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 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 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)

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 yam-derived progesterone increased progestational activity of the molecule In 1951, norethindrone was synthesized Norethynodrel, actually first orally active progestational 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 Experimental 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 position ; orally active Ethinyl estradiol ; very potent oral estrogen

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

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

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

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

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

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

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

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

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

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

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 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

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)

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

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

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 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)