1. 22. Oral contraception
부산백병원
R3 강영미

2. History Ludwig Haberlandt, in the 1920s
First demonstrated that ovarian extracts given orally could prevent fertility(in mice)
By 1931, proposed administration of hormones for birth control
Early death in 1932, at age 47, brought an end to this effort

3. Russell Marker(1) Eccentric chemist
Interested in solving the problem of producing abundant and cheap amounts of progesterone
Required ovaries from 2500 pregnant pigs to produce 1 mg of progesterone
In 1939, devised method(called Marker degradation) to convert sapogenin molecule into progestin
Find plants that contained sufficient amounts of diosgenin, plant steroid(sapogenin)

4. 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

5. 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 yam-derived progesterone increased progestational activity of the molecule
In 1951, norethindrone was synthesized
Norethynodrel, actually first orally active progestational agent

6. 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 Experimental Biology, in 1944

7. 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

8. 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

9. Pharmacology of Steroid Contraception

10. 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 position ; orally active
Ethinyl estradiol ; very potent oral estrogen

11. Estrogen component of combination oral contraceptives(2)
The other estrogen ; 3-methyl ether of ethinyl estradiol, mestranol
Mestranol
weaker than ethinyl estradiol
Must first be converted to ethinyl estradiol in body

12. Estrogen component of combination oral contraceptives(3)
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 pill
Related to estrogen and dose related

13. 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 androgen to that of progestational agent
Progestational derivatives of testosterone ; designated as 19-nortestosterones
Androgenic properties ; not totally eliminated and minimal anabolic and androgenic potential

14. Progestin component of combination oral contraception(2)
Impurity of 19-nortestosterone
Androgenic as well as progestational effects complicated 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

15. Progestin component of combination oral contraception(3)
Norethindrone family ; contain 19-nortestosterone progestins
Norethindrone, norethynodrel, norethindrone acetate, ethynodiol diacetate, lynestrenol, norgestrel, norgestimate, desogestrel, gestodene
Converted to parent compound
Activity d/t rapid conversion to norethindrone

16. Progestin component of combination oral contraception(4)
Definitions used in epidemiologic studies
Low-dose oral contraceptives ; products containing less than 50ug ethinyl estradiol
First generation oral contraceptives ; products containing 50ug or more of ethinyl estradiol
Second generation oral contraceptives ; products containing 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

17. Progestin component of combination oral contraception(5)
Second group of progestins
Acetylation of 17-hydroxy group of 17-hydroxyprogesterone ; orally active but weak progestin
Addition at 6 position ; give sufficient progestational strength
Derivatives of progesterone with substituents at 17 and 6 positions ; widely used medroxyprogesterone acetate

18. 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 being studied

19. Potency(2)
Now, oral contraceptive progestin potency ; no longer consideration
Biologic effect of various progestational components in current low dose oral contraceptives ; same
Progress in lowering doses of steroids contained in oral contraceptives ; yields products with little serious differences
Potency ; no longer important clinical issue

20. New progestins(1)
Throughuot the 1980s, androgenic metabolic effects ; important, esp, cardiovascular ds
Cardiovascular side effects ; d/t dose-related stimulation of thrombosis by estrogen
New progestins
Desogestrel, gestodene, and norgestimate
Comparable with previous low-dose products in regard to cycle control(breakthrough bleeding and amenorrhea)
Impact on carbohydrate metabolism ; negligible
Not statistically significant

21. 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

22. New formulations Multiphasic preparation
Alter dosage of both estrogen and progestin components 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 effects of low-dose monophasic products

23. Mechanism of action(1)
Combination pill, given daily for 3 of every 4weeks
Prevents ovulation by inhibiting gonadotropin secretion 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)

24. Mechanism of action(2) Estrogen in pill ; two other purposes
Provides stability to endometrium -> minimize irregular 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

25. Mechanism of action(3) Progestin in combination pill
Procudes endometrium that is not receptive to ovum 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

26. 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

27. Efficacy(2) Annual failure rate Efficacy ; slightly 
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-only minipills)