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The History of Hormonal Contraception

The History of Hormonal Contraception Johanna F Perlmutter, M.D. Assistant Professor Obstetrics, Gynecology and Reproductive Medicine Harvard Medical School 1827

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The History of Hormonal Contraception

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  1. The History of Hormonal Contraception Johanna F Perlmutter, M.D. Assistant Professor Obstetrics, Gynecology and Reproductive Medicine Harvard Medical School

  2. 1827 • Discovery of the existence of the female egg -- the ovum. Prior to this, it is only known that semen must enter the female body for conception to occur.

  3. 1843 • Scientists learn that conception occurs in human reproduction when the sperm enters the female egg. Prior to this it was assumed that men created life and women just provided the home for it.

  4. 1928 • Almost 30 years after the discovery of hormones, scientists at the University of Rochester in New York identify progesterone, the ovarian hormone. They conclude that this hormone plays a crucial role in preparing the womb for and sustaining a pregnancy.

  5. 1929 • The human sex hormone estrogen is isolated and identified by Edward Doisy at Washington University in St. Louis.

  6. Trends in Hormonal Contraceptive Development Over the Years • Decreased estrogen dose • Decreased progestin dose • Newer progestational agents • New Delivery Systems

  7. Estrogen Dose Minimizing Estrogen Side Effects Enhancing Cycle Control • BTB/BTS • Amenorrhea • Breast Tenderness • Bloating • Nausea Reducing OC Side Effects: A Balancing Act

  8. Contraception: Legal Obstacles and Effect on Physicians • 1873: Anthony Comstock’s Society for Suppression of Vice • 1944: Massachusetts voters refuse proposal to relax ban on birth control • Many texts on contraception available only to physicians in early 1900s • Disclaimer: contraception only for health reasons

  9. Major Events in the Birth Control Movement and Pill Development • 1914: Sanger arrested, dissemination information • 1915: National Birth Control League formed (NY) • 1916: Sanger opens clinic in Brooklyn • 1918; Marie Stopes opens clinic in London • 1927: Sanger’s World Population Congress • 1950: McCormick writes to Sanger regarding funding of contraceptive research • 1951; PPFA sponsors 200 clinics; Sanger meeting with Stone and Pincus for “perfect contraceptive”

  10. Setting for “Creation” of the Pill • Gregory Pincus’ lab: Worcester Foundation for Experimental Biology • McCormick agrees to pay Pincus $125,000 to develop physiologic contraceptive that could be taken like aspirin • Pincus and Harvard gynecologist John Rock agree to test pill to prevent ovulation • Syntex (1951) and Searle(1953) apply for patents for oral progesterone agents

  11. Clinical Trials of the Pill US • 1954: Rock conducts 1st human trials with (unstated) goal of prohibiting ovulation: 50 women Outside US • 1956: Puerto Rico trials • 1957: Haiti and Mexico City trials • Tested in over 20,000 women

  12. Pill Approval Steps • 1957: FDA approves norethindrone • 1960: Searle receives FDA approval for norethynodrel (Enovid) for contraception • Syntex contracts with Ortho giving it marketing rights to norethindrone • 1962: Ortho receives FDA approval for norethindrone for contraception • Marketed as Ortho-Novum

  13. 1960 1962 150 µg 100 µg The Estrogen Dose Pendulum

  14. Side Effects of the Pill • Nausea • Emesis • Bloatedness • Breast Tenderness

  15. 1960 1962 150 µg 1968 1969 100 µg 80 µg 50 µg The Estrogen Dose Pendulum

  16. Health Issues concerning the Pill • Serious threats to health • VTE • Stroke • MI

  17. 1991 20 µg 2002 1974 25 µg 35-30 µg The Estrogen Dose Pendulum 1968 1969 80 µg 50 µg

  18. The Evolution Of OCs Mini-Pill Sequentials Combination Monophasics Combination Multiphasics New Progestins ? 1960s 1970s 1980s 1990s 2000s

  19. Health Issues concerning the Pill • Serious threats to health • VTE • Stroke • MI • Role of dose • Reduction in doses of hormones • Estrogen: 150 mcg →100 mcg →50 mcg • Progestin: 10 mg → 2.5 mg → 0.5 mg

  20. Therapeutic Uses of OCs • Dysfunctional uterine bleeding • Persistent anovulation • Ovarian failure • Dysmenorrhea • Mittelschmerz • Endometriosis • Acne • Control of bleeding with blood dyscrasias

  21. OCs decrease: Ovarian Cancer Endometrial Cancer Salpingitis/PID Benign Breast Disease Dysmenorrhea Ectopic Pregnancy Functional ovarian cysts OCs increase: Menstrual regularity Bone density Noncontraceptive Health Benefits of Oral Contraceptives

  22. Progestins Spironalactone C-21 progestins 19-nor testosterones Pregnanes Estranes Gonanes • Drospirenone • Norgestrel • Levonorgestrel • Norgestimate • Desogestrel • Gestodene • Norethindrone • Noreth acetate • Ethynodiol diacetate • Lynestrenol • Norethynodrel • Medroxyprogesterone acetate • Megestrol acetate • Cyproterone acetate Classification of Progestins

  23. Cycle Control: Impact of Estrogen Dose 20-µg EE/1 mg NETA (n=102/459) 30-µg EE/1.5 mg NETA (n=117/494) 50-µg EE/1 mg NETA (n=100/441) P=0.005 50 44.3 % Patients With BTB/BTS Over 4 Treatment Cycles 40 27.1 30 24 23.4 20.3 18.4 20 13.6 9.8 8.7 10 0 BTB Spotting BTB/Spotting Appel TB, Armon KA, Birdsall C, et al. Contraception. 1987;35:523-532.

  24. Progestin Evolution • Dose reductions • From 10 mg to between 0.15–1 mg • Development of more selective agents (less androgenic /  P vs A ratio) • Norgestimate (NGM) • Desogestrel (DSG) • Drospirenone (DRSP)

  25. Cycle Control: Impact of Progestin Type 20-µg EE/NETA n=89 20-µg EE/LNG n=84 * * % Subjects With BTB/BTS Cycle Randomized, open-label, multicenter study N=173; *P<0.05 Delconte A, Loffer F, Grubb G. Contraception. 1999;59:187-193.

  26. Hormonal Contraceptive Methods Implants Injectables LNG IUS Patch Vaginal Ring

  27. Overview Comparison of Contraceptive Methods

  28. Levonorgestrel Intrauterine System (LNG IUS) Steroidreservoir 32 mm levonorgestrel 20 mcg/day

  29. Single-Rod Implant 2.0 mm Core 40 mm Single Contraceptive Implant: Design Rate-controlling membrane (0.06 mm) Core: 40% Ethylene vinyl acetate 60% Etonogestrel Membrane: 100% Ethylene vinyl acetate

  30. Single-Rod Implant Single Contraceptive Implant: Description • Contains 68 mg of etonogestrel (3-keto-desogestrel), the active metabolite of desogestrel, and comes in disposable sterile inserter • Release rate • 60 micrograms/d initially • 25-30 micrograms/d by end of 3rd year • Inhibits ovulation during the entire treatment period • Effective for 3 years

  31. Single Rod ImplantSummary • High efficacy • Long term reversible method • Hormonal side effects • Requires insertion/removal • Irregular bleeding • Rapid onset of action

  32. Other Implant Options • Jadella is a 2 rod system developed by the Population Counsel and manufactured by Schering. It is a 43mm x 2.5mm, levonorgestrel releasing system for up to 5 years use. This product was FDA approved in 1996

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