Oral contraception


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Oral contraception

  1. 1. 22. Oral contraception 부산백병원 R3 강영미 dr shabeel pn
  2. 2. History <ul><li>Ludwig Haberlandt, in the 1920s </li></ul><ul><ul><li>First demonstrated that ovarian extracts given orally could prevent fertility(in mice) </li></ul></ul><ul><ul><li>By 1931, proposed administration of hormones for birth control </li></ul></ul><ul><ul><li>Early death in 1932, at age 47, brought an end to this effort </li></ul></ul>
  3. 3. Russell Marker(1) <ul><ul><li>Eccentric chemist </li></ul></ul><ul><ul><li>Interested in solving the problem of producing abundant and cheap amounts of progesterone </li></ul></ul><ul><ul><li>Required ovaries from 2500 pregnant pigs to produce 1 mg of progesterone </li></ul></ul><ul><ul><li>In 1939, devised method(called Marker degradation) to convert sapogenin molecule into progestin </li></ul></ul><ul><ul><li>Find plants that contained sufficient amounts of diosgenin, plant steroid(sapogenin) </li></ul></ul>
  4. 4. Russell Marker(2) <ul><ul><li>Too small to provide sufficient amounts for commercial production </li></ul></ul><ul><ul><li>With two partners, formed company in 1944, called syntex </li></ul></ul><ul><ul><li>In 1970, recognized Marker’s work </li></ul></ul>
  5. 5. Carl Djerassi <ul><ul><li>Head a reserch group to concentrate on the synthesis of cortisone </li></ul></ul><ul><ul><li>Turned their attention to sex steroids </li></ul></ul><ul><ul><li>Discovered that removal of the 19-carbon from yam-derived progesterone increased progestational activity of the molecule </li></ul></ul><ul><ul><li>In 1951, norethindrone was synthesized </li></ul></ul><ul><ul><li>Norethynodrel, actually first orally active progestational agent </li></ul></ul>
  6. 6. Gregory Pincus(1) <ul><ul><li>Performed studies of meiotic maturation in mammalian oocytes, in both rabbit and human oocytes </li></ul></ul><ul><ul><li>In 1934, achievement of in vitro fertilization of rabbit eggs -> depicted as evil scientist </li></ul></ul><ul><ul><li>With his friend, Hoagland and M-C Chang </li></ul></ul><ul><ul><ul><li>Establishment of the Worcester Foundation for Experimental Biology, in 1944 </li></ul></ul></ul>
  7. 7. Gregory Pincus(2) <ul><ul><li>Attributed their interest in contraception for the world’s population problem, in 1951 </li></ul></ul><ul><ul><li>Involve physician, John Rock, chief of gynecology and obstetrics at Harvard ; human experiments would be necessary </li></ul></ul><ul><ul><li>Using oocytes from oophorectomies, reported in vitro fertilization in 1944, first demonstration of fertilization of human oocytes in vitro </li></ul></ul>
  8. 8. Gregory Pincus(3) <ul><ul><li>In 1956, first human trial was performed </li></ul></ul><ul><ul><ul><li>50 pts, 10-40mg of synthetic progestin for 20 days each month </li></ul></ul></ul><ul><ul><ul><li>All failed to ovulate drug treatment </li></ul></ul></ul><ul><ul><ul><li>Became pregnant after discontinuing medicaiton </li></ul></ul></ul><ul><ul><li>In 1960, FDA for acceptance of oral contraception </li></ul></ul>
  9. 9. Pharmacology of Steroid Contraception
  10. 10. Estrogen component of combination oral contraceptives(1) <ul><li>Estradiol </li></ul><ul><ul><li>Most potent natural estrogen </li></ul></ul><ul><ul><li>Major estrogen secreted by ovaries </li></ul></ul><ul><li>Major obstacle to use of sex steroids for contraception </li></ul><ul><ul><li>Inactivity of compounds when given orally </li></ul></ul><ul><ul><li>In 1938, addition of ethinyl group at the 17 position ; orally active </li></ul></ul><ul><li>Ethinyl estradiol ; very potent oral estrogen </li></ul>
  11. 11. Estrogen component of combination oral contraceptives(2) <ul><li>The other estrogen ; 3-methyl ether of ethinyl estradiol, mestranol </li></ul><ul><li>Mestranol </li></ul><ul><ul><li>weaker than ethinyl estradiol </li></ul></ul><ul><ul><li>Must first be converted to ethinyl estradiol in body </li></ul></ul>
  12. 12. Estrogen component of combination oral contraceptives(3) <ul><li>Metabolism of ethinyl estradiol </li></ul><ul><ul><li>Varies from individual to individual </li></ul></ul><ul><li>Estrogen content(dosage) of pill </li></ul><ul><ul><li>Major clinical importance </li></ul></ul><ul><ul><li>Thrombosis ; one of most serious side effects of pill </li></ul></ul><ul><ul><li>Related to estrogen and dose related </li></ul></ul>
  13. 13. Progestin component of combination oral contraception(1) <ul><li>At the end of the 1930s </li></ul><ul><ul><li>Ethisterone, orally active derivative of testosterone </li></ul></ul><ul><li>In 1951, removal of 19-carbon from ethisterone -> form norethindrone </li></ul><ul><ul><li>Not destroy oral activity </li></ul></ul><ul><ul><li>Changed major hormonal effect from that of androgen to that of progestational agent </li></ul></ul><ul><ul><li>Progestational derivatives of testosterone ; designated as 19-nortestosterones </li></ul></ul><ul><ul><li>Androgenic properties ; not totally eliminated and minimal anabolic and androgenic potential </li></ul></ul>
  14. 14. Progestin component of combination oral contraception(2) <ul><li>Impurity of 19-nortestosterone </li></ul><ul><ul><li>Androgenic as well as progestational effects complicated in past by metabolism to estrogenic compounds </li></ul></ul><ul><ul><li>Recent study ; norethindrone - converted to ethinhyl estradiol </li></ul></ul><ul><li>Clinically, androgenic and estrogenic activities of progestin component ; insignificant d/t low dosage in current oral contraceptives </li></ul>
  15. 15. Progestin component of combination oral contraception(3) <ul><li>Norethindrone family ; contain 19-nortestosterone progestins </li></ul><ul><ul><li>Norethindrone, norethynodrel, norethindrone acetate, ethynodiol diacetate, lynestrenol, norgestrel, norgestimate, desogestrel, gestodene </li></ul></ul><ul><ul><li>Converted to parent compound </li></ul></ul><ul><ul><li>Activity d/t rapid conversion to norethindrone </li></ul></ul>
  16. 16. Progestin component of combination oral contraception(4) <ul><li>Definitions used in epidemiologic studies </li></ul><ul><ul><li>Low-dose oral contraceptives ; products containing less than 50ug ethinyl estradiol </li></ul></ul><ul><ul><li>First generation oral contraceptives ; products containing 50ug or more of ethinyl estradiol </li></ul></ul><ul><ul><li>Second generation oral contraceptives ; products containing levonorgestrel, norgestimate and other members of northindrone family and 30 or 35ug ethinyl estradiol </li></ul></ul><ul><ul><li>Third generation oral contraceptives ; products containing desogestrel or gestodene with 20 or 30ug ethinyl estradiol </li></ul></ul>
  17. 17. Progestin component of combination oral contraception(5) <ul><li>Second group of progestins </li></ul><ul><ul><li>Acetylation of 17-hydroxy group of 17-hydroxyprogesterone ; orally active but weak progestin </li></ul></ul><ul><ul><li>Addition at 6 position ; give sufficient progestational strength </li></ul></ul><ul><ul><li>Derivatives of progesterone with substituents at 17 and 6 positions ; widely used medroxyprogesterone acetate </li></ul></ul>
  18. 18. Potency(1) <ul><li>Difficult to assign potency values to various progestational components of oral contraceptives </li></ul><ul><ul><li>Progestins ; act on numerous target organs </li></ul></ul><ul><ul><li>Potency ; depeding on target organ and end point being studied </li></ul></ul>
  19. 19. Potency(2) <ul><li>Now, oral contraceptive progestin potency ; no longer consideration </li></ul><ul><ul><li>Biologic effect of various progestational components in current low dose oral contraceptives ; same </li></ul></ul><ul><li>Progress in lowering doses of steroids contained in oral contraceptives ; yields products with little serious differences </li></ul><ul><li>Potency ; no longer important clinical issue </li></ul>
  20. 20. New progestins(1) <ul><li>Throughuot the 1980s, androgenic metabolic effects ; important, esp, cardiovascular ds </li></ul><ul><ul><li>Cardiovascular side effects ; d/t dose-related stimulation of thrombosis by estrogen </li></ul></ul><ul><li>New progestins </li></ul><ul><ul><li>Desogestrel, gestodene, and norgestimate </li></ul></ul><ul><ul><li>Comparable with previous low-dose products in regard to cycle control(breakthrough bleeding and amenorrhea) </li></ul></ul><ul><ul><li>Impact on carbohydrate metabolism ; negligible </li></ul></ul><ul><ul><li>Not statistically significant </li></ul></ul>
  21. 21. New progestins(2) <ul><li>Decreased androgenicity of the progestins in new products ; reflected in  SBG and  free testosterone concentrates </li></ul><ul><li>Clinical value in treatment of acne and hirsutism </li></ul><ul><li>No appropriate comparative clinical studies </li></ul>
  22. 22. New formulations <ul><li>Multiphasic preparation </li></ul><ul><ul><li>Alter dosage of both estrogen and progestin components periodically throughout pill-taking schedule </li></ul></ul><ul><ul><li>Aim of new formulations </li></ul></ul><ul><ul><ul><li>Alter steroid levels in effort to achieve lesser metabolic effects </li></ul></ul></ul><ul><ul><ul><li>Minimize occurrence of breakthrough bleeding and amenorrhea, while maintaining efficacy </li></ul></ul></ul><ul><ul><li>Metabolic studies with multiphasic preparation </li></ul></ul><ul><ul><ul><li>No differences or slight improvements over metabolic effects of low-dose monophasic products </li></ul></ul></ul>
  23. 23. Mechanism of action(1) <ul><li>Combination pill, given daily for 3 of every 4weeks </li></ul><ul><ul><li>Prevents ovulation by inhibiting gonadotropin secretion via effect on both pituitary and hypothalamic centers </li></ul></ul><ul><ul><li>Progestational agent in pill ; suppresses LH secretion(thus prevents ovulation) </li></ul></ul><ul><ul><li>Estrogenic agent ; suppresses FSH secretion (thus prevents selection and emergence of dominant follicle) </li></ul></ul>
  24. 24. Mechanism of action(2) <ul><li>Estrogen in pill ; two other purposes </li></ul><ul><ul><li>Provides stability to endometrium -> minimize irregular shedding and unwanted breakthrough bleeding </li></ul></ul><ul><ul><li>Potentiate action of progestational agents -> allow reduction of progestational dose in pill </li></ul></ul><ul><ul><ul><li>Mechanism ; estrogen’s effect in increasing concentration of intracellular progestational receptors </li></ul></ul></ul>
  25. 25. Mechanism of action(3) <ul><li>Progestin in combination pill </li></ul><ul><ul><li>Procudes endometrium that is not receptive to ovum implantation, decidualized bed with exhausted and atrophied glands </li></ul></ul><ul><ul><li>Cervical mucus ; thick and impervious to sperm transport </li></ul></ul><ul><ul><li>Progestational influences on secretion and peristalsis within fallopian tubes ; provide additional contraceptive effects </li></ul></ul>
  26. 26. Efficacy(1) <ul><li>Strict adherence to 7 pill-free days </li></ul><ul><ul><li>Critical in order to obtain reliable, effective contraception </li></ul></ul><ul><ul><li>28-day pill package, incorporating 7 pills that do not contain steroids ; very useful aid to ensure adherence to necessary schedule </li></ul></ul><ul><ul><li>Most prevalent problems that associated with apparent oral contraceptive failures ; vomiting and diarrhea </li></ul></ul><ul><ul><li>Even if no pills missed, patients should be instructed to use backup method for at least 7 days after episode of gastroenteritis </li></ul></ul>
  27. 27. Efficacy(2) <ul><li>Annual failure rate </li></ul><ul><ul><li>0.1% in motivated subjects </li></ul></ul><ul><ul><li>3.0% during the first year of use in typical usage </li></ul></ul><ul><li>Efficacy ; slightly  </li></ul><ul><ul><li>when estrogen component is removed </li></ul></ul><ul><ul><li>Only a small progestin is administered(progestin-only minipills) </li></ul></ul>