Mestranol


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.
Side effects 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. 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.

Medical uses

Mestranol was employed as the estrogen component in many of the first oral contraceptives, such as mestranol/noretynodrel and mestranol/norethisterone, 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 symptoms.

Side effects

Pharmacology

Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylated in the liver with a conversion efficiency of 70%. It has been found to possess 0.1 to 2.3% of the relative binding affinity of estradiol 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 or as 17α-ethynyl-3-methoxyestra-1,3,5-trien-17β-ol, is a synthetic estrane steroid and a derivative of estradiol. It is specifically a derivative of ethinylestradiol with a methyl 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 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 of noretynodrel had been contaminated with small amounts of the 3-methyl ether of ethinylestradiol. When this impurity was removed, higher rates of breakthrough bleeding occurred. As a result, mestranol, that same year, was developed and serendipitously identified as a very potent synthetic estrogen, 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, Japan, and Chile. It is only marketed in combination with progestins, such as norethisterone.

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, 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.