Oral contraceptives:  Does formulation matter?

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Applied Evidence

Oral contraceptives: Does formulation matter?

J Fam Pract. 2013 October;62(10):E1 - E12

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References

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12. Grimes DA, Lopez LM, O’Brien PA, et al. Progestin-only pills for contraception. Cochrane Database of Systematic Reviews 2010, Issue 1.

13. Van Vliet HAAM, Grimes DA, Helmerhorst FM, et al. Biphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev. 2009, Issue 2.

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15. Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

16. Elomaa K, Rolland R, Brosens I, et al. Omitting the first oral contraceptive pills of the cycle does not automatically lead to ovulation. Am J Obstet Gynecol. 1998;179:41-46.

17. Adams Hillard PJ. Oral contraception noncompliance: The extent of the problem. Adv Contracept. 1992;8(suppl 1):13-20.

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19. Anderson, FD, Hait, H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.

20. Kwiecien M, Edelman A, Nichols MD, et al. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial. Contraception. 2003;67:9-13.

21. Foidard JM, Sulak PJ, Schellschmidt I, et al. The Yasmin Extended Regimen Study Group. The use of an oral contraceptive containing ethinylestradiol and drospirenone in an extended regimen over 126 days. Contraception. 2006;73:34-40.

22. Shakespeare J, Neve E, Hodder E. Is norethisterone a lifestyle drug? Results of database analysis. BMJ. 2000;320:291.

23. Machado RB, de Melo NR, Maia Jr. H, et al. Effect of a continuous regimen of contraceptive combination of ethinylestradiol and drospirenone on lipid, carbohydrate and coagulation profiles. Contraception. 2010;81:102-106.

24. Edelman A, Gallo MF, Nichols, MD, et al. Continuous versus cyclic use of combined oral contraceptives for contraception: systematic Cochrane review of randomized controlled trials. Human Reprod. 2006;21:573-578.

25. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2008, Issue 4.

26. Machado RB, Tachotti F, Cavenague G, et al. Effects of two different oral contraceptives on total body water: a randomized study. Contraception. 2006;73:344-347.

27. Oelkers W, Foidart JM, Dombrovicz N, et al. Effects of a new oral contraceptive containing an anti-mineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clinical Endo Metabolism. 1995;80:1816-1821.

28. Foidart JM, Wuttke W, Bouw GM, et al. A comparative investigation of contraceptive reliability, cycle control, and tolerance of two monophasic oral contraceptives containing either drospirenone or desogestrel. Eur J Contracept Reprod Health Care. 2000;5:124-134.

29. Hussain, SF. Progestogen-only pills and high blood pressure: is there an association? A literature review. Contraception. 2004;69:89-97.

30. Suthipongse W, Taneepanichskul S. An open-label randomized comparative study of oral contraceptives between medications containing 3 mg drospirenone/30 mcg ethinylestradiol and 150 mcg levonorgestrel/30 mcg ethinylestradiol in Thai women. Contraception. 2004;69:23-26.

31. ACOG practice bulletin. No. 73. Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol. 2006;107:1453-1472.

32. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2009, Issue 3.

33. Thorneycroft IH, Stanczyk FZ, Bradshaw KD, et al. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception. 1999;60:255-262.

34. Rosen, MP, Breitkopf, DM, Nagamani, M. A randomized controlled trial of second- versus third-generation oral contraceptives in the treatment of acne vulgaris. Am J Obstet Gynecol. 2003;188:1158-1160.

35. Huber J, Foidart JM, Wuttke W, et al. Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone. Eur J Contracept Reprod Health Care. 2000;5:25-34.

36. Sangthawan, M, Taneepanichskul, S. A comparative study of monophasic oral contraceptives containing either drospirenone 3 mg or levonorgestrel 150 mcg on premenstrual symptoms. Contraception. 2005;71:1-77.

37. Lopez LM, Kaptein AA, Helmerhorst FM. Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database of Systematic Reviews. 2009, Issue 2.

38. Wong CL, Farquhar C, Roberts H, et al. Oral contraceptive pill for primary dysmenorrhoea. Cochrane Database Syst Rev. 2009, Issue 4.

39. Endrikat J, Klipping C, Cronin M, et al. An open label, comparative study of the effects of a dose-reduced oral contraceptive containing 20 mcg ethinyl estradiol and 100 mcg levonorgestrel on hemostatic, lipids, and carbohydrate metabolism variables. Contraception. 2002;65:215-221.

40. Brill K, Then A, Beisiegel U, et al. Investigation of the influence of two low-dose monophasic oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, on lipid metabolism in an open randomized trial. Contraception. 1996;54:291-297.

41. Barkfeldt J, Virkkunen A, Dieben T. The effects of two progestogen-only pills containing either desogestrel (75 mcg/day) or levonorgestrel (30 mcg/day) on lipid metabolism. Contraception. 2001; 64:295-299.

42. Knopp RH, Broyles FE, Cheung M, et al. Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel. Contraception. 2001;63:1-11.

43. Foulon T, Payen N, Laporte F, et al., Effects of two low-dose oral contraceptives containing ethinylestradiol and either desogestrel of levonorgestrel on serum lipids and lipoproteins with particular regards to LDL size. Contraception. 2001;64:11-16.

44. Ouyang P, Michos ED, Karas RH. Hormone replacement therapy and the cardiovascular system: lessons learned and unanswered questions. J Am Coll Cardiol. 2006;47:1741-1753.

45. Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost. 2001;86:395-403.

46. Vessey M, Mant D, Smith A, et al. Oral contraceptives and venous thromboembolism: findings in a large prospective study. BMJ. 1986;292:526.

47. Gerstman BB, Piper TM, Tomita DK, et al. Oral contraceptive estrogen dose and the risk of venous thromboembolic disease. Am J Epidemiol. 1991;133:32-137.

48. Rosendaal FR, Van Hylckama Vlieg A, et al. Estrogens, progestogens and thrombosis. J Thromb Haemost. 2003;1:1371-1380.

49. Farley TM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing risks. Hum Reprod Update. 1999;5:721-735.

50. Vandenbroucke JP, Helmerhorst FM, Bloemenkamp KW, et al. Third generation oral contraceptive and deep venous thrombosis: from epidemiologic controversy to new insight in coagulation. Am J Obstet Gynecol. 1997;177:887-891.

51. Hannaford P. Health consequences of oral combined oral contraceptives. Br Med Bull. 2000;56:749-760.

52. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ. 2001;323:131-134.

53. Heinemann LA, Dinger JC, Assmann A, et al. Use of oral contraceptives containing gestodene and risk of venous thromboembolism: outlook 10 years after the third-generation “pill scare”. Contraception. 2010;81:401-407.

54. Paoletti AM, Orru M, Floris S, et al. Evidence that treatment with monophasic oral contraceptive formulations containing ethinylestradiol plus gestodene reduces bone reabsorption in young women. Contraception. 2000;61:259-263.

55. Lopez LM, Grimes DA, Schulz KF, et al. Steroidal contraceptives: effect on bone fractures in women. Cochrane Database Syst Rev. 2009, Issue 2.

56. Schlesselman JJ. Oral contraceptives and neoplasia of the uterine corpus. Contraception. 1991;43:557-580.

57. Hankinson SE, Colditz GA, Hunter DJ, et al. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol. 1992;80:708-714.

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60. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 347:1713-27, 1996

61. World Health Organization. Carcinogenicity of combined hormonal contraceptives and combined menopausal treatment. September 2005. http://www.who.int/reproductivehealth/topics/ageing/cocs_hrt_statement.pdf. Accessed Aug 28, 2013.

Premenstrual symptoms. A 2005 open-label RCT compared the effects of DRSP/20 mcg EE with the second-generation progestin LNG/30 mcg EE on premenstrual symptoms after 6 menstrual cycles. In the premenstrual phase, the DRSP/EE group showed less negative mood and weight gain.³⁶

A 2012 Cochrane review examined the effects of OCs containing DRSP on premenstrual dysphoric disorder (PMDD) vs placebo and other OC formulations. The review included 5 trials and found that DRSP is associated with significantly greater improvements than placebo in symptoms of PMDD but was inconclusive on whether DRSP formulations have greater effects on PMDD than other OC formulations.³⁷

Dysmenorrhea. A 2009 Cochrane review compared 10 studies examining the role of different formulations of combined OCs in management of dysmenorrhea and concluded there is no difference in improvement between different OC preparations.³⁸

OCs and coronary heart disease

Estrogen has several favorable effects on circulating lipoproteins, including increasing high-density lipoprotein (HDL), and increasing low-density lipoprotein (LDL) receptor activity, thereby enhancing removal of LDL.

Women using a 20 mcg EE/100-mcg LNG OCP experienced reductions in HDL and small increases in LDL and triglycerides compared with a 30 mcg EE/150-mcg LNG OCP.³⁹ A study of gestodene 75 mcg with either EE 20 mcg or 30 mcg for 13 cycles, found that there was a greater increase in triglyceride levels in the formulation with a higher dose of estrogen (p = 0.029).⁴⁰

Barkfeldt and colleagues⁴¹ conducted a double-blind RCT that evaluated the effects of lipid metabolism on 98 women who received 2 different types of progestin-only pills, desogestrel 75 mcg/day vs LNG 30 mcg/day. There were minimal changes in the lipid profile except for decreasing trends in levels of HDL, its subfractions, and apolipoprotein-I and -II. No differences were observed between the 2 formulations despite the higher progestin dose found in desogestrel, including no changes in LDL or apolipoprotein-B.⁴¹

Third generation progestins with “lesser androgenicity” may allow more “expression” of the effects of estrogen on lipids. A prospective study of 66 women over 9 months comparing either desogestrel (50/100/150 mcg) and EE (35/30/30 mcg), or LNG (50/100/150 mcg) and EE (30/40/30 mcg), showed that the desogestrel formulation increased HDL whereas LNG decreased HDL.⁴² Another study compared monophasic desogestrel/EE with triphasic LNG/EE in 37 healthy young women. While both preparations led to an increase in total cholesterol, the desogestrel formulation led to a reduction in the LDL.⁴³ A 1995 study of drospirenone (DRSP) compared with LNG for 6 months, showed that HDL increased in the DRSP group (P < 0.05) but triglyceride levels showed a greater increase in the DRSP (P <0.05).²⁷

The use of OCs in the absence of risk factors does not appear to promote CAD and there is no reason to withhold OCs from dyslipidemic women. In women with LDL greater than 160 mg/dL or multiple cardiac risk factors, ACOG recommends an alternative non-hormonal method such as an intrauterine device (IUD).³¹

OCs and glucose metabolism, thromboembolism

Glucose metabolism. Oelkers and colleagues²⁷ studied glucose levels in 80 healthy women assigned to 4 equal groups who received 3 mg of drospirenone combined with 30-, 20-, and 15-mcg doses of EE or LNG/30-mcg EE. Each woman performed oral glucose tolerance tests at pre-treatment and at the end of the 6-month OCP cycle. On treatment, fasting glucose was unchanged for all groups, but the area under the curve for the glucose tolerance increased for all formulations. Although not statistically significant between groups, the drospirenone/30-mcg EE group had a 19% worsening of glucose tolerance.²⁷ This research suggests that women with Type 1 or 2 diabetes who are otherwise healthy, non-smokers and younger than 35 years of age can safely use OCs.

Thromboembolism. Estrogen has been known to increase the risk of venous thromboembolism (VTE) by increasing prothrombin and decreasing antithrombin III.⁴⁴ In OC users, the incidence of VTE is increased by a factor of 3 to 5.⁴⁵ While several studies have compared high-dose estrogen (50 mcg) with low-dose (35 mcg or less) OCs^46,47 there is no information about any differences in low (25-35 mcg) EE vs ultra-low doses (10 mcg). ACOG recommends a nonestrogen hormonal alternative such as progestin-only pills or an IUD, for obese women.

Third generation desogestrel-containing OCs have a slightly increased risk of VTE compared with second generation pills⁴⁸unexplained by bias and confounding factors.^49,50 It has been estimated that 25 additional cases of VTE occur every year among 100,000 women using thirrd generation OCs compared with 10 additional cases per 100,000 women using second generation OCs.⁵¹ A meta-analysis that included 9 case control and 3 cohort studies estimated an odds ratio for third vs second generation OCs of 1.7 (95% CI, 1.4 to 2.0).⁵² A 2010 meta-analysis refutes these finding and found no differences in third generation gestodene progestin vs other OCs.⁵³ Because obesity (BMI >30 kg/m2) is an independent risk factor for VTE, ACOG recommends an alternative non-estrogen hormonal method such as progestin-only pills or IUD in obese women.³¹