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Mestranol/noretynodrel
	A 10 mg bottle of Enovid, the first mestranol/noretynodrel medication
Combination of
Mestranol	Estrogen
Norethynodrel	Progestogen
Clinical data
Trade names	Enavid, Enovid
Routes of; administration	By mouth
ATC code	G03FA09 (WHO) ;
Legal status
Legal status	Discontinued;
Identifiers
CAS Number	8015-30-3;
PubChem CID	66444;
CompTox Dashboard (EPA)	DTXSID6020563 ;

Mestranol/norethynodrel was the first combined oral contraceptive pill (COCP) being mestranol and norethynodrel. It sold as Enovid in the United States and as Enavid in the United Kingdom. Developed by Gregory Pincus at G. D. Searle & Company, it was first approved on June 10, 1957, by the U.S. Food and Drug Administration for treatment of menstrual disorders.^[1] The FDA approved an additional indication for use as a contraceptive on June 23, 1960, though it only became legally prescribable nationwide and regardless of the woman's marital status after Eisenstadt v. Baird in 1972.^[2]^[3]^[4]^[5] In 1961, it was approved as a contraceptive in the UK and in Canada.^[6]^[7]

Medical uses

Mestranol/noretynodrel was indicated in the treatment of gynecological and menstrual disorders. Originally it was not legal to use contraception so it was marketed for menstrual relief with the side effect of inability to conceive.^[8] It has also been used to suppress lactation and to treat endometriosis in women.^[9]^[10]

Available forms

The medication contained 0.15 mg mestranol and 10 mg noretynodrel.^[8] Additional formulations containing 0.075 mg mestranol and 5 mg noretynodrel as well as 0.1 mg mestranol and 2.5 mg noretynodrel were subsequently introduced.^[8] One formulation also contained 0.075 mg mestranol and 3 mg noretynodrel.^[8]

History

Creation

Enovid was first manufactured when scientists isolated progesterone from diosgenin, then removed 19-carbon from the molecule. This new form of progesterone had higher progestational activity, which prevented pregnancy.^[11]

Social impact

Initially sold in 1957, Enovid was first marketed as a treatment for gynecological disorders. In 1960, its sale as an oral contraceptive was approved by the FDA. This was seen as a major improvement to contraceptives as a whole, being preferred over other methods such as condoms and diaphragms.^[12]

Complications and legal proceedings

The first published case report of a blood clot and pulmonary embolism in a woman using Enavid (Enovid 10 mg in the U.S.) at a dose of 20 mg/day did not appear until November 1961, four years after its approval, by which time it had been used by over one million women.^[3]^[13]^[14] It would take almost a decade of epidemiological studies to conclusively establish an increased risk of venous thrombosis in oral contraceptive users and an increased risk of stroke and myocardial infarction in oral contraceptive users who smoke or have high blood pressure or other cardiovascular or cerebrovascular risk factors.^[15] These risks of oral contraceptives were dramatized in the 1969 book The Doctors' Case Against the Pill by feminist journalist Barbara Seaman who helped arrange the 1970 Nelson Pill Hearings called by Senator Gaylord Nelson.^[16] The hearings were conducted by senators who were all men and the witnesses in the first round of hearings were all men, leading Alice Wolfson and other feminists to protest the hearings and generate media attention.^[17] Their work led to mandating the inclusion of patient package inserts with oral contraceptives to explain their possible side effects and risks to help facilitate informed consent.^[18]^[19]^[20] Today's standard dose oral contraceptives contain an estrogen dose that is one third lower than the first marketed oral contraceptive and contain lower doses of different, more potent progestins in a variety of formulations.^[15]^[17]^[21]

Enovid was discontinued in the U.S. in 1988, along with other first-generation high-estrogen COCPs.^[22]^[23]

References

^ Junod SW (1998). "FDA's Approval of the First Oral Contraceptive, Enovid". Histories of Product Regulation. Update (bimonthly publication of the Food and Drug Law Institute). U.S. Food and Drug Administration. Archived from the original on 14 January 2012.
^ "FDA Approved Drug Products". FDA.
^ ^a ^b Junod SW, Marks L (April 2002). "Women's trials: the approval of the first oral contraceptive pill in the United States and Great Britain". Journal of the History of Medicine and Allied Sciences. 57 (2): 117–160. doi:10.1093/jhmas/57.2.117. PMID 11995593.
^ Tone A (2001). Devices & Desires: A History of Contraceptives in America. New York: Hill and Wang. ISBN 0-8090-3817-X.
^ Watkins ES (1998). On the Pill: A Social History of Oral Contraceptives, 1950–1970. Baltimore: Johns Hopkins University Press. ISBN 0-8018-5876-3.
^ "ANNOTATIONS". British Medical Journal. 2 (5258): 1007–1009. October 1961. doi:10.1136/bmj.2.3490.1009. PMC 1970146. PMID 20789252.
^ "Medical News". Br Med J. 2 (5258): 1032–1034. October 14, 1961. doi:10.1136/bmj.2.5258.1032. PMC 1970195.
^ ^a ^b ^c ^d Marks L (2010). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 75, 77–78. ISBN 978-0-300-16791-7.
^ Vorherr H (2 December 2012). "Suppression of Laction". The Breast: Morphology, Physiology, and Lactation. Elsevier Science. pp. 202–. ISBN 978-0-323-15726-1.
^ Olive DL (29 November 2004). "Medical therapy of endometriosis". In Olive D (ed.). Endometriosis in Clinical Practice. CRC Press. pp. 246–. ISBN 978-0-203-31939-0.
^ Hampson, Elizabeth (2023-01-01). "Oral contraceptives in the central nervous system: Basic pharmacology, methodological considerations, and current state of the field". Frontiers in Neuroendocrinology. 68: 101040. doi:10.1016/j.yfrne.2022.101040. ISSN 0091-3022. PMID 36243109.
^ Junod, Suzanne (2002-04-01). "Women's Trials: The Approval of the First Oral Contraceptive Pill in the United States and Great Britain". Journal of the History of Medicine and Allied Sciences. 57 (2): 117–160. doi:10.1093/jhmas/57.2.117. PMID 11995593. Retrieved 2023-11-29.
^ Winter IC (March 1965). "The incidence of thromboembolism in Enovid users". Metabolism. 14 (Supplement): 422–428. doi:10.1016/0026-0495(65)90029-6. PMID 14261427.
^ Jordan WM, Anand JK (November 18, 1961). "Pulmonary embolism". Lancet. 278 (7212): 1146–1147. doi:10.1016/S0140-6736(61)91061-3.
^ ^a ^b Marks L (2001). Sexual Chemistry: A History of the Contraceptive Pill. New Haven: Yale University Press. ISBN 0-300-08943-0.
^ Seaman B (1969). The Doctors' Case Against the Pill. New York: P. H. Wyden. ISBN 0-385-14575-6.
^ ^a ^b Watkins ES (1998). On the Pill: A Social History of Oral Contraceptives, 1950–1970. Baltimore: Johns Hopkins University Press. ISBN 0-8018-5876-3.
^ FDA (June 11, 1970). "Statement of policy concerning oral contraceptive labeling directed to users". Federal Register. 35 (113): 9001–9003.
^ FDA (January 31, 1978). "Oral contraceptives; requirement for labeling directed to the patient". Federal Register. 43 (21): 4313–4334.
^ FDA (May 25, 1989). "Oral contraceptives; patient package insert requirement". Federal Register. 54 (100): 22585–22588.
^ Speroff L, Darney OD (2005). "Oral Contraception". A Clinical Guide for Contraception (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 21–138. ISBN 0-7817-6488-2.
^ "Searle, 2 others to stop making high-estrogen pill". St. Louis Post-Dispatch. Reuters News Service. 1988-04-15. pp. 7D. Retrieved 2009-08-29.
^ "High-estrogen 'pill' going off market". San Jose Mercury News. 1988-04-15. Retrieved 2009-08-29.