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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

The History of Hormonal Contraception

Johanna F Perlmutter, M.D.

Assistant Professor Obstetrics, Gynecology and Reproductive Medicine

Harvard Medical School

slide2
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.
slide3
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.
slide4
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.
slide5
1929
  • The human sex hormone estrogen is isolated and identified by Edward Doisy at Washington University in St. Louis.
trends in hormonal contraceptive development over the years
Trends in Hormonal Contraceptive Development Over the Years
  • Decreased estrogen dose
  • Decreased progestin dose
  • Newer progestational agents
  • New Delivery Systems
reducing oc side effects a balancing act

Estrogen Dose

Minimizing Estrogen Side Effects

Enhancing Cycle Control

  • BTB/BTS
  • Amenorrhea
  • Breast Tenderness
  • Bloating
  • Nausea
Reducing OC Side Effects: A Balancing Act
contraception legal obstacles and effect on physicians
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
major events in the birth control movement and pill development
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”
setting for creation of the pill
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
clinical trials of the pill
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
pill approval steps
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
side effects of the pill
Side Effects of the Pill
  • Nausea
  • Emesis
  • Bloatedness
  • Breast Tenderness
the estrogen dose pendulum32

1960

1962

150 µg

1968

1969

100 µg

80 µg

50 µg

The Estrogen Dose Pendulum
health issues concerning the pill
Health Issues concerning the Pill
  • Serious threats to health
    • VTE
    • Stroke
    • MI
the estrogen dose pendulum34

1991

20 µg

2002

1974

25 µg

35-30 µg

The Estrogen Dose Pendulum

1968

1969

80 µg

50 µg

the evolution of ocs
The Evolution Of OCs

Mini-Pill

Sequentials

Combination Monophasics

Combination Multiphasics

New Progestins

?

1960s

1970s

1980s

1990s

2000s

health issues concerning the pill37
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
therapeutic uses of ocs
Therapeutic Uses of OCs
  • Dysfunctional uterine bleeding
  • Persistent anovulation
  • Ovarian failure
  • Dysmenorrhea
  • Mittelschmerz
  • Endometriosis
  • Acne
  • Control of bleeding with blood dyscrasias
noncontraceptive health benefits of oral contraceptives
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
classification of progestins

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
slide41

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.

progestin evolution
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)
slide43

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.

hormonal contraceptive methods
Hormonal Contraceptive Methods

Implants

Injectables

LNG IUS

Patch

Vaginal Ring

levonorgestrel intrauterine system lng ius
Levonorgestrel Intrauterine System (LNG IUS)

Steroidreservoir

32 mm

levonorgestrel 20 mcg/day

single contraceptive implant design

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

single contraceptive implant description

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
single rod implant summary
Single Rod ImplantSummary
  • High efficacy
  • Long term reversible method
  • Hormonal side effects
  • Requires insertion/removal
  • Irregular bleeding
  • Rapid onset of action
other implant options
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
contraceptive vaginal rings
Contraceptive Vaginal Rings
  • Long development process – first published data in 1970 (Mishell/Lumkin)
  • Several rings in development
characteristics of vaginal contraceptive rings
Characteristics of Vaginal 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
etonogestrel ethinyl estradiol vaginal ring54

Vaginal Ring

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.

summary

Vaginal Ring

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.

monthly injectable
Monthly Injectable
  • Currently not available
  • Will probably not become available in the near future
quarterly injectable
Quarterly Injectable
  • 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
quarterly injection tips
Quarterly Injection Tips
  • 12 month failure rate 0-0.7/HWY
  • Dosage does not need to be adjusted for body weight
estrogen and progestin delivery

Contraceptive Patch

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.

ngmn and ee levels patch vs oc

Contraceptive Patch

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.

slide62

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).

new oral contraceptives
New Oral Contraceptives
  • Chewable oral contraceptive
  • Newer dose regimes for pills
    • 24/4 oral contraceptives
    • 90/7 Continuous hormones
    • Yearly
emergency contraceptives
Emergency Contraceptives
  • 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
emergency contraceptive options in the united states
Emergency Contraceptive Options 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
emergency contraceptive effectiveness
Emergency Contraceptive Effectiveness
  • 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

progestin only emergency contraceptive pills
Progestin-Only Emergency Contraceptive Pills
  • 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
copper iud insertion
Copper IUD Insertion
  • 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%