Mestranol

Last updated
Mestranol
Mestranol.svg
Mestranol molecule ball.png
Clinical data
Trade names Enovid, Norinyl, Ortho-Novum, others
Other namesEthinylestradiol 3-methyl ether; EEME; EE3ME; CB-8027; L-33355; RS-1044; 17α-Ethynylestradiol 3-methyl ether; 17α-Ethynyl-3-methoxyestra-1,3,5(10)-trien-17β-ol; 3-Methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17β-ol
AHFS/Drugs.com International Drug Names
MedlinePlus a601050
Routes of
administration 		By mouth [1]
Drug class Estrogen; Estrogen ether
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolites Ethinylestradiol
Elimination half-life Mestranol: 50 min [2]
EE: 7–36 hours [3] [4] [5] [6]
Identifiers
  • (8R,9S,13S,14S,17R)-17-ethynyl-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.707 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H26O2
Molar mass 310.437 g·mol−1
3D model (JSmol)
  • O(c1cc4c(cc1)[C@H]3CC[C@]2([C@@H](CC[C@]2(C#C)O)[C@@H]3CC4)C)C
  • InChI=1S/C21H26O2/c1-4-21(22)12-10-19-18-7-5-14-13-15(23-3)6-8-16(14)17(18)9-11-20(19,21)2/h1,6,8,13,17-19,22H,5,7,9-12H2,2-3H3/t17-,18-,19+,20+,21+/m1/s1 Yes check.svgY
  • Key:IMSSROKUHAOUJS-MJCUULBUSA-N Yes check.svgY
   (verify)

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. [1] [7] [8] [9] It is formulated in combination with a progestin and is not available alone. [9] It is taken by mouth. [1]

Contents

Side effects of mestranol include nausea, breast tension, edema, and breakthrough bleeding among others. [10] It is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. [11] Mestranol is a prodrug of ethinylestradiol in the body. [11]

Mestranol was discovered in 1956 and was introduced for medical use in 1957. [12] [13] It was the estrogen component in the first birth control pill. [12] [13] 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. [14] [9] Mestranol remains available only in a few countries, including the United States, United Kingdom, Japan, and Chile. [9]

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. [7] [8] [9] 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. [1]

Side effects

Pharmacology

Ethinylestradiol (EE), the active form of mestranol. Ethinylestradiol.svg
Ethinylestradiol (EE), the active form of mestranol.

Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylated in the liver (via O-Dealkylation) with a conversion efficiency of 70% (50 μg of mestranol is pharmacokinetically bioequivalent to 35 μg of ethinylestradiol). [15] [16] [11] 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. [17] [18]

The elimination half-life of mestranol has been reported to be 50 minutes. [2] The elimination half-life of the active form of mestranol, ethinylestradiol, is 7 to 36 hours. [3] [4] [5] [6]

The effective ovulation-inhibiting dosage of mestranol has been studied in women. [19] [20] [21] It has been reported to be about 98% effective at inhibiting ovulation at a dosage of 75 or 80 μg/day. [22] [21] [23] 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. [24]

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors
Estrogen Other names RBA Tooltip Relative binding affinity (%)a REP (%)b
ER ERα ERβ
Estradiol E2100100100
Estradiol 3-sulfate E2S; E2-3S ?0.020.04
Estradiol 3-glucuronide E2-3G ?0.020.09
Estradiol 17β-glucuronide E2-17G ?0.0020.0002
Estradiol benzoate EB; Estradiol 3-benzoate101.10.52
Estradiol 17β-acetate E2-17A31–4524 ?
Estradiol diacetate EDA; Estradiol 3,17β-diacetate ?0.79 ?
Estradiol propionate EP; Estradiol 17β-propionate19–262.6 ?
Estradiol valerate EV; Estradiol 17β-valerate2–110.04–21 ?
Estradiol cypionate EC; Estradiol 17β-cypionate ?c4.0 ?
Estradiol palmitate Estradiol 17β-palmitate0 ? ?
Estradiol stearate Estradiol 17β-stearate0 ? ?
Estrone E1; 17-Ketoestradiol115.3–3814
Estrone sulfate E1S; Estrone 3-sulfate20.0040.002
Estrone glucuronide E1G; Estrone 3-glucuronide ?<0.0010.0006
Ethinylestradiol EE; 17α-Ethynylestradiol10017–150129
MestranolEE 3-methyl ether11.3–8.20.16
Quinestrol EE 3-cyclopentyl ether ?0.37 ?
Footnotes:a = Relative binding affinities (RBAs) were determined via in-vitro displacement of labeled estradiol from estrogen receptors (ERs) generally of rodent uterine cytosol. Estrogen esters are variably hydrolyzed into estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented. b = Relative estrogenic potencies (REPs) were calculated from half-maximal effective concentrations (EC50) that were determined via in-vitro β‐galactosidase (β-gal) and green fluorescent protein (GFP) production assays in yeast expressing human ERα and human ERβ. Both mammalian cells and yeast have the capacity to hydrolyze estrogen esters. c = The affinities of estradiol cypionate for the ERs are similar to those of estradiol valerate and estradiol benzoate (figure). Sources: See template page.
Potencies of oral estrogens [data sources 1]
CompoundDosage for specific uses (mg usually) [lower-alpha 1]
ETD [lower-alpha 2] EPD [lower-alpha 2] MSD [lower-alpha 2] MSD [lower-alpha 3] OID [lower-alpha 3] TSD [lower-alpha 3]
Estradiol (non-micronized) 30≥120–3001206--
Estradiol (micronized) 6–1260–8014–421–2>5>8
Estradiol valerate 6–1260–8014–421–2->8
Estradiol benzoate -60–140----
Estriol ≥20120–150 [lower-alpha 4] 28–1261–6>5-
Estriol succinate -140–150 [lower-alpha 4] 28–1262–6--
Estrone sulfate 1260422--
Conjugated estrogens 5–1260–808.4–250.625–1.25>3.757.5
Ethinylestradiol 200 μg1–2280 μg20–40 μg100 μg100 μg
Mestranol300 μg1.5–3.0300–600 μg25–30 μg>80 μg-
Quinestrol 300 μg2–4500 μg25–50 μg--
Methylestradiol -2----
Diethylstilbestrol 2.520–30110.5–2.0>53
DES dipropionate -15–30----
Dienestrol 530–40420.5–4.0--
Dienestrol diacetate 3–530–60----
Hexestrol -70–110----
Chlorotrianisene ->100-->48-
Methallenestril -400----
Sources and footnotes:
  1. ↑ Dosages are given in milligrams unless otherwise noted.
  2. 1 2 3 Dosed every 2 to 3 weeks
  3. 1 2 3 Dosed daily
  4. 1 2 In divided doses, 3x/day; irregular and atypical proliferation.

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. [44] [45] [46] It is specifically a derivative of ethinylestradiol (17α-ethynylestradiol) with a methyl ether at the C3 position. [44] [45]

History

In April 1956, noretynodrel was investigated, in Puerto Rico, in the first large-scale clinical trial of a progestogen as an oral contraceptive. [12] [13] 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. [47] 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). [12] [13] When this impurity was removed, higher rates of breakthrough bleeding occurred. [12] [13] As a result, mestranol, that same year (1956), [48] 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. [12] [13] 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. [12] [13]

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. [14] 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. [14] Whether this actually did result in a lower incidence of venous thromboembolism has never been assessed. [14]

Society and culture

Generic names

Mestranol is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, USP Tooltip United States Pharmacopeia, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, and JAN Tooltip Japanese Accepted Name, while mestranolo is its DCIT Tooltip Denominazione Comune Italiana. [44] [45] [1] [9]

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. [7] [44] [49] [45] Today, it continues to be sold in combination with progestins under brand names including Lutedion, Necon, Norinyl, Ortho-Novum, and Sophia. [9]

Availability

Mestranol remains available only in the United States, the United Kingdom, Japan, and Chile. [9] It is only marketed in combination with progestins, such as norethisterone. [9]

Research

Mestranol has been studied as a male contraceptive and was found to be highly effective. [50] [51] [52] [53] 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. [50] [51] [53] [52] Gynecomastia occurred in all of the men. [50] [51] [53] [52] These findings contributed to the conclusion that estrogens would be unacceptable as contraceptives for men. [51]

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. [54]

Related Research Articles

<span class="mw-page-title-main">Combined oral contraceptive pill</span> Birth control method which is taken orally

The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. It is the oral form of combined hormonal contraception. The pill contains two important hormones: a progestin and estrogen. When taken correctly, it alters the menstrual cycle to eliminate ovulation and prevent pregnancy.

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

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 female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Quinestrol</span> Pharmaceutical drug

Quinestrol, also known as ethinylestradiol cyclopentyl ether (EECPE), sold under the brand name Estrovis among others, is an estrogen medication which has been used in menopausal hormone therapy, hormonal birth control, and to treat breast cancer and prostate cancer. It is taken once per week to once per month by mouth.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

<span class="mw-page-title-main">Estradiol valerate</span> Chemical compound

Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norelgestromin</span> Pharmaceutical drug

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women. The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Norgestrel</span> Progestin medication used for birth control

Norgestrel is a progestin which is used in birth control pills sold under the brand name Ovral in combination with the estrogen ethinylestradiol and Opill by itself. It is also used in menopausal hormone therapy. It is taken by mouth.

<span class="mw-page-title-main">Etynodiol diacetate</span> Chemical compound

Etynodiol diacetate, or ethynodiol diacetate, sold under the brand name Ovulen among others, is a progestin medication which is used in birth control pills. The medication is available only in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

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 low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.

Birth control pills come in a variety of formulations. The main division is between combined oral contraceptive pills, containing both estrogens and synthetic progestogens (progestins), and progestogen only pills. Combined oral contraceptive pills also come in varying types, including varying doses of estrogen, and whether the dose of estrogen or progestogen changes from week to week.

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Noretynodrel</span> Chemical compound

Noretynodrel, or norethynodrel, sold under the brand name Enovid among others, is a progestin medication which was previously used in birth control pills and in the treatment of gynecological disorders but is now no longer marketed. It was available both alone and in combination with an estrogen. The medication is taken by mouth.

<span class="mw-page-title-main">Estradiol benzoate butyrate</span> Chemical compound

Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide, a progestin, and is used specifically as a combined injectable contraceptive. EBB is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.

<span class="mw-page-title-main">Estrogen (medication)</span> Type of medication

An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

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