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22. Oral contraception

22. Oral contraception. 부산백병원 R3 강영미. 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

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22. Oral contraception

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  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 • 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)

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