THE BALANCE OF BENEFITS & RISK OF ORAL CONTRACEPTIVES-USE

1. THE BALANCE OF BENEFITS & RISK OF ORAL CONTRACEPTIVES-USE Prof.Dr. Merih BAYRAM Gazi Üniversitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum Anabilim Dalı

2. Types of Hormonal Contraceptives Combination Oral Contraceptives Progestin-only Contraceptives Thickening of cervical mucus, decrease sperm penetration Endometrial alterations to impair implantation Decreasing the frequency of GnRH pulses Inhibit ovulation by suppressing HPO function Modify mid-cycle surges of LH/FSH Diminish ovarian hormone production • LH and FSH levels are suppressed • Mid-cycle surge of LH is absent • Endogenous steroid levels are diminished • Inhibit ovulation • Progesterone diminishes the frequency of GnRH pulses • Thicken cervical mucus to impede sperm transit • Produce unfavorable endometrial changes for ovum implantation

3. Types of Hormonal Contraceptives Combination Oral Contraceptives Progestin-only Contraceptives Theoretical Efficacy is 99 % Norethindrone Norgestrel MPA Theoretical Efficacy is 99.9 % Estrogens: Ethinyl estradiol Mestranol Progestins: 19-nor compounds Estranes: Norethindrone Lynestrenol Gonanes: Levonorgestrel Desogestrel Gestodene Norgestimate Spironolactone derivate:Drospirenone

4. Combination Oral Contraceptives Cardiovascular effects • Any increased risk of MI in past users • Higher risk of MI in current users • The more increased risk of MI in COC-users than non-users OR 2.48 (95% CI, 1.91-3.22) • Insignificant risk of MI in past users versus non-users OR 1.15 (95% CI, 0.98-1.35) • The OR with second-generation 2.5 (CI 1.5-4.1) was higher than third-generation with OR 1.3 (CI 0.7-2.5) • Hypertension, smoking and hyperchlosterolemia, the factors increasing the risk of MI Kiley J,Hammond C. Clin Obstet Gynecol,2007:50:868 Tanis BJ,et al. N Engl Med.2001;345:1787

5. Combination Oral Contraceptives Cardiovascular effects • Hypertension in 4% to 5% of normotensive women with early high-dose COC • Increase of hypertension in 10% to 15% of preexisting hypertensive women with early high-dose COC • The much lower incidence with newer low-dose preparations • The increased serum HDL and LDL levels with estrogens and the opposite effect with progestins • No significant change in total serum cholesterol or lipoprotein profils, but slight increases in triglycerides with low-dose preparations Godmann-Gilmann’s, The Pharmacologyical Basis of Therapeutics 2006

6. Cardiovascular Mortality Risk with Smoking and COC-use Oral contraceptive nonuser Oral contraceptive user Cases per 100,000 Woman-Years Nonsmoker Nonsmoker Smoker Smoker Attributable Risk/100,000 User-Years 3.03 19.4 0.06 1.73 ≥ 35 years of age < 35 years of age Sherif K. Am J Obstet Gynecol. 1999;180(Pt 2):S343-S348.

7. Progestin-Only ContraceptivesCardiovascular effects • No effect on blood pressure • Decreased HDL levels and increased LDL levels Godmann-Gilmann’s, The Pharmacologyical Basis of Therapeutics 2006

8. Combination Oral ContraceptivesCancers • The incidence of cancer of endometrial, cervical, ovarian, breast and liver may increase because of growth-promoting effects of estrogens • About twofold risk of cervical cancer in long-term users (>5 years) • About twofold risk of liver cancer after 4 to 8 years of use Moodley J,2004, Godmann-Gilmann’s, The Pharmacologyical Basis of Therapeutics 2006

9. Oral Contraceptive Use and Gynecological Carcinomas *Comparison for >97 monthsof users with nonusers. †Age-adjusted comparison of women ever using an oral contraceptive with women who never used one. Vessey M, Painter R. Br J Cancer. 2006;95:385-389.

10. Combination Oral ContraceptivesCancers • The low risk of breast cancer in women of childbearing age , RR: 1.1 to 1.2 • No affect on the incidence of breast cancer with duration of use, type of component, age at first use, parity • No difference in breast cancer incidence between past users and never users at 10 years after discontinuation • The similar incidence of the phenotype of breast cancer (lobular and ductal ) Newcomer LM,et al. Cancer Causes Control.2003;14:225 Nyante SJ,et al.Int J Cancer.2008;122:936

11. Combination Oral ContraceptivesCancers • The Oxford Family Planning Study, a large cohort study of 17.032 women followed for up to 16 years, Breast cancer RR 1.0 (95% CI 0.8-1.1) • The meta-analyses of 54 worldwide studies, the Collaborative Group on Hormonal Factors in Breast Cancer; • a modest risk of increase during COC-use RR=1.24 (95% CI1.15-1.33) • 1 to 4 years after cessation of use RR=1.16 (95% CI 1.08-1.23) • 5 to 9 years after cessation of use RR=1.07 (95% CI 1.02-1.13) • No increased risk after cessation of 10 or more years of use Vessey M,Painter R. Br J Cancer,2006 ;95:385 Collaborative Group on Hormonal Factors in Breast Cancer.Lancet.1996;347:1713

12. A Case-Control Study Shows No Increased Risk for Breast Cancer With Oral Contraceptive Use • NICHD Women’s CARE Study • Subjects: >9200 women from 35 to 64 years of age • Case-control study design: half of the subjects had a diagnosis of breast cancer • Study setting: metropolitan areas of Atlanta, Detroit, Los Angeles, Philadelphia, and Seattle • Study method: interview about oral contraceptive and hormone use • Neither current users (relative risk [RR] 1.0, confidence interval [CI] 0.8–1.3) nor previous users (RR 0.9, CI 0.8–1.0) had no increased incidence of breast cancer diagnosis • No difference was found between the high-dose (>50 µg) and the low-dose (<50 µg) estrogen formulations *National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study Marchbanks PA, et al. NEJM.2002;346:2025-2032.

13. Combination Oral ContraceptivesCancers • 40% less likely of ovarian cancer in users • 80% less likely of ovarian cancer in users of 10 years or more • It is unclear whether COC-user confers similar benefit in patients with the BRCA1 or BRCA2 mutations • 45% increased risk in carriers of BRCA1 • 25% increased risk in carriers of BRCA2 • COC reduce ovarian cancer risk in carriers of BRCA1 and BRCA2 mutations • 15% reduction with short-term oral contraceptive use (≥1 year) • 60% reduction with long-term oral contraceptive use (≥6 years) Vessey MP,Painter R.Br J Cancer.1995;71:1340 Whittemore AS, et al. Br J Cancer. 2004;91:1911-1915;Narod SA, et al. N Engl J Med. 1998;339:424-428

14. Combination Oral ContraceptivesCancers • The mechanism of lowering the risk of ovarian cancer ; • Decrease of recurrent ovarian injury with suppression of ovulation • Chronic suppression of gonadotropin secretion • Greater protection with progestins Schildkraut JM, et al.J Natnl Cancer Inst.2002;94:32

15. Collaborative Group an Epidemiological Studies of Ovarian Cancer.Lancet.2008;371:303

16. Combination Oral ContraceptivesCancers The decrease of 50% incidence of endometrial cancer • 20% and 80% reduction after 1 year and 10 years use respectively • Adenocarcinoma and adenosquamous carcinoma, the most common endometrial carcinomas of reduced incidence with COC-use Kiley J,Hammond C.Clin Obstet Gynecol.2007;50:868

17. Progestin-Only ContraceptivesCancers • Numerous human studies showing no any increases in breast, endometrial, cervical or ovarian cancer Westhoff C. Contraception. 2003;68:75

18. Combination Oral ContraceptivesVenous Thromboembolism • The fourfold risk versus no use • OR : 3.2 (CI 2.3-4.3) with second-generation • OR : 4.8 (3.4-6.7) with third-generation • OR1.5 (CI 1.1-2.1) with third-generation products versus second-generation products • The risk of VTE is dose-dependent 50 mcg or more of EE Blickstein D,et al.Curr Opin Obstet Gynecol.2007;19:370

19. Risks of Oral Contraceptives:Nonfatal Venous Thromboembolism Estimated Average Risk/ 100,000 Women/Year Non-Oral Contraceptive Users Pregnant Women Oral Contraceptive Users Food and Drug Administration. FDA Talk Paper. Nov. 24, 1995.

20. Combination Oral ContraceptivesVenous Thromboembolism Additive factors of VTE together with COC • Hereditary thrombophilias • Factor V Leiden mutation OR: 6.4 to 99 • Smoking • Age Probably mechanisms: • Increase levels of D-dimers • Increase thrombin-activatable fibrinolysis inhibitor • Induce a prolongation of the clot lysis time • a blocking anti-factor XI antibody Mohllajee AP,et al.Contraception.2006;73:166

21. Progestin-Only ContraceptivesVenous Thromboembolism • There is no evidence that the progestin-only preparations increase thromboembolic events • Progestin-only pill don’t change the fibrinolytic parameters Godmann-Gilmann’s, The Pharmacologyical Basis of Therapeutics 2006 Kemmeren JM, et al. Blood. 2004;103:927

22. Combination Oral ContraceptivesStroke • Stroke is a rare event among COC-users ≥50 mcg EE RR=3.95 (95% CI,2.4-6.5) <50 mcg EE RR=2.19 (95% CI,1.1-4.2) • The risk of stroke twofolds among current COC-users, but do not correlate with increasing dose of estrogen or type of progestin • The relative risk of stroke in users of any type versus non-users 2.3 (CI 1.6-3.3) • First-generation OCs OR 1.7 (CI 0.7-4.4) • Second-generation OCs OR 2.4 (CI 1.6-3.7) • Third-generation OCs OR 2.0 (CI1.2-3.5) Kemmeren JM,et al.Stroke.2002;33:1202Kiley J,Hammond C.Clin Obstet Gynecol.2007;50:868

23. Combination Oral ContraceptivesMetabolic Effects The effects of sex streoids on glucose metabolism and insulin sensitivity are complex: • High dose OC impaires glucose tolerance (increase in fasting glucose and insulin levels) and responses to glucose challenge • Low-dose COC may improve insulin sensitivity • High dose progestins raise LDL and reduce HDL levels • 100 mg of levonorgestrel exert undesirable effects on blood lipids • Desogestrel, norgestimate and gestodene improve HDL/LDL ratios Hatcher RA,et al.Contraseptive Tecnology. 18th ed.2004 Bushnell CD.Lancet Neurol.2005;4:743

24. No statistical difference in weight gain (0.5 kg) between users of oral contraceptives (30 g EE) and nonusers Weight Gain and Oral Contraceptives: Controlled Studies Do Not Show Link Placebo-controlled double-blind crossover (N=380) ouble-blind crossover (N=380) Weight gain (5 lb) in ~ 25% of women; no significant difference between the placebo group and the users of oral contraceptive ( 50 g ethinylestradiol [EE]) Goldzieher et al., 1971 Reubinoff et al., Prospective, randomized (N=49) 1995 Gallo et al., No association between combination oral contraceptives and weight gain Systematic review of randomized controlled trials 2006 Huber LRB,et al., 2007 Goldzieher JW, et al. FertilSteril. 1971;22:609-623; Reubinoff BE, et al. FertilSteril. 1995;63:516-521;Gallo MF, et al. Cochrane Database Syst Rev. 2006;(1):CD003987. Brunner LRB and Toth J.Am J Epidemiology.2007;166:1307

25. Progestin-Only ContraceptivesMetabolic Effects • Mood changes and weight gain have been reported Westhoff C. Contraception.2003;68:75

26. Combination Oral ContraceptivesNoncontraceptive Benefits • Decrease of quantity of menstruel flow, severity of dysmenorrhea, acne, benign breast disease incidence and several other physical parameters Kiley J,Hammond C.Clin Obstet Gynecol.2007;4:868

27. Combination Oral ContraceptivesMenstrual Benefits • Decrease menstrual and periovulatory pain by decreasing prostaglandin release • Control menorrhagia • 43% reduction in menstrual flow with 30 mcg EE/150 mcg levonorgestrel • Reduce the risk of iron deficiency anemia • Reduce the frequency and severity of menstrual associated mastalgia, mood dysphoria and fluid retention with drospirenone-containing formulations Larsson G,et al.Contraception.2002;46:327

28. Combination Oral ContraceptivesBenign Breast Disease (BBD) • Benefits depend on the estrogen dose, progestin type and underlying breast pathology • The decrease risk for nonproliferative BBD with long-term-use • The decrease risk for proliferative BBD without atypia • Not seem to reduce risk of breast cancer between BBD and breast carcinoma, but may augment the risk • The degree of risk reduction is positively correlated with duration of use, >7 years-use reduce their risk by as much as 40% (RR 0.64, CI 0.47-0.87) Charreau I,et al.Eur J Cancer Prev.1993;2:147 Rohan TE,et al.Int J Cancer.1992;82:191 Collaborative Group on Hormonal Factors in Breast Cancer.Lancet.1996;347:1713

29. Combination Oral ContraceptivesBone Mineral Density • Prevents osteoporosis with many mechanisms • Increase cortical and trabecular bone mass Kuohung W,et al.Contraception.2000;61:77 Vessey M,et al.Contraception.1998;57:231

30. Progestin-Only Contraceptives Bone Mineral Density • There have been several reports of decreased bone density • BMD and BMC in oligomenorrheic or eumenorrheic female runners are yielded 43% reduction • The rate of stress fracture is 38% Cobb KLL,et al.Medicine & Science in Sports & Exercise.2007 ;39:1464

31. Combination Oral ContraceptivesPelvic Inflammatory Disease Reduce the risk of acute pelvic inflammatory disease • 50% to 80% reduction in the risk of acute salpingitis among pill users • Proposed mechanisms: • tickening of cervical mucus • altered tubal motility • impeding ascent of pathogens • decreased menstruum to serve nidus for infection Rubin GL,et al.Am J Obstet Gynecol.1982;144:630 Wolner-Hassen P,et al.Obstet Gynecol.1985;66:233 Ness RB,et al.Am J Obstet Gynecol.1997;176:580

32. Combination Oral ContraceptivesDermatologic Benefits •  Androgen secretion in the ovaries and adrenal glands through their estrogenic effects •  Production of testosterone •  Levels of free testosterone •  Production of dihydrotestosterone •  Sex hormone-binding globulin to bind androgens •  5-reductase activity • Reduce the incidence and severity of acne van derVange N, et al. Contraception.1990;41:345; Cassidenti DL, et al. Obstet Gynecol. 1991;78:103

33. EE/LNG Oral Contraceptives Decrease Inflammatory Skin Lesions 0 Placebo EE/LNG *P<0.05 -5 Mean Change From Baseline in Inflammatory Lesion Counts * -10 * * -15 2 5 6 1 3 4 0 28-Day Cycle EE/LNG=20 µg ethinyl estradiol/100 µg levonorgestrel Adapted from Leyden J et al. J Am Acad Dermatol. 2002;47(3):399-409.

34. Oral Contraceptives Containing 20-µg EthinylEstradiol Decrease the Total Number of Acne Lesions Baseline Cycle 3 Baseline Cycle 3 EE/NETA EE/LNG EE/LGN = 20 g ethinyl estradiol/100 g levonorgestrel; EE/NETA = 20 g ethinyl estradiol/1,000 g norethindrone acetate Thorneycroft IH, et al. Contraception. 1999;60:255-262. Thorneycroft IH, et al. Contraception. 1999;60:255-262.

35. Oral Contraceptives Decrease Dysmenorrhea-Related Pain in Adolescents *P=0.004 vs. placebo * Mean (±SD) MMDQ Pain Score Baseline 3 Months MMDQ = Moos Menstrual Distress Questionnaire; Oral Contraceptive = 20 µg ethinyl estradiol/100 µg levonorgestrel. Davis AR, et al. Obstet Gynecol. 2005;106:97-104.

36. Extended Use of the Contraceptive Ring: Premenstrual Symptom Improvement 28-day cycle 49-day cycle 91-day cycle 364-day cycle Study Exit Interviews (%) Menstrual Pain Less * Premenstrual Syndrome Less† Headache Less/Much Less† Overall Satisfaction *Compared with past contraceptive method use † Among those reporting a history of premenstrual syndrome Miller L, et al. Obstet Gynecol. 2005;106:473

37. Adolescents’ Anticipated vs. Reported Side Effects: EE 20 µg/LNG 100 µg Formulation Anticipated at baseline Reported at 6 months Percent Breast Tenderness Weight Gain Spotting Nausea Mood Changes Headaches Symptom Rosenthal SL et al. 12th World Congress of Pediatric & Adolescent Gynecology. June 1998;Helsinki, Finland.

38. Combination Oral ContraceptivesNoncontraceptive Benefits • COCs reduce the risk of ectopic pregnancy by inhibiting ovulation • Cycle-related: • Irregular cycles • Dysmenorrhea • Menorrhagia • Anemia • Functional ovarian cysts • Endometriosis, adenomyosis Adapted from Grimes DA et al, eds. Modern Contraception: Updatesfrom The Contraception Report. Emron;1997:1-100

39. Conclusion Beneficial Effects with Combination Oral Contraceptives • Indisputably have beneficial effects on menorrhagia, dysmenorrhea, ovulatory pain, acne and hirsutism • Varying magnitude have preventive effects on salpingitis, endometriosis, adenomyosis and myomas • Lower the risk of endometrial, ovarian and possibly colon cancer • Increase bone mass • May reduce the risk of ovarian cysts, rheumatoid arthritis and benign breast disease • May have protective effect against atherosclerosis

40. Conclusion Untoward Effects with Combination Oral Contraceptives • Cardiovascular effects hypertension myocardial infarction • Stroke ; ischemic or haemorrhagic • Venous trombosis and embolism, especially with third-generation • Cancers increase breast hepatocellular cervical • Endocrin and metabolic effect, impaires glucose tolerance and responses to glucose challenge • Special infections, HIV, HPV