral contraceptive. 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. It was discovered early into the study that the initial

chemical syntheses As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In moder ...

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

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. 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.

Society and culture

Generic names

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

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

Availability

Mestranol remains available only in the United States, the United Kingdom,

, and Chile. It is only marketed in combination with

s, such as

norethisterone Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both ...

Research

Mestranol has been studied as a male contraceptive and was found to be highly effective. 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 An erection (clinically: penile erection or penile tumescence) is a physiological phenomenon in which the penis becomes firm, engorged, and enlarged. Penile erection is the result of a complex interaction of psychological, neural, vascular, a ...

, and

testicular size A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

. Gynecomastia occurred in all of the men. These findings contributed to the conclusion that estrogens would be unacceptable as contraceptives for men.

Environmental presence

In 2021, mestranol was one of the 12 compounds identified in sludge samples taken from 12

wastewater treatment Wastewater treatment is a process used to remove contaminants from wastewater and convert it into an effluent that can be returned to the water cycle. Once returned to the water cycle, the effluent creates an acceptable impact on the environme ...

plants in California that were collectively associated with

estrogenic Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...

activity in in vitro.

References

{{Estrogen receptor modulators Ethynyl compounds Estranes Estrogen ethers Hormonal contraception Prodrugs Synthetic estrogens