Oral contraception

22. Oral contraception

부산백병원R3 강영미

History

• Ludwig Haberlandt, in the 1920s• First demonstrated that ovarian extracts given ora

lly could prevent fertility(in mice)• By 1931, proposed administration of hormones f

or birth control• Early death in 1932, at age 47, brought an end to

this effort

Russell Marker(1)

Eccentric chemist Interested in solving the problem of producing abu

ndant and cheap amounts of progesterone Required ovaries from 2500 pregnant pigs to prod

uce 1 mg of progesterone In 1939, devised method(called Marker degradatio

n) to convert sapogenin molecule into progestin Find plants that contained sufficient amounts of di

osgenin, plant steroid(sapogenin)

Russell Marker(2)

Too small to provide sufficient amounts for commercial production

With two partners, formed company in 1944, called syntex

In 1970, recognized Marker’s work

Carl Djerassi

Head a reserch group to concentrate on the synthesis of cortisone

Turned their attention to sex steroids Discovered that removal of the 19-carbon from ya

m-derived progesterone increased progestational activity of the molecule

In 1951, norethindrone was synthesized Norethynodrel, actually first orally active progestati

onal agent

Gregory Pincus(1)

Performed studies of meiotic maturation in mammalian oocytes, in both rabbit and human oocytes

In 1934, achievement of in vitro fertilization of rabbit eggs -> depicted as evil scientist

With his friend, Hoagland and M-C Chang Establishment of the Worcester Foundation for Experimen

tal Biology, in 1944

Gregory Pincus(2)

Attributed their interest in contraception for the world’s population problem, in 1951

Involve physician, John Rock, chief of gynecology and obstetrics at Harvard ; human experiments would be necessary

Using oocytes from oophorectomies, reported in vitro fertilization in 1944, first demonstration of fertilization of human oocytes in vitro

Gregory Pincus(3)

In 1956, first human trial was performed 50 pts, 10-40mg of synthetic progestin for 20 days each

month All failed to ovulate drug treatment Became pregnant after discontinuing medicaiton

In 1960, FDA for acceptance of oral contraception

Pharmacology of Steroid Contraception

Estrogen component of combination oral contraceptives(1)

Estradiol Most potent natural estrogen Major estrogen secreted by ovaries

Major obstacle to use of sex steroids for contraception Inactivity of compounds when given orally In 1938, addition of ethinyl group at the 17 positio

n ; orally active Ethinyl estradiol ; very potent oral estrogen


The other estrogen ; 3-methyl ether of ethinyl estradiol, mestranol

Mestranol weaker than ethinyl estradiol Must first be converted to ethinyl estradiol in body


Metabolism of ethinyl estradiol Varies from individual to individual

Estrogen content(dosage) of pill Major clinical importance Thrombosis ; one of most serious side effects of pi

ll Related to estrogen and dose related

Progestin component of combination oral contraception(1)

At the end of the 1930s Ethisterone, orally active derivative of testosterone

In 1951, removal of 19-carbon from ethisterone -> form norethindrone Not destroy oral activity Changed major hormonal effect from that of androg

en to that of progestational agent Progestational derivatives of testosterone ; design

ated as 19-nortestosterones Androgenic properties ; not totally eliminated and

minimal anabolic and androgenic potential


Impurity of 19-nortestosterone Androgenic as well as progestational effects comp

licated in past by metabolism to estrogenic compounds

Recent study ; norethindrone - converted to ethinhyl estradiol

Clinically, androgenic and estrogenic activities of progestin component ; insignificant d/t low dosage in current oral contraceptives


Norethindrone family ; contain 19-nortestosterone progestins Norethindrone, norethynodrel, norethindrone acetat

e, ethynodiol diacetate, lynestrenol, norgestrel, norgestimate, desogestrel, gestodene

Converted to parent compound Activity d/t rapid conversion to norethindrone


Definitions used in epidemiologic studies Low-dose oral contraceptives ; products containing les

s than 50ug ethinyl estradiol First generation oral contraceptives ; products contain

ing 50ug or more of ethinyl estradiol Second generation oral contraceptives ; products con

taining levonorgestrel, norgestimate and other members of northindrone family and 30 or 35ug ethinyl estradiol

Third generation oral contraceptives ; products containing desogestrel or gestodene with 20 or 30ug ethinyl estradiol


Second group of progestins Acetylation of 17-hydroxy group of 17-hydroxyproge

sterone ; orally active but weak progestin Addition at 6 position ; give sufficient progestation

al strength Derivatives of progesterone with substituents at 1

7 and 6 positions ; widely used medroxyprogesterone acetate

Potency(1)

Difficult to assign potency values to various progestational components of oral contraceptives Progestins ; act on numerous target organs Potency ; depeding on target organ and end point b

eing studied

Potency(2)

Now, oral contraceptive progestin potency ; no longer consideration Biologic effect of various progestational component

s in current low dose oral contraceptives ; same Progress in lowering doses of steroids contain

ed in oral contraceptives ; yields products with little serious differences

Potency ; no longer important clinical issue

New progestins(1)

Throughuot the 1980s, androgenic metabolic effects ; important, esp, cardiovascular ds Cardiovascular side effects ; d/t dose-related stim

ulation of thrombosis by estrogen New progestins

Desogestrel, gestodene, and norgestimate Comparable with previous low-dose products in reg

ard to cycle control(breakthrough bleeding and amenorrhea)

Impact on carbohydrate metabolism ; negligible Not statistically significant

New progestins(2)

Decreased androgenicity of the progestins in new products ; reflected in SBG and free testosterone concentrates

Clinical value in treatment of acne and hirsutism

No appropriate comparative clinical studies

New formulations

Multiphasic preparation Alter dosage of both estrogen and progestin compo

nents periodically throughout pill-taking schedule Aim of new formulations

Alter steroid levels in effort to achieve lesser metabolic effects

Minimize occurrence of breakthrough bleeding and amenorrhea, while maintaining efficacy

Metabolic studies with multiphasic preparation No differences or slight improvements over metabolic effe

cts of low-dose monophasic products

Mechanism of action(1)

Combination pill, given daily for 3 of every 4weeks Prevents ovulation by inhibiting gonadotropin secre

tion via effect on both pituitary and hypothalamic centers

Progestational agent in pill ; suppresses LH secretion(thus prevents ovulation)

Estrogenic agent ; suppresses FSH secretion (thus prevents selection and emergence of dominant follicle)


Estrogen in pill ; two other purposes Provides stability to endometrium -> minimize irreg

ular shedding and unwanted breakthrough bleeding Potentiate action of progestational agents -> allow

reduction of progestational dose in pill Mechanism ; estrogen’s effect in increasing concentration

of intracellular progestational receptors


Progestin in combination pill Procudes endometrium that is not receptive to ovu

m implantation, decidualized bed with exhausted and atrophied glands

Cervical mucus ; thick and impervious to sperm transport

Progestational influences on secretion and peristalsis within fallopian tubes ; provide additional contraceptive effects

Efficacy(1)

Strict adherence to 7 pill-free days Critical in order to obtain reliable, effective

contraception 28-day pill package, incorporating 7 pills

that do not contain steroids ; very useful aid to ensure adherence to necessary schedule

Most prevalent problems that associated with apparent oral contraceptive failures ; vomiting and diarrhea

Even if no pills missed, patients should be instructed to use backup method for at least 7 days after episode of gastroenteritis

Efficacy(2)

Annual failure rate 0.1% in motivated subjects 3.0% during the first year of use in typical usage

Efficacy ; slightly when estrogen component is removed Only a small progestin is administered(progestin-o

nly minipills)

Oral contraception

Education

Transcript of Oral contraception