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Dúvidas Arquivo Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais Site
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The anatomy of the female internal genitalia and accessory sex organs
Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
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The anatomy of the female internal genitalia and accessory sex organs
Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
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Ovarian cycle Rupture of mature follice and release of ovum (ovulatory phase) Growth and development of the follice (follicular phase) Corpus luteum formation (luteal phase) Corpus luteum degeneration Foyes Principles of Medicinal Chemistry – Fig. 29.2
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Approximate plasma concentrations of the gonadotropins and ovarian hormones during the normal female sexual cycle 800 600 400 200 Progesterone 8 6 4 2 Ovulation Estradiol Menstruation Progesterone (ng/ml) Estradiol (pg/ml) 800 600 400 200 LH Ovulation FSH and LH (ng/ml) FSH Days of female sexual cycle Guyton & Hall – Textbook of Medical Physiology – fig 81.3
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Estrogens excreted in urine
Estrogen secretion throughout the sexual life of the female human being 400 300 200 100 Puberty Menopause Estrogens excreted in urine (µg/24 hr) Age (yr) Guyton & Hall – Textbook of Medical Physiology – fig 81.10
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6 mo 10-14 yr 50 yr Trimesters Plasma gonadotropins (um/M) 100 70 10
2nd 3rd Birth Trimesters Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
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Neuroendocrine Regulation of Menstrual Cycle
Hypothalamic regulation of pituitary gonadotrophin production and release Ovarian feedback modulation of pituitary gonadotropin production and release GnRH Hours FSH FSH Estrogen GnRH LH LH Pulsed release of GnRH by hypothalamus (1 pulse/ 1-2 hr) permits anterior pitutary production and release of FSH and LH (normal) Presence of pulsed GnRH and low estrogen and progesterone levels result in increased levels of pulsed LH and FSH (negative feedback) Hours FSH FSH GnRH Estrogen GnRH LH LH Continuos, excessive, absent or more frequent GnRH release inhibits FSH and LH production and release (downloading) Presence of pulsed GnRH, rapidly increasing levels of estrogen, and small amounts of progesterone result in hight pulsed LH and moderately increased pulsed FSH levels (positive feedback) Hours FSH FSH GnRH Estrogen GnRH LH LH Decreased pulsed release of GnRH decreases LH secretion but increases FSH secretion (slow-pulsing model) Presence of pulsed GnRH and high levels of estrogen and progesterone result in decreased LH and FSH levels (negative feedback)
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Correlation of serum gonadotrophic and ovarian hormone levels and feedback mechanisms
FSH-LH (pulses/hr) Follicular phase Hypothalamus GnRH (pulses /hr) Pituitary LH-FSH Ovary Estrogen Progesterone FSH Estrogen 50 40 30 20 10 500 400 300 200 100 10 9 8 7 6 5 4 3 2 1 Serum levels Menses LH Progesterone ng ml pg ml mlU ml Days
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Postulated mechanism of ovulation
Luteinizing hormone Folicular steroid hormones (progesterone) Proteolytic enzymes (collagenase) Follicular hyperemia and prostaglandin secretion Weakened follicle wall Plasma transudation into follicle Degeneration of stigma Follicle swelling Follicle rupture Evagination of ovum Guyton & Hall – Textbook of Medical Physiology – fig 81.5
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OH HO Estradiol Foyes Principles of Medicinal Chemistry – pag 685
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17α-Ethinyl estrogens, and Estradiol Esters
OH OR1 CCH X RO RO Ethinyl estradiol: R = X = H Mestranol: R = CH3; X = X 2-Hydroxyethinylestradiol: R = H; X = OH Estradiol 17β-valerate: R = H: R1 = CH3(CH2)3CO Estradiol 17β-cyclopentylpropionate R = H R1 = CH2CH2CO Foyes Principles of Medicinal Chemistry – fig. 29.6
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O O Progesterone Foyes Principles of Medicinal Chemistry – pag 685
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Progestins and 19-norandrostane 19-Nor-14β, 17α-preg-4-ene-3,20-dione
OH OH C CH C CCH3 O O Ethisterone Dimethisterone O O H O O 19-Nor-14β, 17α-preg-4-ene-3,20-dione 19-Norprogesterone Foyes Principles of Medicinal Chemistry – fig
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19-Norandrostanes used clinically in oral contraceptives
OH OH OH C≡CH C≡CH C≡CH O O O Norethisterone Norethynodrel Norethindrone O C-CH3 OH O OH C≡CH C≡CH C≡CH HO N O Desogestrel Norgestimate Norgestrel O C-CH3 OH O C≡CH C≡CH O O H3C-C-O 3-Ketodesogestrel (etonogestrel) Ethynodiol diacetate Foyes Principles of Medicinal Chemistry – fig
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Estrógenos Síntese de DNA e RNA hepático, Enzimas hepáticas
Enzimas séricas formadas no fígado Proteínas plasmáticas
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Mechanism of Action of Estrogen/Progestin Contraceptives
Inhibition of ovulation by suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) Alteration of cervical mucus to inhibit sperm transport Interference with ovum transport Inhibition of implantation by suppression of normal endometrial development Essential of Reproductive Medicine – Tab. 26.1
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Combination Oral Contraceptives
Hypothalamus Combination oral contraceptives (estrogen and progestin) Estrogen and progesterone GnRH Anterior pituitary Unfavorable endometrial environment Altered transportation of sperm, egg, fertilized ovum FSH LH Granulosa cells Ovary Uterus Cholesterol O Changes cervix environment Theca cells Combination Oral Contraceptives HO Pregnenolone O O Progesterone O OH O O Androstenedione Testosterone OH O OH OH HO HO HO Estriol Estrone Estradiol Normal cervix
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Pílula de Primeira Geração
Etinilestradiol - doses altas (50mcg ou maior) Progestágeno - Levonorgestrel, noretisterona ou etinodiol diacetato.
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Pílula de segunda geração
Etinilestradiol (dose até 30 mcg) Progestágeno - levonorgestrel ou noretisterona
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Pílula de Terceira Geração
Etinilestradiol (20-30 mcg) Progestágeno - desogestrel, gestodeno ou norgestimato
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ETINILESTRADIOL + GESTODENO etinilestradiol 15 mcg + gestodeno 60 mcg
etinilestradiol 15 mcg + gestodeno 60 mcg etinilestradiol 20 mcg + gestodeno 75 mcg etinilestradiol 30 mcg + gestodeno75 mcg MINESSE MIRELLE DIMINUT FEMIANE GINESSE HARMONET MICROPIL R21 TÂMISA 20 CICLO 21 GESTINOL 28 GYNERA MINULET TÂMISA 30 ETINILESTRADIOL + DESOGESTREL etinilestradiol 20 mcg + desogestrel 150 mcg etinilestradiol 30 mcg + desogestrel 150 mcg) FEMINA MERCILON MINIAN PRIMERA MICRODIOL ETINILESTRADIOL+DROSPERINONA etinilestradiol 20 mcg + drosperinona 3 mg etinilestradiol 30 mcg + drosperinona 3 mg Yaz YASMIN ETINILESTRADIOL+CLORMADINONA etinilestradiol 30 mcg + clormadinona 2mg BELARA ETINILESTRADIOL E OUTROS etinilestradiol 30 mcg + levonorgestrel 150 mcg etinilestradiol 20 mcg + levonorgestrel 150 mcg Comp. azul: Desogestrel 0,025 mg + Etinilestradiol 0,04 mg; Comp. branco: Desogestrel 0,125 mg + Etinilestradiol 0,03 mg CICLON GESTRELAN NOCICLIN MICROVLAR NORDETTE LEVEL GRACIAL etinilestradiol 50 mcg + levonorgestrel 250 mcg EVANOR NEOVLAR
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Drug Summary Table – Pharmacology of Reproduction
Progestin-Only Contraceptives Mechanism – Altered GnRH release leads to ↓ ovulation Drug Clinical Uses Side Effects/Toxicities Notes Norgestrel Norethindrone Contraception Breakthrough Sporting Norgestrel also available as subdermal implant Less effective than estrogen/progestin combination Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
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Contraceptive use in the United States, 1995. Hysterectomy/ Menopause
Percentage of Women Ages 15-50 30 25 20 15 10 5 26% 24% 19% 7% 6% 3% 1% 1% 1% Pill Sterilization Condom Withdrawa/ Rhythm Hysterectomy/ Menopause Injectable Spermicide IUD Implants Method Essential of Reproductive Medicine – Fig. 26.2
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Noncontraceptive Health Benefits of Oral Contraceptives
Percent Reduction/ Protection (%) Minium Use Required Duration of Effect OCP Formulation Comments Definitive evidence Ovarian cancer months At least >20 µg EE Also protective against years hereditary ovarian cancer Endometrial cancer months years All monophasic No data on multiphasic or progestin-only forms Benign breast disease months year >20 µg EE Effect consistent across all age groups Pelvic inflamatory months Current use >20 µg EE ? Effect on outpatient disease cases of PID Ectopic pregnancy Current use Current use >20 µg EE No increased risk for ectopic pregnancy in women who become pregnant with OCP use Essential of Reproductive Medicine – Tab. 26.2
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Noncontraceptive Health Benefits of Oral Contraceptives
Percent Reduction/ Protection (%) Conflicting evidence, favor beneficial effect Bone mineral density Unknown Unknown >35 µg EE Decreased incidence of hip fractures with higher doses Colorectal cancer months Unknown >50 µg EE Increasing protection with increased duration Uterine leiomyomas , years; Unknown Unclear If used in setting of fibroids no 7 years clinically significant uterine growth Toxic shock syndrome Current use Current use Unclear May be influenced by change in tampon composition/absorbency Minium Use Required Duration of Effect OCP Formulation Comments Essential of Reproductive Medicine – Tab. 26.2
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Noncontraceptive Health Benefits of Oral Contraceptives
Percent Reduction/ Protection (%) Conflicting evidence, favor no effect Functional ovarian cysts 80, 48, 8 Current use Current use Monophasic No statistically significant effect >35 µg EE; Monophasic <35 mcg EE triphasic all types Rheumatoid arthritis Current use Current use Unclear May alter severity and clinical course rather development Minium Use Required Duration of Effect OCP Formulation Comments Essential of Reproductive Medicine – Tab. 26.2
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Benefícios dos AOC Menor risco de câncer endometrial e ovariano.
Menor risco de prenhez ectópica Menstruação mais regular (menor fluxo, menor dismenorréia, menor anemia) Menor incidência de salpingite Aumento da densidade óssea
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AOC e câncer Redução de 50% do risco de câncer de endométrico
Redução de 40% do risco de câncer de ovário Sem efeito no câncer de cérvix uterina ou no câncer de mama.
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Number of deaths from cardiovascular diseases per 100,000 women by smoking status or nonuse of oral contraceptives. 250 200 150 100 50 nonuser, nonsmoker user, nonsmoker nonuser, heavy smoker user, heavy smoker Deaths / 100,000 women 0 0 20-24 25-29 30-34 35-39 40-44 Age group (years) Essential of Reproductive Medicine – Fig. 26.4
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Relative Risk and Actual Incidence of Venous Thromboembolism
Population Relative Risk Incidence Young women-general population per 100,000 per year Pregnant women High-dose oral contraceptives Low dose oral contraceptives Leiden mutation carrier Leiden carrier and oral contraceptives Leiden mutation – homozygous A Clinical Guide for Contraception – tab. Pag 53
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The carrier frequencies of the Leiden mutation in American population (the percentages are similar in men and women) are as follows Caucasian Americans 5.27% Hispanic Americans % Native Americans % Black Americans % Asian Americans % A Clinical Guide for Contraception – tab. Pag 53
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In the Transnational case-control study of myocardial infarctions collected from 16 centers in Austria, France, Germany, Switzerland, and United Kingdom, the results were as follows Confidence Cases Controls Odds Ratio Interval Any OC use 50 µg estrogen OCs Old progestin OCs New progestin OCs A Clinical Guide for Contraception – tab. Pag 55
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Incidence of Myocardial Infarction in Reproductive Age Women
Overall incidence 5 per 100,000 per year Women less than age 35 Nonsmokers 4 Nonsmokers & OCs 4 Smokers 8 Smokers & OCs 43 Women 35 years old and older Nonsmokers 10 Nonsmokers & OCs 40 Smokers 88 Smokers & OCs 485 A Clinical Guide for Contraception – tab. Pag 57
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Incidence of Stroke in Reproductive Age Women
ischemic stroke 5 per 100,000 per year 1-3 per year in women under age 35 10 per 100,000 per year in women over age 35 hemorrhagic stroke 6 per 100,000 per year Excess cases 2 per 100,000 per year in low-dose OC users per year due to 1 per 100,000 per year in low-dose OC users under age 35 OCs, including 8 per 100,000 per year in high-dose users smokers and hypertensives A Clinical Guide for Contraception – tab. Pag 61
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Possible Contradications to Use of Combined Oral Contraceptive Pills
Absolute Contraindications 1. Thrombophlebitis or Thromboembolic disorders 2. Past history of deep vein thrombophlebitis or thromboembolic disorders 3. Cerebrovascular or coronary artery disease 4. Known or suspected breast carcinoma 5. Known or suspected estrogen-dependent neoplasia 6. Pregnancy 7. Benign or malignant liver tumor 8. Known impaired liver function 9. Previous cholestasis during pregnancy or with prior pill use Essential of Reproductive Medicine – Tab. 26.6
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Possible Contradications to Used of Combined Oral Contraceptive Pills (cont)
Strong Relative Contraindications 10. Severe headaches, particularly vascular or migraine headaches, that start after initiation of oral contraceptives 11. Hypertension with resting diastolic BP of 140 mmHg or greater on three or more separate visits or an accurate measurement of 110 mmHg diastolic or more on single visit 12. Mononucleosis, acute phase 13. Elective major surgery or major surgery requiring immobilization planned in next 4 week 14. Long-leg cast or major injury to lower leg 15. Over 40 years old, accompanied by a second risk factor for the development of cardiovascular disease (such as diabetes or hypertension) 16. Over 35 years old and currently a heavy smoker (15 or more cigarettes/day) 17. Abnormal genital bleeding Essential of Reproductive Medicine – Tab. 26.6
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Possible Contradications to Used of Combined Oral Contraceptive Pills (cont)
Other Considerations Diabetes, prediabetes, or a strong family history of diabetes Sickle cell disease or sickle C disease Active gallbladder disease Congenital hyperbilirubinemia (Gilbert’s disease) Undiagnosed abnormal genital bleeding Over 50 years old Completion of term pregnancy within past 10 to 14 days Weight gain of 10 lb or more while on the pill Cardiac renal disease (or history thereof) Conditions likely to make patient unreliable at following pill instructions (mental retardation, major psychiatric illness, alcoholism, or other chemical abuse, history of repeatedly taking oral contraceptives or other medication incorrectly) Lactation Family history of death of a parent or sibling due to myocardial infarction before age 50; myocardial infarction in a mother or sister is especially significant and indicates a need for lipid evaluation Family history of hyperlipidemia Essential of Reproductive Medicine – Tab. 26.6
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Contraindicado formalmente em doença colestática aguda ou crônica
AOC e Fígado Transporte ativo de componentes biliares é inibido por estrógenos e progestágenos. Contraindicado formalmente em doença colestática aguda ou crônica
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Importante Não há evidências de aumento de incidência de doença hepática séria causado por uso de ACO
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Contraceptivo Oral e Trombose
Estrógenos, mas não progestágenos, aumentam a produção de fatores de coagulação. Tabagismo e uso de estrógenos apresentam efeito aditivo no risco de trombose arterial. Contraceptivos de dose baixa de estrógeno (< 50 microg EE) não aumentam o risco de IM ou AVC em mulheres saudáveis, não fumantes, independente da idade. IM e AVC podem ocorrer em mulheres que usam contraceptivos de alta dose, ou que apresentam fatores de risco cardiovascular acima da idade de 35 anos.
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Anel Vaginal (RING)
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Emplastro dérmico (patch)
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40 mm 2 mm Core: 40% Ethylene vinyl acetate (EVA)
60% Etogestrel (68 mg) Rate-controlling membrane: (.06 mm) 100% EVA
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Required Equipment for Implanon Insertion
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Implantation technique
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Technique for the Tcu-380A
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Drug Summary Table – Pharmacology of Reproduction
Progesterone Receptor Antagonists Mechanism – Inhibit progesterone binding to receptor Drug Clinical Uses Side Effects/Toxicities Notes Mifepristone Medical abortion Bleeding Must be able to verify age of fetus Coadministered with misoprostol (causes ulterine contractions, nausea) Antagonist at glucocorticoid receptor as well as progesterone receptor Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
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Drug Summary Table – Pharmacology of Reproduction
Progesterone Receptor Antagonists (Cont.) Mechanism – Inhibit progesterone binding to receptor Drug Interactions / Contraindications Mifepristone Pregnancy >49 days Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
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Drug Summary Table – Pharmacology of Reproduction
Mixed Estrogen / Progestin Oral Contraceptives Mechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation Drug Clinical Uses Side Effects/Toxicities Notes Estrogens Ethinyl Estradiol Mestranol Progestins Norgestrel, levonorgestrel Norethindrome Ethynodiol, norgestimate Desogestrel Prevention of pregnancy Postcoital contraception Slightly ↑ risk stroke ↑ Triglyceride levels ↑ Risk DVT Breakthrough bleeding ↑ Blood pressure Formulation exist as monophasic, biphasic, triphasic dosage forms Monofasic: Constant estrogen and progestin Biphasic: Higher progestin in second half of cycle + midcycle ↑ estrogen Triphasic: higher progestin in second half of cycle + midcycle ↑ estrogen No Clinical differences in efficacy or side effects among monophasic, biphasic or triphasic Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
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Drug Summary Table – Pharmacology of Reproduction
Mixed Estrogen / Progestin Oral Contraceptives (Cont.) Mechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation Drug Interactions/Contraindications Estrogens Ethinyl Estradiol Mestranol Progestins Norgestrel, levonorgestrel Norethindrome Ethynodiol, norgestimate Desogestrel Contraindications: Previous DVT or stroke History of strogen-dependent tumor Liver Disease Pregnancy Hypertriglyceridemia Women > 35 y/o who smoke Drug Interactions: Rifampin, phenytoin, and phenobarbital all ↑ metabolism of OCPs Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
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Drug Summary Table – Pharmacology of Reproduction
Progestins Used in Breast Cancer Mechanism – Unknown Drug Clinical Uses Side Effects/Toxicities Megestrol acetate Medroxyprogesterone acetate Advanced breast cancer ↑ Risk DVT Hot flashes Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
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OH O Testosterone Foyes Principles of Medicinal Chemistry – pag 685
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5α-Dihydrotestosterone
OH O H 5α-Dihydrotestosterone Foyes Principles of Medicinal Chemistry – pag 685
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O HO Estrone Foyes Principles of Medicinal Chemistry – pag. 686
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OH OH HO Estriol Foyes Principles of Medicinal Chemistry – pag. 686
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Biosynthesis of sex steroid hormones
Cholesterol a O b HO Pregnenolone c,d O O OH HO O 17α-Hydroxypregnenolone Progesterone e O O O O c,d g Foyes Principles of Medicinal Chemistry – fig. 29.3 HO O HO Dehydroepiandrosterone Androstenedione Estrone f h OH OH OH O i g O O HO H 5α-Dihydrotestosterone Testosterone Estradiol
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Estrogen metabolism Foyes Principles of Medicinal Chemistry – fig. 29.5
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Conjugated and esterified estrogens
HO Equilin Equilin sodium sulfate R = H R = SO3 –Na+ O Estrone Estrone sodium sulfate Piperazine estrone sulfate R = H R = SO3 –Na+ R = SO3 + N NH H RO H Foyes Principles of Medicinal Chemistry – fig. 29.7
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Metabolism of progesterone
OH O CH HO O O H OH 20α/β-Hydroxyprogesterone 5β-Pregnanediol 6α-Hydroxyprogesterone H H OH Conformation of rings A and B for 5β-preganediol Conformation of rings A and B for progesterones Foyes Principles of Medicinal Chemistry – fig
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Metabolism of testosterone
OH OH O HO HO O H Estradiol Epi-testosterone Androsterone OH OH O O OH Testosterone 6α-Hydroxytestostenore O OH HO O Foyes Principles of Medicinal Chemistry – fig H H etiocholanolone 5α-Dihydrotestosterone H O H O H Conformation of rings A and B for 5α-dihydrotestosterone Conformation of rings A and B for testosterone OH Conformation of rings A and B for etiocholanolone
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Mifepristrone Onapristrone CH3 CH3 N N H3C H3C OH OH C ≡ CCH3
CH2-CH2CH2OH O O Mifepristrone Onapristrone Foyes Principles of Medicinal Chemistry – pag. 703
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The tetracyclic ring system characteristic of steroids
Organic Chemistry – fig. 26.9
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