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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 l.jpg

The History of Hormonal Contraception

Johanna F Perlmutter, M.D.

Assistant Professor Obstetrics, Gynecology and Reproductive Medicine

Harvard Medical School


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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.


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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.


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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.


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1929

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


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Trends in Hormonal Contraceptive Development Over the Years

  • Decreased estrogen dose

  • Decreased progestin dose

  • Newer progestational agents

  • New Delivery Systems


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Estrogen Dose

Minimizing Estrogen Side Effects

Enhancing Cycle Control

  • BTB/BTS

  • Amenorrhea

  • Breast Tenderness

  • Bloating

  • Nausea

Reducing OC Side Effects: A Balancing Act


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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


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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”


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Setting for “Creation” of the Pill Development

  • 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


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Clinical Trials of the Pill Development

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


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Pill Approval Steps Development

  • 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


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1960 Development

1962

150 µg

100 µg

The Estrogen Dose Pendulum


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Side Effects of the Pill Development

  • Nausea

  • Emesis

  • Bloatedness

  • Breast Tenderness


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1960 Development

1962

150 µg

1968

1969

100 µg

80 µg

50 µg

The Estrogen Dose Pendulum


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Health Issues concerning the Pill Development

  • Serious threats to health

    • VTE

    • Stroke

    • MI


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1991 Development

20 µg

2002

1974

25 µg

35-30 µg

The Estrogen Dose Pendulum

1968

1969

80 µg

50 µg


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The Evolution Of OCs Development

Mini-Pill

Sequentials

Combination Monophasics

Combination Multiphasics

New Progestins

?

1960s

1970s

1980s

1990s

2000s


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Health Issues concerning the Pill Development

  • 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


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Therapeutic Uses of OCs Development

  • Dysfunctional uterine bleeding

  • Persistent anovulation

  • Ovarian failure

  • Dysmenorrhea

  • Mittelschmerz

  • Endometriosis

  • Acne

  • Control of bleeding with blood dyscrasias


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OCs decrease: Development

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


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Progestins Development

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


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Cycle Control: Development

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.


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Progestin Evolution Development

  • 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)


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Cycle Control: DevelopmentImpact 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.


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Hormonal DevelopmentContraceptive Methods

Implants

Injectables

LNG IUS

Patch

Vaginal Ring


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Overview Development

Comparison of Contraceptive Methods


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Levonorgestrel Intrauterine System (LNG IUS) Development

Steroidreservoir

32 mm

levonorgestrel 20 mcg/day


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Single-Rod Implant Development

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


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Single-Rod Implant Development

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


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Single Rod Implant DevelopmentSummary

  • High efficacy

  • Long term reversible method

  • Hormonal side effects

  • Requires insertion/removal

  • Irregular bleeding

  • Rapid onset of action


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Other Implant Options Development

  • 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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Contraceptive Vaginal Rings Development

  • Long development process – first published data in 1970 (Mishell/Lumkin)

  • Several rings in development


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Vaginal Ring Development

Etonogestrel/Ethinyl Estradiol Vaginal Ring


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Characteristics of DevelopmentVaginal Contraceptive Rings

  • Convenient, reliable, easily reversible

  • Rapid absorption, sustained delivery of low-dose hormones

  • Under user’s control

  • Unrelated to intercourse

  • No “first-pass” hepatic effect

  • Provides good cycle control

  • Safe and well-tolerated


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Vaginal Ring Development

Etonogestrel/Ethinyl Estradiol Vaginal Ring

Progestin: Etonogestrel: 120 µg/day

Estrogen: Ethinyl estradiol: 15 µg/day

Pregnancy rate 0.65 per 100 woman–years

Roumen FJ, et al. Hum Reprod. 2001;16(3):469-475.


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Vaginal Ring Development

Summary

  • Good cycle control

    • Irregular bleeding was rare (2.6% - 6.4% of evaluable cycles)

    • Withdrawal bleeding occurred (97.9% - 99.4% of evaluable cycles)

  • Compliance with the regimen was met in 90.8% of cycles

Roumen FJ, et al. Hum Reprod. 2001;16(3):469-475.


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Monthly Injectable Development

  • Currently not available

  • Will probably not become available in the near future


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Quarterly Injectable Development

  • Medroxyprogesterone acetate

    • IM injection of 150 mg

    • SQ injection of 104 mg

    • Warning

      • Reduces bone density

        • Partial recovery of bone loss occurs after discontinuation of medication

      • Should not be used long term use (> 2 years) unless other methods of contraceptive are inadequate


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Quarterly Injection Tips Development

  • 12 month failure rate 0-0.7/HWY

  • Dosage does not need to be adjusted for body weight


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Contraceptive Patch Development

Application of the Transdermal Patch on Abdomen


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Contraceptive Patch Development

Estrogen and Progestin Delivery

  • Patch contains 6.00 mg norelgestromin and 0.75 mg ethinyl estradiol

  • Delivers continuous systemic doses of hormones

    • 150 µg norelgestromin (NGMN)

      +

    • 20 µg ethinyl estradiol (EE)

  • Direct comparisons to oral contraceptive delivery doses cannot be made

Per day

Abrams L, et al. FASEB J. 2000;14:A1479.


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Contraceptive Patch Development

NGMN and EE LevelsPatch vs OC*

150

2.1

Patch EE

Patch NGMN

125

1.8

EE

NGMN

100

1.5

Reference Range

EE Serum Concentration (pg/mL)

NGMN Serum Concentration (ng/mL)

75

1.2

Patch Removed

.9

50

25

.6

0

.3

0

1

2

3

4

5

6

7

8

9

10

11

12

Days

*Noncomparative data

Abrams L, et al. Contraception. 2001;64:287-294.


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Fig. 2. Mean EE C-T curves for subjects (ASPE group) treated with NuvaRing (n=8), the transdermal contraceptive patch (n=6) and the COC (n=8).


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New Oral Contraceptives treated with NuvaRing (

  • Chewable oral contraceptive

  • Newer dose regimes for pills

    • 24/4 oral contraceptives

    • 90/7 Continuous hormones

    • Yearly


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Emergency Contraception treated with NuvaRing (


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Emergency Contraceptives treated with NuvaRing (

  • Prevent pregnancy after unprotected intercourse

  • Inhibit ovulation, fertilization, or implantation

  • Do not cause an abortion

  • Will not interrupt an established pregnancy

  • Do not protect against STIs


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Emergency Contraceptive Options treated with NuvaRing (in the United States

  • Emergency use of oral contraceptive pills containing only LNG (only dedicated oral product available

  • Emergency use of oral contraceptive pills containing EE and LNG or norgestrel

  • Emergency Copper-T IUD insertion


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Emergency Contraceptive Effectiveness treated with NuvaRing (

  • 80 (8%) will become pregnant without treatment

  • 20 (2%) will become pregnant following use of combined ECPs (a 75% reduction)

  • 10 (1%) will become pregnant following use of progestin-only ECPs (an 88% reduction)

  • 1 (0.1%) will become pregnant following emergency IUD insertion (a 99% reduction)

If 1000 women have unprotected sex once in the second or third week of their cycle


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Progestin-Only Emergency Contraceptive Pills treated with NuvaRing (

  • Dedicated product (Plan B) containing only LNG, 1 tablet/dose

  • Birth control pills containing only LNG, 20 tablets/dose

  • 2 doses of LNG 750 mcg (total of 1.5 mg)

  • First dose ASAP after unprotected coitus

    • Should be within 72 hours second dose 12 hours later

    • Take both pills (doses) at same time

    • Take each pill (dose) 24 hours apart

  • Less nausea and vomiting than combined ECPs


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Copper IUD Insertion treated with NuvaRing (

  • Copper-T 380A IUD

  • Insertion within 5 days after unprotected intercourse

  • 10 more years of highly effective contraception

  • Reduces the risk of pregnancy by 99%


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