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Rini Banerjee Ratan, MD DISCLOSURES Sadly, none. Rini Banerjee Ratan, MD D EPA RT M E N T OF OBST ET R I C S & GYNECO LOGY COLUMBIA UNIVERSITY COLLEGE OF PHYSICIANS & SURGEONS HISTORY OBJECTIVES To review the mechanisms of action of combination estrogen-progestin oral contraceptives To understand the indications, contraindications and efficacy of currently available contraceptive methods To understand the non-contraceptive benefits of combination oral contraceptives To understand the risks and side effects associated with estrogen-progestin oral contraceptives Introduction Mechanisms Indications & Efficacy Risks & Side Effects 1921 – Ludwig Haberlandt demonstrated temporary hormonal contraception in a female rabbit by transplanting ovaries from a second pregnant animal 1930s – Structure of steroid hormones determined High doses of estrogen inhibit ovulation 1938 - First orally active semisynthetic steroidal estrogen, EE (17α-ethynylestradiol) synthesized Case Studies EE is the estrogen in nearly all OCs currently used Introduction Mechanisms Indications & Efficacy Risks & Side Effects HISTORY TODAY 1957 – Enovid – first combination OC approved by FDA for treatment of menstrual disorders 1989 –FDA removed all age limits for OC use for healthy, non-smoking women 1960 – FDA approves Enovid to be marketed as contraceptive Today, OC use may be continued until menopause Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Case Studies Rini Banerjee Ratan, MD PRIMARY CONTRACEPTIVE METHODS AMONG WOMEN AGE 15 TO 44 YEARS: UNITED STATES 2002 COMBINATION ORAL CONTRACEPTIVE PILLS Why so popular? Simple Effective Not dependent on partner use Safe MMWR Weekly 2005; 54:152 2008 UpToDate Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies MECHANISMS OF ACTION: ESTROGEN MECHANISMS OF ACTION: PROGESTERONE Primary: Atrophy of endometrium, making it less suitable for implantation Prevent ovulation Inhibition of mid-cycle gonadotropin surge Alterations in cervical mucus, making it less permeable to penetration by sperm Secondary: Impairment of normal tubal motility Inhibit follicular development Suppression of ovarian steroid production Possible decrease in responsiveness of the pituitary to gonadotropin-releasing hormone. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies ORAL CONTRACEPTIVE PREPARATIONS: Monophasic Pills: Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies ORAL CONTRACEPTIVE PREPARATIONS: Low Androgenic Activity All 21 hormonally active pills contain the same amount of estrogen and progestin Ethynodiol • Demulen 1/35 Current OCs contain 20-35 mcg EE Norgestimate • Ortho-Cyclen • Ortho-Tricyclen Multiphasic Pills: Introduced in 1970s-80s to further lower steroid dose Desogestrel Varying doses of estrogen and/or progestin No proven clinical advantage over monophasic pills • Desogen • Ortho-Cept Drospirenone • Yasmin • Also effective for acne and hirsutism Adapted from: Osathanondh, R, Stelluto, MR, Carlson, KJ. Contraception. In: Primary Care of Women, Carson, KJ, Eisenstat (Eds), Mosby, St Louis, 1995. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Rini Banerjee Ratan, MD ORAL CONTRACEPTIVE PREPARATIONS: NEW DEVELOPMENTS: Lower Estrogen Pills: Lo Loestrin Fe Natazia: 24 pills contain 10mcg EE + 1mg norethindrone Estradiol valerate +new progestin Dienogest 2 pills contain 10mcg EE only First four-phase OC 2 pills contain 75mg ferrous fumarate Varying doses of estradiol valerate (1, 2 or 3 mg) One year, open-label, unpublished study of > 1000 women ages 18 to 35 with BMI <35kg/m2 26 hormonally active pills 2 hormone-free pills Pregnancy rate was 2.92 pregnancies per 100 women-years of use (95% CI 1.94-4.21) Jensen JT. Evaluation of a new estradiol oral contraceptive: estradiol valerate and dienogest. Expert Opin Pharmacother. 2010;11(7):1147. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies INITIATION INITIATION Screening Requirements Quick Start Careful medical history Begin taking OCs on the day prescription is given Blood pressure measurement Pregnancy must be reasonably excluded Documentation of body mass index Use back-up method of contraception for first 7 days Not necessary to perform prior to starting OC: Sunday Start Pap smear Begin taking OCs on first Sunday after period starts STI testing Most pill packs arranged for Sunday start to avoid withdrawal bleed on weekend Breast examination Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies MAINTENANCE REGIMENS Monthly cycle Extended cycle Continuous Hormone-free interval may be 0, 2,4 or 7 days Compliance increased if prescription given for 1 year OC follow-up may be addressed at routine periodic exams scheduled for other health maintenance issues Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Rini Banerjee Ratan, MD MISSED PILLS? EFFICACY If a single pill is missed: Theoretical failure rate 0.1% • Take the pill as soon as noticed • Take the next pill when it is due • No additional contraception required Actual failure rate 8% If ≥ 2 consecutive pills are missed: Why the difference? • Back-up method of contraception should be used for 7 days Missed pills Failure to resume after pill-free interval If ≥ 2 consecutive pills are missed in first week of cycle: • Consider use of Emergency Contraception if intercourse occurs If ≤ 7pills are left in pack after the missed pill, • Finish pack and begin new pack the next day (skip hormone-free days) Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Large cohort study of 17,032 women participating in the Oxford-Family Planning Association showed no association between weight and risk of unintended pregnancy in women using either POP or COC Retrospective cohort study of women in HMO taking COC (<35 mcg EE) found women >70.5 kg had a higher risk of pregnancy (RR 1.6, 95% CI 1.1-2.4) Vessey M. Oral contraceptive failures and body weight: findings in a large cohort study. J Fam Plann Reprod Health Care. 2001 Apr;27(2):90-1. Risks & Side Effects Case Studies Risks & Side Effects Based on available evidence, the decreased efficacy of oral contraceptives in obese women would result in an additional 2-4 pregnancies per 100 woman-years of oral contraceptive use Insufficient evidence for recommending specific EE dose or for using a higher dose OC Holt VL, Scholes D, Wicklund KG, Cushing-Haugen KL, Daling JR. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol. 2005;105(1):46. Holt VL, Cushing-Haugen KL, Daling JR. Body weight and risk of oral contraceptive failure. Obstet Gynecol. 2002;99(5 Pt 1):820. Indications & Efficacy Indications & Efficacy The Bottom Line: OCs are OK Conflicting data Mechanisms Mechanisms EFFICACY IN OBESE WOMEN: EFFICACY IN OBESE WOMEN Introduction Introduction Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies NONCONTRACEPTIVE BENEFITS NONCONTRACEPTIVE BENEFITS Treatment of Hyperandrogenism: Acne and Hirsutism Treatment of Menstrual Disorders: Menorrhagia Inhibition of gonadotropin secretion, resulting in increased binding of androgens and thereby a decrease in ovarian androgen secretion Progestins suppress ovulation and cause endometrial atrophy over time Increase in serum SHBG concentrations, resulting in decrease in serum free androgen concentration Reduction of monthly menstrual blood flow Inhibition of adrenal androgen secretion Treatment of Menstrual Disorders: Dysmenorrhea Lighter, shorter predictable periods CAUTION: Levonorgestrel-containing preparations may aggravate hyperandrogenism and should be avoided Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Shortening pill-free interval may reduce symptoms associated with menses (headache, pelvic pain) Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Rini Banerjee Ratan, MD NONCONTRACEPTIVE BENEFITS NONCONTRACEPTIVE BENEFITS Treatment of Endometriosis Risk Reduction of Endometrial Cancer Induce decidualization and atrophy of endometrial tissue Use of estrogen-progestin OC decreases risk of endometrial cancer by 50% or greater May be as effective as GnRH agonist for pain control Protective effect persists for > 10 to 20 years after cessation of use Treatment of Premenstrual dysphoric disorder (PMDD) Likely due to progestin component and suppression of endometrial proliferation To minimize hormonal fluctuations Efficacy has not been studied in clinical trials Mueck AO, Seeger H, Rabe T. Hormonal contraception and risk of endometrial cancer: a systematic review. Endocr Relat Cancer. 2010 Dec;17(4):R263-71. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects NONCONTRACEPTIVE BENEFITS ABSOLUTE CONTRAINDICATIONS Risk Reduction of Ovarian Cancer Venous thromboembolism Prolonged use of oral contraceptives (OCs) reduces the risk of ovarian cancer Pregnancy Larger reductions in ovarian cancer risk occur with increasing duration of OC use Hepatocellular adenoma or malignant hepatoma • RR decreased by ~20 % for each 5 years of use • By 15 years, risk reduced by 50% Case Studies Cirrhosis Undiagnosed abnormal uterine bleeding Coronary artery disease Protective effect persists for 30 years after cessation of OCs, although effect attenuated over time • Less pronounced reduction with mucinous tumors Complicated valvular heart disease Women with inherited thrombophilias Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls.. Lancet. 2008;371(9609):303. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies ABSOLUTE CONTRAINDICATIONS Age ≥35 years and smoking ≥15 cigarettes per day Hypertension Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies WHO AND CDC GUIDELINES BOX. Categories for Classifying Hormonal Contraceptives and IUDs 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. (systolic ≥160 mmHg or diastolic ≥100 mmHg) History of stroke Breast cancer Migraine with aura Systemic lupus erythematosus (positive or unknown antiphospholipid antibodies) http://www.cdc.gov/Mmwr/preview/mmwrhtml/rr59e0528a13.htm Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Rini Banerjee Ratan, MD DRUG INTERACTIONS Metabolism of OCs accelerated by any drug that increases liver microsomal enzyme activity Contraceptive efficacy of OCs likely to be decreased in women taking these drugs Antibiotics Rifampin is the only antibiotic proven to decrease serum EE and progestin levels Back-up contraception is NOT required for any other antibiotic Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects DRUG INTERACTIONS DRUG INTERACTIONS Anticonvulsants Anticonvulsants WHO recommends that women taking following medications should NOT use hormonal contraception Anticonvulsants that do not appear to reduce contraceptive efficacy include: Case Studies (except DMPA) In one study, COCs decreased plasma concentrations of lamotrigine by 45-60% Contraceptive Technology Update June 2004; 25:61. Introduction Mechanisms Indications & Efficacy T Gabapentin Levetiracetam Tiagabine Lamotrigine Phenytoin Carbamazepine Barbiturates Topiramate Oxcarbazepine Risks & Side Effects Wilbur K, Ensom MH. Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants. Clin Pharmacokinet. 2000;38(4):355. Case Studies DRUG INTERACTIONS Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies OC WHILE BREASTFEEDING St. John’s Wort induces cytochrome P450, which may accelerate OC metabolism and decrease therapeutic efficacy Theoretical risk Estrogen-progestin contraceptives may suppress milk production in the early postpartum period CDC Delay initiation of OCs until 30 days postpartum if no additional risk factors for VTE ACOG Delay initiation of OCs until at least four weeks postpartum, and then only if lactation well-established WHO Delay initiation of OCs until six months postpartum Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Photo courtesy of www.breastfeeding.com Risks & Side Effects Case Studies Rini Banerjee Ratan, MD RISKS: CARDIOVASCULAR DISEASE RISKS: CARDIOVASCULAR DISEASE Myocardial Infarction Hypertension Thrombotic mechanism rather than development of atherosclerotic plaques Nurses' Health Study prospectively evaluated 70,000 nurses aged 25 to 42 years who used OC <35mcg EE Some, but not all, studies report that OC use may be associated with an increased risk of MI Adjusted for age, weight, smoking, family history, and other risk factors MI is a very rare event in healthy women of reproductive age, so even a doubling of the risk would result in an extremely low attributable risk Relative Risk of hypertension compared with women who never used OCs was 1.8 for current users and 1.2 for previous users. Women who use OC are not at increased risk for coronary heart disease later in life LidegaardØ, Løkkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366(24):2257. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies RISKS: CARDIOVASCULAR DISEASE Chasan-Taber L, Willett WC, Manson JE, Spiegelman D, Hunter DJ, Curhan G, Colditz GA, Stampfer MJ. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation. 1996;94(3):483. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies RISKS: VENOUS THROMBOEMBOLISM Stroke Stroke Small but significant increase in ischemic stroke risk Small but significant increase in ischemic stroke risk OC preparations containing <50 mcg EE associated with a lower risk of stroke than high-dose pills. OC preparations containing <50 mcg EE associated with a lower risk of stroke than high-dose pills. Absolute risk of stroke was very low in young women (11.3 per 100,000 patients per year) Absolute risk of stroke was very low in young women (11.3 per 100,000 patients per year) Risk appears to be similar for different progestins Risk appears to be similar for different progestins No increased risk of hemorrhagic stroke No increased risk of hemorrhagic stroke If stroke develops, STOP OC and DO NOT RESUME use If stroke develops, STOP OC and DO NOT RESUME use Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel Stroke in users of low-dose oral contraceptives.. N Engl J Med. 1996;335(1):8. Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel Stroke in users of low-dose oral contraceptives.. N Engl J Med. 1996;335(1):8. Schwartz SM, Siscovick DS, Longstreth WT Jr, Psaty BM, Beverly RK, Raghunathan TE, Lin D, Koepsell TD. Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med. 1997;127(8 Pt 1):596. Schwartz SM, Siscovick DS, Longstreth WT Jr, Psaty BM, Beverly RK, Raghunathan TE, Lin D, Koepsell TD. Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med. 1997;127(8 Pt 1):596. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies SIDE EFFECTS Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies SIDE EFFECTS Breakthrough Bleeding Amenorrhea Most common side effect Common with continuous and extended regimens Most common cause is missed pills Reassurance Increases with lower doses of EE Sexual function Observe for 3 cycles before intervention Consider cervical examination to rule out polyp, etc. No definitive evidence of negative effect on libido Weight Gain Fibroids Review of 44 trials found no evidence to support a causal relationship between OC use and weight gain Safe to use - OCs do not cause fibroids to grow ESHRE Capri Workshop Group, Collins J, Crosignani Endometrial bleeding. Hum Reprod Update. 2007;13(5):421. Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel Stroke in users of low-dose oral contraceptives.. N Engl J Med. 1996;335(1):8. Gallo MF, Lopez LM, Grimes DA, Schulz KF, Helmerhorst FM. Combination contraceptives: effects on weight.. Cochrane Database Syst Rev. 2006. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Schwartz SM, Siscovick DS, Longstreth WT Jr, Psaty BM, Beverly RK, Raghunathan TE, Lin D, Koepsell TD. Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med. 1997;127(8 Pt 1):596. Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Rini Banerjee Ratan, MD SIDE EFFECTS CONCLUSIONS Postpill Amenorrhea If no menses 3 months after discontinuing OC, begin usual evaluation for amenorrhea Headache No evidence to support strong association Do NOT use in patients with migraines + focal symptoms Do NOT use in patient with pseudotumor cerebri Oral contraceptives are a safe, reliable method of contraception which have numerous noncontraceptive benefits as well Most important mechanism of action for OCs is estrogen-induced inhibition of midcycle LH surge, thereby preventing ovulation OCs can be started at any time during the cycle Frequency tends to improve with continued use Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel Stroke in users of low-dose oral contraceptives.. N Engl J Med. 1996;335(1):8. Schwartz SM, Siscovick DS, Longstreth WT Jr, Psaty BM, Beverly RK, Raghunathan TE, Lin D, Koepsell TD. Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med. 1997;127(8 Pt 1):596. Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies CONCLUSIONS CASE STUDY 1 Missed pills are a common cause of contraceptive failure - back-up contraception should be advised for seven days after two missed pills 22 year old woman presents to your office requesting birth control. She reports that her menses are regular, but increasingly heavy and painful. She also has worsening facial acne. A number of medical conditions pose an unacceptable health risk for OC use. The WHO and CDC have published medical eligibility criteria (tables) for contraceptive use Relevant History: Plans to begin graduate school in fall Non-smoker Monogamous partner Normotensive Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies CASE STUDY 1 CASE STUDY 2 Good Options: 19 year old woman who is planning to become sexually active presents to your office requesting OCs. She takes Levetiracetam for a seizure disorder. Her last seizure was 6 months ago. OC with low androgenic activity • Norgestimate • Desogestrel • Drospirenone Relevant History: Avoid: Non-smoker OC with levonorgestrel may aggravate symptoms of hyperandrogenism Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies Normotensive Levetiracetam Introduction Mechanisms levels are therapeutic Indications & Efficacy Risks & Side Effects Case Studies Rini Banerjee Ratan, MD CASE STUDY 2 THANK YOU! Questions? Good Options: OC use is acceptable for this patient Continue to follow Levetiracetam levels OC with 20mcg EE Introduction Mechanisms Indications & Efficacy Risks & Side Effects Case Studies REFERENCES ACOG Practice Bulletin. Emergency Contraception. Number 69. December 2005 ACOG Practice Bulletin. Intrauterine Device. Number 59. January 2005 ACOG Practice Bulletin. Use of Hormonal Contraception in Women With Coexisting Medical Conditions . Number 73. June 2006 ACOG Patient Education Pamphlet. Birth Control. 2007 ACOG Patient Education Pamphlet. Birth Control Pills. 2006 ACOG Patient Education Pamphlet. Hormonal Contraception – Injections, Implants, Rings and Patches. 2007 Dempsey-Fanning, Angela. Medical Student Presentation on Contraception. Columbia University P&S 2007-8. Fulfilling the Promise: Public Policy and U.S. Family Planning Clinics, New York: Alan Guttmacher Institute 2000. Finer LB; Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health. 2006 Jun;38(2):90-6. Forrest JD, Timing of reproductive life stages, Obstetrics & Gynecology, 1993, 82(1):105–111. Planned Parenthood® Federation of America, Inc. Birth Control - Health Topics. www.plannedparenthood.com Singh S et al. Adding it Up: Benefits of Investing in Sexual and Reproductive Health Care, New York: AGI, 2004. World Health Organization Department of Reproductive Health and Research (WHO/RHR) and Johns Hopkins Bloomberg School of Public Health/Center for Communication Programs (CCP), INFO Project. Family Planning: A Global Handbook for Providers. Baltimore and Geneva: CCP and WHO, 2007. Zieman M. Overview of Contraception. 2008 UpToDate Zieman M. Hatcher RA et al. A Pocket Guide to Managing Contraception. Tiger, Georgia: Bridging the Gap Foundation, 2007. DELIVERY SYSTEMS FOR COMBINED HORMONAL CONTRACEPTION Transdermal Patch Vaginal Ring Introduction PROGESTIN-ONLY PILLS Contraceptive Counseling Methods Summary Case Studies EMERGENCY CONTRACEPTION Advantages Do not contain estrogen Mechanisms Inhibits/delays ovulation Prevents fertilization Prevents implantation Disadvantages Irregular cycles Efficacy vulnerable and highly dependent on consistent and correct use Methods Progesterone-only Combined pills oral contraception pills IUD There are NO medical contraindications to EC Introduction Contraceptive Counseling Methods Summary Case Studies Introduction Contraceptive Counseling Methods Summary Case Studies Rini Banerjee Ratan, MD EMERGENCY CONTRACEPTIVE PILLS: 75-95% EFFECTIVE 100 women after a single act of unprotected intercourse 8 pregnancies 1-2 pregnancies Placement of copper IUD within 5 days of unprotected intercourse is >99% effective Introduction Contraceptive Counseling Methods Summary Case Studies RHEDI/The Center for Reproductive Health Education In Family Medicine, Montefiore Medical Center, New York City. Copyright ©2007 RHEDI.