Evolution of the pill

Evolution of the pill Dr Diana Mansour Clinical Director, Sexual Health Services, Newcastle and North Tyneside, UK Deanery Advisor, Faculty of Sexual...
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Evolution of the pill Dr Diana Mansour Clinical Director, Sexual Health Services, Newcastle and North Tyneside, UK Deanery Advisor, Faculty of Sexual and Reproductive Healthcare, UK

Evolution of COCs: key aspects Pill story Reduction in estrogen dose New progestogens

Changes in dosing schedule Regimens Phasic nature

What‟s in the pipeline? COCs=combined oral contraceptives

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Evolution of combined oral contraceptives

1. Pill story

Pill story

Mexican yam

John Rock

Katherine McCormick

Margaret Sanger

Gregory Pincus

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Pill development for use in treating infertility In 1952, John Rock gave increasing oral doses of estrogen (diethylstilbestrol 5–30 mg/day) and progesterone (50–300 mg/day) to 80 infertile women1 16% became pregnant within 4 months of discontinuation

In 1953, at Pincus' suggestion, Rock used a cyclical progesterone-only regimen for 20 days each month2 15.4% pregnancy rate after discontinuation of medication No amenorrhea but 20% had BTB (breakthrough bleeding), and ovulation suppressed in only 85% of the women

A more orally active progestogen was needed 1.Rock J, et al. Recent Prog Horm Res. 1957;13:323-39; 2.Pincus G, Postgrad Med. 1958 Dec;24(6):654-660

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First oral contraceptive Norethynodrel and norethindrone synthesized1 Contaminated with mestranol BTB occurred when mestranol reduced to less than 1%

0.15–0.23 mg mestranol combined with 10 mg norethynodrel ENOVID2 First contraceptive trial in Puerto Rico started in 19563

June 10, 1957, FDA approved ENOVID for gynecological disorders4

1.Diczfalusy E. Acta Obstet Gynecol Scand Suppl. 1982;105:7–15; 2.Pincus G, Postgrad Med. 1958 Dec;24(6):654-660; 3.Speroff L. Oral contraception. In: Clinical Gynecologic Endocrinology and Infertility; Philadelphia:Lippincott Williams & Wilkins, 2005: 861–942; 4.Junod SW, J Hist Med Allied Sci. 2002 Apr;57(2):117-160.

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First oral contraceptive June 23, 1960 – FDA approves ENOVID 10 mg for contraception1,2 FDA insisted lower dosage forms withdrawn from application Available for 3 years in USA At least half a million women had taken it for “menstrual disorders”

1.Junod SW, J Hist Med Allied Sci. 2002 Apr;57(2):117-60; 2.Speroff L. Oral contraception. In: Clinical Gynecologic Endocrinology and Infertility; Philadelphia:Lippincott Williams & Wilkins, 2005

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Evolution of combined oral contraceptives

2. Reduction in estrogen dose

Reduction in estrogen dose

FDA approval of ENOVID® Norethynodrel 10 mg + mestranol 150 mcg

German approval of Anovlar® Norethisterone 4 mg + ethinylestradiol 50 mcg

EMEA approval of Minesse® Gestodene 0.06 mg + ethinylestradiol 15 mcg

1960 1961

2000

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Reduction in dose, 1964 to 1988 Retail oral contraceptive prescriptions by estrogen dose, United States – marked reduction in COC estrogen dose

Gerstman B et al. Am J Pub Health 1991;81:90–96

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Estrogen dose and venous thromboembolism

Estrogen (ethinyl estradiol) dose 30–40 mcg

Odds ratio (95% CI) 1 (reference)

50 mcg

1.6 (0.9–2.8)

20 mcg

0.6 (0.4–0.9)*

*P=0.02

Lidegaard O, et al. Contraception. 2002;65:187–96.

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High-dose estrogen and cerebrovascular risk Cerebral thromboembolic risk with oral contraceptives according to estrogen content

3.5

Odds ratio

3 2.5 2 1.5 1 0.5 0

OC non-users

Lidegaard Ø et al. BMJ 1993;3:06956–963

Progestogen only

30–40 mcg estrogen

50 mcg estrogen

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Other side effects of estrogen at higher dose Ratio of COC-related symptoms with 35 mcg EE pill compared with 20 mcg EE pill Relative risk ratio

2 1.5

*

*

*

1 0.5 0

Bloating

Breast tenderness

Nausea

*P100%; „++‟ = >200%; „+++‟ = >400%; „++++‟ = >800%; „+/–‟ =