User login
Oral contraceptives: Does formulation matter?
• Consider prescribing monophasic pills as the first choice for women starting oral contraceptives (OCs) given the lack of advantage in using multiphasic formulations, and the larger number of studies showing the safety and efficacy of monophasic pills.
• Avoid prescribing OCs with estrogen—even with ultra-low estrogen—to women at high risk for venous thromboembolism, given that there are no studies that show differences in low (25-35 mcg) ethinyl estradiol vs ultra-low doses (10 mcg) formulas.
Strength of recommendation (SOR)
• Good-quality patient-oriented evidence
• Inconsistent or limited-quality patient-oriented evidence
• Consensus, usual practice, opinion, disease-oriented evidence, case series
For a healthy woman interested in contraception, there are multiple oral contraceptive (OC) formulations on the market from which to choose. But are there any significant differences in their effectiveness or safety profiles that make one formulation superior?
Comparative trials of OCs have attempted to answer these questions by evaluating formulations that contain the synthetic components: ethinyl estradiol, norethindrone, levonorgestrel, desogestrel, norgestimate, gestodene, and drospirenone.
Unfortunately, many studies that have evaluated OCs have had methodological weaknesses, making their clinical significance confusing. Few randomized controlled trials (RCTs) have been double blinded or powered to find infrequent outcomes like pregnancy or adverse events. Trials are rarely reproduced by other researchers and many have been funded by pharmaceutical companies with conflicts of interest. Despite these shortcomings, it is possible to glean valuable data from existing studies.
With that in mind, our purpose here is to review whether there are significant differences in effectiveness, cycle control (bleeding), side effects, or satisfaction that may help physicians and patients select the appropriate formulation.
Comparing OC Effectiveness
OC effectiveness is determined by the inherent properties to prevent ovulation, conception, and/or implantation when the formulation is used correctly.1,2 and during typical inconsistent use in the population (ie, adherence).3 Effectiveness is also measured by whether the method is discontinued and there is a gap in contraception allowing pregnancy to occur.
There is no evidence that any combined or progesterone-only hormonal formulation is inherently better at preventing ovulation, conception, or implantation. (For more on combined OCs, see “A closer look at combined OCs,” on page E3.) Theoretically, progestins with longer half-lives may be more effective at preventing ovulation if a pill is not taken the same time each day, and extended cycle pills provide more continuous suppression of ovulation. But, no studies have found any formulation to be more effective.
A 2004 Cochrane review4 compared progestins in OCs by examining 22 different trials with various study protocols. The review found a lower rate of discontinuation in patients taking OCs with second generation progestins compared with first generation progestins (relative risk [RR]=0.79; 95% Extended-cycle OCs have a greater risk of breakthrough bleeding, which can decrease adherence and increase discontinuation, thus increasing the risk of pregnancy. confidence interval [CI] 0.61-0.91), and an even lower rate of discontinuation with third generation OCs. Additionally, cycle control was better in second generation progestin OCs compared with first generation progestin OCs. Rates of effectiveness, cycle control and side effects were similar between drospirenone and desogestrel. The review concluded that second and third generation progestins are preferred over first generation progestins in combined OCs,4 although the evidence is not strong.
What about generics? To be considered an FDA-approved bioequivalent generic to a brand name formulation, pharmacokinetic studies must demonstrate that a product provides equivalent serum levels. There are no studies evaluating differences in effectiveness of generic vs brand name OCs. Generic medications typically cost about 50% less than brand name OCs.5 The Society of Obstetricians and Gynaecologists of Canada supports generic formulations “providing increased choice and less expensive options.”6
What are the differences among the options?
While OCs, in general, have a reputation of causing side effects, when compared with a placebo, no significant findings have been noted in the frequency of headache, nausea, vomiting, breast pain, or weight gain.7,8 That being the case, it is unlikely there are differences among formulations.
Ultra-low estrogen. Estrogen in OCs has been reduced to 10 to 35 mcg to minimize side effects and adverse events, yet remain at a level sufficient to provide menstrual cycle control with minimal breakthrough bleeding. Advantages of ultra-low estrogen 10 mcg products include reduction of estrogen, side effects9 but the disadvantage includes breakthrough bleeding, which can negatively affect adherence.10 In a double-blind RCT of 649 women comparing OCs with gestodene 75 mcg and either 20 mcg or 30 mcg ethinyl estradiol (EE), more intermenstrual breakthrough bleeding occurred with the 20 mcg group (P<0.05). This difference was not enough to cause an increased discontinuation rate in the 20-mcg EE group.11
Progestin-only pills (POPs) are recommended for women who cannot or should not take estrogen in OCs, and women who are breastfeeding. The advantages of POPs include a simplified and fixed regimen. Disadvantages include irregular bleeding and menstrual cycle length. A 2010 Cochrane review examined various POP formulations in 6 different trials and concluded that there is not sufficient research to compare POPs in terms of efficacy, acceptability, and continuation rates.12
Monophasic vs multiphasic OCs. Biphasic and triphasic OCs were introduced in an effort to decrease the amount of hormone and the side effects. Their phasic nature also attempts to mimic the pattern of rising and falling estrogen and progesterone levels seen during a normal menstrual cycle. Cochrane reviews in 200913 and 201014 compared the cycle control and side effects of biphasic vs monophasic, and triphasic vs monophasic formulations of OCs, respectively. The 2009 review comparing biphasic and monophasic OCPs was limited to one study of 533 women using biphasic pills and 481 women using monophasic pills. No differences were found in intermenstrual bleeding, amenorrhea, or discontinuation due to intermenstrual bleeding.
The 2011 review comparing triphasic and monophasic OCs included 21 studies, and found no significant difference in discontinuation due to medical reasons, cycle disturbance, intermenstrual bleeding, or adverse events. Both of the Cochrane reviews concluded that monophasic pills should be the first choice for women starting OCs given the lack of advantage in using multiphasic formulations, and the larger number of studies showing the safety and efficacy of monophasic pills.
The 2009 Cochrane review compared biphasic and triphasic OCPs in terms of cycle control and side effects.13The first trial examined in this review included 458 women and compared 2 biphasic pills and one triphasic pill, all containing LNG and EE. It found no important differences between all 3 formulations, but found that 252 women of the initial 458 (55%) discontinued the study for various reasons.
The second trial included 469 women (169 of whom withdrew from the study or 36%), and compared a biphasic pill containing norethindrone with 2 triphasic pills, one containing LNG and the other containing norethindrone. This study showed no differences between the biphasic and triphasic pills containing norethindrone, but inferior cycle control in the biphasic pill containing norethindrone compared with the triphasic containing LNG. The review concluded that the choice of progestin type (LNG preferred over norethindrone) might be more important than the choice of phasic regimen.13
Monthly vs extended cycle OCs. When OCs were first introduced, researchers believed that women would prefer a 21-day formulation followed by a 7-day pill free time that mimicked an average woman’s menstrual cycle because the withdrawal bleeding would be an indicator that she was not pregnant. Extending the time between menses has garnered increased interest. Extended-cycle preparations are available for durations ranging from 84 to 365 days.15
A study of 99 women evaluated the impact of omitting the first 3 combined OC pills (second and third generation) on ovulation during a 28-day cycle. While none of the women experienced ovulation, follicle-stimulating hormone reached a maximal serum concentration in most women during the first 7 pill-free days, indicating complete pituitary recovery. Additionally, the researchers detected increases in serum estradiol, indicating that follicular growth up to preovulatory size is common in women missing the first one to 3 pills of their contraceptive cycle.16 Non-adherence often occurs during transitions between successive packs of Ocs.17 It has been reported that 47% of women using OCPs miss one pill and 22% miss 2 pills per cycle.18 Ovulation and pregnancy are more likely to occur if pills are missed in the first week after menses.
Extended-cycle OCs prevent hormonal fluctuations and provide continuous suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH), decreasing the likelihood of ovulation and, therefore, pregnancy. Since the extended-cycle regimen decreases the number of transitions between packs of OCs, one might expect a reduction in the risk associated with non-adherence at the beginning of a cycle. However, extended cycles have a greater risk of breakthrough bleeding, which can decrease adherence and increase discontinuation of the method and, thereby, increase the risk of pregnancy.
A multicenter RCT of 682 women examined the efficacy and safety of the extended-cycle OC Seasonale (30 mcg EE/150 mcg LNG) compared with a traditional cycle OC Nordette-28 (30 mcg EE/150 mcg LNG). Women received either 4, 91-day extended cycles (n=456) or 13, 28-day regular cycle (n=226) regimens over the course of one year. On average, 38% of women in the extended cycle group reported unscheduled (breakthrough) bleeding, while 18% of women in the conventional cycle group reported unscheduled bleeding. Breakthrough bleeding decreased with each successive cycle of the extended regimen, from a median of 12 days with the first cycle, to a median of 4 days during the fourth and final cycle. This study also reported no significant differences in side effects between the extended and traditional cycle regimens, including changes in lipids, body weight, blood pressure, or endometrial hyperplasia.19
Another RCT examined the difference in bleeding patterns, side effects, and acceptability between a standard 28-day cycle OC and an extended regimen 168-day cycle OC in 32 women. Both OCs contained 20 mcg EE and 100 mcg LNG, and the study was conducted over 6 months. Women in the extended cycle regimen reported significantly fewer days of bloating (0.7 vs 11.1 days; P=0.04), and menstrual pain (1.9 vs 13.3 days; P<0.01). There was no significant difference in reported headache, breast tenderness, nausea, depression, or premenstrual symptoms. Women in the extended cycle group also reported significantly fewer bleeding days that required sanitary pads (18.4 vs 33.8 days; P<0.01). However, there was no statistically significant difference in the total number of days where any degree of bleeding occurred (34.9 days in the monthly cycle group, 25.9 days in the extended cycle group; P=0.33).20
In a study of 126-day extended-cycle OCs with 30 mcg EE and 3 mg drospirenone, the bleeding profile improved over time and endometrial biopsies revealed no hyperplasia.21 Another benefit of the extended cycle is personal preference, ie, controlling the timing of one’s menses,22 for example, in athletes during training and competition.
Continuous use of OCs prevents the cyclic fluctuations of serum levels of EE and progestogen and, hence, the cyclic variations of related serum-based metabolic parameters. Extended cycle OCs can make it easier to titrate other medications affected by hormonal fluctuations. Another study of extended cycle drospirenone OCs compared with monthly OCs over 6 months showed no difference in lipid, carbohydrate, and coagulation markers.23
Six RCTs were reviewed in a Cochrane review of monthly vs extended cycle combined pills. It found no significant differences in efficacy, adherence, discontinuation rates, and patient satisfaction. The only difference was improvement of menstrual-associated symptoms of “headaches, genital irritation, tiredness, bloating and menstrual pain” with the extended cycle regimen.24
OCs effect on weight, BP, and premenstrual symptoms
Weight gain. A 2008 Cochrane review examined 3 placebo-controlled RCTs and concluded that the available evidence was insufficient to determine the effect of combined hormonal contraceptives on weight, and that larger doses of estrogen were not shown to cause larger weight gain.25
One RCT examined the effects of OCs on variations of total body water, fat mass, and fat-free mass throughout the menstrual cycle to determine if different doses of estrogen (15 mcg vs 30 mcg EE) or different types of progestins (gestodene 60 mcg vs drospirenone 3 mg) impact weight gain. This study only included 80 women randomized to the 2 treatment groups and an additional control group using male condoms. No differences were found in total body water or fat mass. There was, however, a significant increase in the fat-free mass in women of the EE/gestodene group when compared to controls, indicating a possible effect of the androgenic properties of gestodene compared with drospirenone (which has anti-androgen properties) in increasing muscle mass.26
In a 6 month study of drospirenone compared with LNG, mean body weight fell by 0.8 to 1.7 kg in women treated with drospirenone compared with a 0.7 kg weight gain in the LNG group (P < 0.05).27 A multicenter RCT comparing OCs with EE 30 mcg/drospirenone 3 mg, and EE 30 mcg/desogestrel 150 mcg, concluded that EE/drospirenone has a more favorable effect on body weight than EE/desogestrel. This finding may have resulted from the antimineralocorticoid, mild diuretic effects of drospirenone.28
Hypertension. In a review of progestin-only OCs in normotensive women, the authors could find no evidence to show a statistically significant increase in blood pressure.29
In a study of 120 women randomized to drospirenone/EE or LNG/EE, the drospirenone group had a mean decrease in systolic blood pressure from 107 to 103 mm Hg, and a significantly lower group mean blood pressure compared with the LNG group.30 Another study of 80 women over 6 months randomized into 3groups each having 3 mg of drospirenone with either a 30-, 20-, or 15-mcg dose of EE found that systolic blood pressure decreased by 1 to 4 mm Hg compared with an elevation of blood pressure of 4 mm Hg in the LNG/EE group.27
In women with well-controlled blood pressure who were less than 35 years old, non-smokers and otherwise healthy, the American College of Obstetricians and Gynecologists (ACOG) recommends31 a trial of OCs with monitoring of their blood pressure.
Acne. One Cochrane review looked at studies that compared combined OCs to placebo, and found OCs improved the condition. However, there was insufficient evidence regarding the difference in effectiveness of various formulations of OCs in treating the disease.32 There was no difference between first and second generation progestins,33 between second and third generations,34 or third generation vs drospirenone.35
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) OCs46,47 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
Bone mineral density (BMD). A 2000 study compared 2 OCs with the same dose of progestin (gestodene 75 mcg) and 2 doses of EE (20 vs 30 mcg) to determine if there was a correlation between dose of estrogen and loss of BMD in young post-adolescent women taking OCs. It concluded that pills with 20 and 30 mcg of estrogen were associated with the same reduction in BMD.54
However a 2009 Cochrane review concluded that combined OCs do not affect bone health, ie, fracture rate, BMD, or biochemical markers of bone change. Thirteen RCTs were reviewed and researchers concluded that the relationship between OC use and fracture risk cannot be determined from the limited data currently available.55
Cancer. Research does not support the notion that OCs contribute to cancer. In fact, reduced endometrial and ovarian cancers have been shown among users of OCs containing 50 mcg EE.56-58 Low-dose formulations (≤35 mg EE) have been less studied but also confer a substantial risk reduction.59
Data are conflicting regarding a slight increase in risk for breast cancer in current or recent users of OC from older, higher-estrogen doses; that risk returns to normal over time.60 The World Health Organization recognizes this slight risk, but has concluded that the benefits of OCs outweigh the risks. 61
Evidence-based guidelines are lacking
There is a paucity of RCTs with sufficient duration and sample size that compare different OC formulations to provide evidence-based guidance for physicians. While some pharmaceutical companies market their product for particular benefits, these finding too often come from non-comparative trials, ie, their product vs placebo.
So here’s what we know...
No OC formulation is more effective at preventing pregnancy than any others. Cycle control, ie, less intermenstrual bleeding, is improved with 30 to 35 mcg EE formulations compared with ultra-low dose (20 mcg) EE. There are no advantages to choosing a multiphasic formulation over a monophasic OC. While extended-cycle formulations have more breakthrough bleeding than monthly cycles, overall they have fewer days of menstrual bleeding, which tend to decrease even further in successive cycles. Extended-cycle formulations have decreased days of bloating and menstrual cramping.
There is no evidence that different doses of estrogen or progestin affect weight gain or total body water. DRSP leads to a more favorable lean body mass profile than LNG and desogestrel, which may be related to its anti-mineralocorticoid effect. While both second and third generation progestin formulations have been shown to improve acne, there is no evidence to indicate a preference.
There is also little evidence to recommend a particular OC to avoid adverse events such as CAD or VTE; in fact the evidence is often contradictory. Epidemiologic studies confirm that venous thromboembolic disease is similar for 20 and 30 mcg EE. There may be an increase in VTE with desogestrel, but recent evidence finds no significant increase. The clinical significance that DRSP increases triglyceride levels while it decreases LDL and HDL, and the significance of LDL reduction by desogestrel requires further investigation.
There is no evidence that OCs affect bone health indices such as fracture rate, BMD, or biochemical markers of bone change. OC formulations with While extended-cycle formulations have more breakthrough bleeding than monthly cycles, they have overall fewer days of menstrual bleeding.higher doses of estrogen have been shown to reduce ovarian and endometrial cancer, presumably due to fewer ovulatory cycles. However, similar reductions should therefore be observed with lower EE dose formulations as well.
Clearly, the literature indicates that there is little evidence to recommend one OC formulation over another. All currently marketed OCs have low dose EE. However, when counseling patients, keep in mind that extended cycle formulations decrease some side effects and generic formulations reduce costs.
CORRESPONDENCE
Eric A. Schaff, MD, Philadelphia Women’s Center, 777 Appletree Street, #7, Philadelphia, PA 19106; [email protected]
1. Chandra A, Martinez GM, Mosher WD, et al. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat. 2005;25:1-160.
2. Keam SJ, Wagstaff AJ. Ethinyl estradiol/drospirenone: a review of its use as an oral contraceptive. Treatments Endocrinol. 2003;2:49-70.
3. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception. 2000;62:29-38.
4. Maitra NN, Kulier R, Bloemenkamp K, et al. Progestogens in combined oral contraceptives for contraception. Cochrane Database Syst Rev. 2004, Issue 3.
5. Oral Contraceptives at Drugstore.com. http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?search=oral+contraceptive [accessed January 24, 2011]
6. Society of Obstetricians and Gynaecologists of Canada Statement on Generic Contraceptions. J Obstet Gynecol Canada. 2008;30:271-272.
7. Coney P, Washenik K, Langley RG, et al. Weight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials. Contraception. 2001;63:297-302.
8. O’Connell K, Davis AR, Kerns J. Oral contraceptives: side effects and depression in adolescent girls. Contraception. 2007;75:299-304.
9. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol. 1997;89:615-622.
10. Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse and discontinuation of oral contraceptives. J Reprod Med. 1995;40:355-360.
11. Endrikat J, Muller U, Dusterberg B. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, with respect to efficacy, cycle control, and tolerance. Contraception. 1997;55:131-137.
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.
14. Grimes DA, Lopez LM, Schulz KF et al. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev. 2009, Issue 2.
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.
18. Rosenberg M, Waugh MS. Causes and consequences of oral contraceptive noncompliance. Am J Obstet Gynecol. 1999;180:S276-279.
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.
58. LaVecchia C, Franceschi S, Decarli A. Oral contraceptive use and the risk of epithelial ovarian cancer. Br J Cancer. 1984;50:31-34.
59. Royar J, Becher H, Chang-Claude J. Low-dose oral contraceptives: protective effect on ovarian cancer risk. Int J Cancer. 2001;95:370-374.
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.
• Consider prescribing monophasic pills as the first choice for women starting oral contraceptives (OCs) given the lack of advantage in using multiphasic formulations, and the larger number of studies showing the safety and efficacy of monophasic pills.
• Avoid prescribing OCs with estrogen—even with ultra-low estrogen—to women at high risk for venous thromboembolism, given that there are no studies that show differences in low (25-35 mcg) ethinyl estradiol vs ultra-low doses (10 mcg) formulas.
Strength of recommendation (SOR)
• Good-quality patient-oriented evidence
• Inconsistent or limited-quality patient-oriented evidence
• Consensus, usual practice, opinion, disease-oriented evidence, case series
For a healthy woman interested in contraception, there are multiple oral contraceptive (OC) formulations on the market from which to choose. But are there any significant differences in their effectiveness or safety profiles that make one formulation superior?
Comparative trials of OCs have attempted to answer these questions by evaluating formulations that contain the synthetic components: ethinyl estradiol, norethindrone, levonorgestrel, desogestrel, norgestimate, gestodene, and drospirenone.
Unfortunately, many studies that have evaluated OCs have had methodological weaknesses, making their clinical significance confusing. Few randomized controlled trials (RCTs) have been double blinded or powered to find infrequent outcomes like pregnancy or adverse events. Trials are rarely reproduced by other researchers and many have been funded by pharmaceutical companies with conflicts of interest. Despite these shortcomings, it is possible to glean valuable data from existing studies.
With that in mind, our purpose here is to review whether there are significant differences in effectiveness, cycle control (bleeding), side effects, or satisfaction that may help physicians and patients select the appropriate formulation.
Comparing OC Effectiveness
OC effectiveness is determined by the inherent properties to prevent ovulation, conception, and/or implantation when the formulation is used correctly.1,2 and during typical inconsistent use in the population (ie, adherence).3 Effectiveness is also measured by whether the method is discontinued and there is a gap in contraception allowing pregnancy to occur.
There is no evidence that any combined or progesterone-only hormonal formulation is inherently better at preventing ovulation, conception, or implantation. (For more on combined OCs, see “A closer look at combined OCs,” on page E3.) Theoretically, progestins with longer half-lives may be more effective at preventing ovulation if a pill is not taken the same time each day, and extended cycle pills provide more continuous suppression of ovulation. But, no studies have found any formulation to be more effective.
A 2004 Cochrane review4 compared progestins in OCs by examining 22 different trials with various study protocols. The review found a lower rate of discontinuation in patients taking OCs with second generation progestins compared with first generation progestins (relative risk [RR]=0.79; 95% Extended-cycle OCs have a greater risk of breakthrough bleeding, which can decrease adherence and increase discontinuation, thus increasing the risk of pregnancy. confidence interval [CI] 0.61-0.91), and an even lower rate of discontinuation with third generation OCs. Additionally, cycle control was better in second generation progestin OCs compared with first generation progestin OCs. Rates of effectiveness, cycle control and side effects were similar between drospirenone and desogestrel. The review concluded that second and third generation progestins are preferred over first generation progestins in combined OCs,4 although the evidence is not strong.
What about generics? To be considered an FDA-approved bioequivalent generic to a brand name formulation, pharmacokinetic studies must demonstrate that a product provides equivalent serum levels. There are no studies evaluating differences in effectiveness of generic vs brand name OCs. Generic medications typically cost about 50% less than brand name OCs.5 The Society of Obstetricians and Gynaecologists of Canada supports generic formulations “providing increased choice and less expensive options.”6
What are the differences among the options?
While OCs, in general, have a reputation of causing side effects, when compared with a placebo, no significant findings have been noted in the frequency of headache, nausea, vomiting, breast pain, or weight gain.7,8 That being the case, it is unlikely there are differences among formulations.
Ultra-low estrogen. Estrogen in OCs has been reduced to 10 to 35 mcg to minimize side effects and adverse events, yet remain at a level sufficient to provide menstrual cycle control with minimal breakthrough bleeding. Advantages of ultra-low estrogen 10 mcg products include reduction of estrogen, side effects9 but the disadvantage includes breakthrough bleeding, which can negatively affect adherence.10 In a double-blind RCT of 649 women comparing OCs with gestodene 75 mcg and either 20 mcg or 30 mcg ethinyl estradiol (EE), more intermenstrual breakthrough bleeding occurred with the 20 mcg group (P<0.05). This difference was not enough to cause an increased discontinuation rate in the 20-mcg EE group.11
Progestin-only pills (POPs) are recommended for women who cannot or should not take estrogen in OCs, and women who are breastfeeding. The advantages of POPs include a simplified and fixed regimen. Disadvantages include irregular bleeding and menstrual cycle length. A 2010 Cochrane review examined various POP formulations in 6 different trials and concluded that there is not sufficient research to compare POPs in terms of efficacy, acceptability, and continuation rates.12
Monophasic vs multiphasic OCs. Biphasic and triphasic OCs were introduced in an effort to decrease the amount of hormone and the side effects. Their phasic nature also attempts to mimic the pattern of rising and falling estrogen and progesterone levels seen during a normal menstrual cycle. Cochrane reviews in 200913 and 201014 compared the cycle control and side effects of biphasic vs monophasic, and triphasic vs monophasic formulations of OCs, respectively. The 2009 review comparing biphasic and monophasic OCPs was limited to one study of 533 women using biphasic pills and 481 women using monophasic pills. No differences were found in intermenstrual bleeding, amenorrhea, or discontinuation due to intermenstrual bleeding.
The 2011 review comparing triphasic and monophasic OCs included 21 studies, and found no significant difference in discontinuation due to medical reasons, cycle disturbance, intermenstrual bleeding, or adverse events. Both of the Cochrane reviews concluded that monophasic pills should be the first choice for women starting OCs given the lack of advantage in using multiphasic formulations, and the larger number of studies showing the safety and efficacy of monophasic pills.
The 2009 Cochrane review compared biphasic and triphasic OCPs in terms of cycle control and side effects.13The first trial examined in this review included 458 women and compared 2 biphasic pills and one triphasic pill, all containing LNG and EE. It found no important differences between all 3 formulations, but found that 252 women of the initial 458 (55%) discontinued the study for various reasons.
The second trial included 469 women (169 of whom withdrew from the study or 36%), and compared a biphasic pill containing norethindrone with 2 triphasic pills, one containing LNG and the other containing norethindrone. This study showed no differences between the biphasic and triphasic pills containing norethindrone, but inferior cycle control in the biphasic pill containing norethindrone compared with the triphasic containing LNG. The review concluded that the choice of progestin type (LNG preferred over norethindrone) might be more important than the choice of phasic regimen.13
Monthly vs extended cycle OCs. When OCs were first introduced, researchers believed that women would prefer a 21-day formulation followed by a 7-day pill free time that mimicked an average woman’s menstrual cycle because the withdrawal bleeding would be an indicator that she was not pregnant. Extending the time between menses has garnered increased interest. Extended-cycle preparations are available for durations ranging from 84 to 365 days.15
A study of 99 women evaluated the impact of omitting the first 3 combined OC pills (second and third generation) on ovulation during a 28-day cycle. While none of the women experienced ovulation, follicle-stimulating hormone reached a maximal serum concentration in most women during the first 7 pill-free days, indicating complete pituitary recovery. Additionally, the researchers detected increases in serum estradiol, indicating that follicular growth up to preovulatory size is common in women missing the first one to 3 pills of their contraceptive cycle.16 Non-adherence often occurs during transitions between successive packs of Ocs.17 It has been reported that 47% of women using OCPs miss one pill and 22% miss 2 pills per cycle.18 Ovulation and pregnancy are more likely to occur if pills are missed in the first week after menses.
Extended-cycle OCs prevent hormonal fluctuations and provide continuous suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH), decreasing the likelihood of ovulation and, therefore, pregnancy. Since the extended-cycle regimen decreases the number of transitions between packs of OCs, one might expect a reduction in the risk associated with non-adherence at the beginning of a cycle. However, extended cycles have a greater risk of breakthrough bleeding, which can decrease adherence and increase discontinuation of the method and, thereby, increase the risk of pregnancy.
A multicenter RCT of 682 women examined the efficacy and safety of the extended-cycle OC Seasonale (30 mcg EE/150 mcg LNG) compared with a traditional cycle OC Nordette-28 (30 mcg EE/150 mcg LNG). Women received either 4, 91-day extended cycles (n=456) or 13, 28-day regular cycle (n=226) regimens over the course of one year. On average, 38% of women in the extended cycle group reported unscheduled (breakthrough) bleeding, while 18% of women in the conventional cycle group reported unscheduled bleeding. Breakthrough bleeding decreased with each successive cycle of the extended regimen, from a median of 12 days with the first cycle, to a median of 4 days during the fourth and final cycle. This study also reported no significant differences in side effects between the extended and traditional cycle regimens, including changes in lipids, body weight, blood pressure, or endometrial hyperplasia.19
Another RCT examined the difference in bleeding patterns, side effects, and acceptability between a standard 28-day cycle OC and an extended regimen 168-day cycle OC in 32 women. Both OCs contained 20 mcg EE and 100 mcg LNG, and the study was conducted over 6 months. Women in the extended cycle regimen reported significantly fewer days of bloating (0.7 vs 11.1 days; P=0.04), and menstrual pain (1.9 vs 13.3 days; P<0.01). There was no significant difference in reported headache, breast tenderness, nausea, depression, or premenstrual symptoms. Women in the extended cycle group also reported significantly fewer bleeding days that required sanitary pads (18.4 vs 33.8 days; P<0.01). However, there was no statistically significant difference in the total number of days where any degree of bleeding occurred (34.9 days in the monthly cycle group, 25.9 days in the extended cycle group; P=0.33).20
In a study of 126-day extended-cycle OCs with 30 mcg EE and 3 mg drospirenone, the bleeding profile improved over time and endometrial biopsies revealed no hyperplasia.21 Another benefit of the extended cycle is personal preference, ie, controlling the timing of one’s menses,22 for example, in athletes during training and competition.
Continuous use of OCs prevents the cyclic fluctuations of serum levels of EE and progestogen and, hence, the cyclic variations of related serum-based metabolic parameters. Extended cycle OCs can make it easier to titrate other medications affected by hormonal fluctuations. Another study of extended cycle drospirenone OCs compared with monthly OCs over 6 months showed no difference in lipid, carbohydrate, and coagulation markers.23
Six RCTs were reviewed in a Cochrane review of monthly vs extended cycle combined pills. It found no significant differences in efficacy, adherence, discontinuation rates, and patient satisfaction. The only difference was improvement of menstrual-associated symptoms of “headaches, genital irritation, tiredness, bloating and menstrual pain” with the extended cycle regimen.24
OCs effect on weight, BP, and premenstrual symptoms
Weight gain. A 2008 Cochrane review examined 3 placebo-controlled RCTs and concluded that the available evidence was insufficient to determine the effect of combined hormonal contraceptives on weight, and that larger doses of estrogen were not shown to cause larger weight gain.25
One RCT examined the effects of OCs on variations of total body water, fat mass, and fat-free mass throughout the menstrual cycle to determine if different doses of estrogen (15 mcg vs 30 mcg EE) or different types of progestins (gestodene 60 mcg vs drospirenone 3 mg) impact weight gain. This study only included 80 women randomized to the 2 treatment groups and an additional control group using male condoms. No differences were found in total body water or fat mass. There was, however, a significant increase in the fat-free mass in women of the EE/gestodene group when compared to controls, indicating a possible effect of the androgenic properties of gestodene compared with drospirenone (which has anti-androgen properties) in increasing muscle mass.26
In a 6 month study of drospirenone compared with LNG, mean body weight fell by 0.8 to 1.7 kg in women treated with drospirenone compared with a 0.7 kg weight gain in the LNG group (P < 0.05).27 A multicenter RCT comparing OCs with EE 30 mcg/drospirenone 3 mg, and EE 30 mcg/desogestrel 150 mcg, concluded that EE/drospirenone has a more favorable effect on body weight than EE/desogestrel. This finding may have resulted from the antimineralocorticoid, mild diuretic effects of drospirenone.28
Hypertension. In a review of progestin-only OCs in normotensive women, the authors could find no evidence to show a statistically significant increase in blood pressure.29
In a study of 120 women randomized to drospirenone/EE or LNG/EE, the drospirenone group had a mean decrease in systolic blood pressure from 107 to 103 mm Hg, and a significantly lower group mean blood pressure compared with the LNG group.30 Another study of 80 women over 6 months randomized into 3groups each having 3 mg of drospirenone with either a 30-, 20-, or 15-mcg dose of EE found that systolic blood pressure decreased by 1 to 4 mm Hg compared with an elevation of blood pressure of 4 mm Hg in the LNG/EE group.27
In women with well-controlled blood pressure who were less than 35 years old, non-smokers and otherwise healthy, the American College of Obstetricians and Gynecologists (ACOG) recommends31 a trial of OCs with monitoring of their blood pressure.
Acne. One Cochrane review looked at studies that compared combined OCs to placebo, and found OCs improved the condition. However, there was insufficient evidence regarding the difference in effectiveness of various formulations of OCs in treating the disease.32 There was no difference between first and second generation progestins,33 between second and third generations,34 or third generation vs drospirenone.35
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) OCs46,47 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
Bone mineral density (BMD). A 2000 study compared 2 OCs with the same dose of progestin (gestodene 75 mcg) and 2 doses of EE (20 vs 30 mcg) to determine if there was a correlation between dose of estrogen and loss of BMD in young post-adolescent women taking OCs. It concluded that pills with 20 and 30 mcg of estrogen were associated with the same reduction in BMD.54
However a 2009 Cochrane review concluded that combined OCs do not affect bone health, ie, fracture rate, BMD, or biochemical markers of bone change. Thirteen RCTs were reviewed and researchers concluded that the relationship between OC use and fracture risk cannot be determined from the limited data currently available.55
Cancer. Research does not support the notion that OCs contribute to cancer. In fact, reduced endometrial and ovarian cancers have been shown among users of OCs containing 50 mcg EE.56-58 Low-dose formulations (≤35 mg EE) have been less studied but also confer a substantial risk reduction.59
Data are conflicting regarding a slight increase in risk for breast cancer in current or recent users of OC from older, higher-estrogen doses; that risk returns to normal over time.60 The World Health Organization recognizes this slight risk, but has concluded that the benefits of OCs outweigh the risks. 61
Evidence-based guidelines are lacking
There is a paucity of RCTs with sufficient duration and sample size that compare different OC formulations to provide evidence-based guidance for physicians. While some pharmaceutical companies market their product for particular benefits, these finding too often come from non-comparative trials, ie, their product vs placebo.
So here’s what we know...
No OC formulation is more effective at preventing pregnancy than any others. Cycle control, ie, less intermenstrual bleeding, is improved with 30 to 35 mcg EE formulations compared with ultra-low dose (20 mcg) EE. There are no advantages to choosing a multiphasic formulation over a monophasic OC. While extended-cycle formulations have more breakthrough bleeding than monthly cycles, overall they have fewer days of menstrual bleeding, which tend to decrease even further in successive cycles. Extended-cycle formulations have decreased days of bloating and menstrual cramping.
There is no evidence that different doses of estrogen or progestin affect weight gain or total body water. DRSP leads to a more favorable lean body mass profile than LNG and desogestrel, which may be related to its anti-mineralocorticoid effect. While both second and third generation progestin formulations have been shown to improve acne, there is no evidence to indicate a preference.
There is also little evidence to recommend a particular OC to avoid adverse events such as CAD or VTE; in fact the evidence is often contradictory. Epidemiologic studies confirm that venous thromboembolic disease is similar for 20 and 30 mcg EE. There may be an increase in VTE with desogestrel, but recent evidence finds no significant increase. The clinical significance that DRSP increases triglyceride levels while it decreases LDL and HDL, and the significance of LDL reduction by desogestrel requires further investigation.
There is no evidence that OCs affect bone health indices such as fracture rate, BMD, or biochemical markers of bone change. OC formulations with While extended-cycle formulations have more breakthrough bleeding than monthly cycles, they have overall fewer days of menstrual bleeding.higher doses of estrogen have been shown to reduce ovarian and endometrial cancer, presumably due to fewer ovulatory cycles. However, similar reductions should therefore be observed with lower EE dose formulations as well.
Clearly, the literature indicates that there is little evidence to recommend one OC formulation over another. All currently marketed OCs have low dose EE. However, when counseling patients, keep in mind that extended cycle formulations decrease some side effects and generic formulations reduce costs.
CORRESPONDENCE
Eric A. Schaff, MD, Philadelphia Women’s Center, 777 Appletree Street, #7, Philadelphia, PA 19106; [email protected]
• Consider prescribing monophasic pills as the first choice for women starting oral contraceptives (OCs) given the lack of advantage in using multiphasic formulations, and the larger number of studies showing the safety and efficacy of monophasic pills.
• Avoid prescribing OCs with estrogen—even with ultra-low estrogen—to women at high risk for venous thromboembolism, given that there are no studies that show differences in low (25-35 mcg) ethinyl estradiol vs ultra-low doses (10 mcg) formulas.
Strength of recommendation (SOR)
• Good-quality patient-oriented evidence
• Inconsistent or limited-quality patient-oriented evidence
• Consensus, usual practice, opinion, disease-oriented evidence, case series
For a healthy woman interested in contraception, there are multiple oral contraceptive (OC) formulations on the market from which to choose. But are there any significant differences in their effectiveness or safety profiles that make one formulation superior?
Comparative trials of OCs have attempted to answer these questions by evaluating formulations that contain the synthetic components: ethinyl estradiol, norethindrone, levonorgestrel, desogestrel, norgestimate, gestodene, and drospirenone.
Unfortunately, many studies that have evaluated OCs have had methodological weaknesses, making their clinical significance confusing. Few randomized controlled trials (RCTs) have been double blinded or powered to find infrequent outcomes like pregnancy or adverse events. Trials are rarely reproduced by other researchers and many have been funded by pharmaceutical companies with conflicts of interest. Despite these shortcomings, it is possible to glean valuable data from existing studies.
With that in mind, our purpose here is to review whether there are significant differences in effectiveness, cycle control (bleeding), side effects, or satisfaction that may help physicians and patients select the appropriate formulation.
Comparing OC Effectiveness
OC effectiveness is determined by the inherent properties to prevent ovulation, conception, and/or implantation when the formulation is used correctly.1,2 and during typical inconsistent use in the population (ie, adherence).3 Effectiveness is also measured by whether the method is discontinued and there is a gap in contraception allowing pregnancy to occur.
There is no evidence that any combined or progesterone-only hormonal formulation is inherently better at preventing ovulation, conception, or implantation. (For more on combined OCs, see “A closer look at combined OCs,” on page E3.) Theoretically, progestins with longer half-lives may be more effective at preventing ovulation if a pill is not taken the same time each day, and extended cycle pills provide more continuous suppression of ovulation. But, no studies have found any formulation to be more effective.
A 2004 Cochrane review4 compared progestins in OCs by examining 22 different trials with various study protocols. The review found a lower rate of discontinuation in patients taking OCs with second generation progestins compared with first generation progestins (relative risk [RR]=0.79; 95% Extended-cycle OCs have a greater risk of breakthrough bleeding, which can decrease adherence and increase discontinuation, thus increasing the risk of pregnancy. confidence interval [CI] 0.61-0.91), and an even lower rate of discontinuation with third generation OCs. Additionally, cycle control was better in second generation progestin OCs compared with first generation progestin OCs. Rates of effectiveness, cycle control and side effects were similar between drospirenone and desogestrel. The review concluded that second and third generation progestins are preferred over first generation progestins in combined OCs,4 although the evidence is not strong.
What about generics? To be considered an FDA-approved bioequivalent generic to a brand name formulation, pharmacokinetic studies must demonstrate that a product provides equivalent serum levels. There are no studies evaluating differences in effectiveness of generic vs brand name OCs. Generic medications typically cost about 50% less than brand name OCs.5 The Society of Obstetricians and Gynaecologists of Canada supports generic formulations “providing increased choice and less expensive options.”6
What are the differences among the options?
While OCs, in general, have a reputation of causing side effects, when compared with a placebo, no significant findings have been noted in the frequency of headache, nausea, vomiting, breast pain, or weight gain.7,8 That being the case, it is unlikely there are differences among formulations.
Ultra-low estrogen. Estrogen in OCs has been reduced to 10 to 35 mcg to minimize side effects and adverse events, yet remain at a level sufficient to provide menstrual cycle control with minimal breakthrough bleeding. Advantages of ultra-low estrogen 10 mcg products include reduction of estrogen, side effects9 but the disadvantage includes breakthrough bleeding, which can negatively affect adherence.10 In a double-blind RCT of 649 women comparing OCs with gestodene 75 mcg and either 20 mcg or 30 mcg ethinyl estradiol (EE), more intermenstrual breakthrough bleeding occurred with the 20 mcg group (P<0.05). This difference was not enough to cause an increased discontinuation rate in the 20-mcg EE group.11
Progestin-only pills (POPs) are recommended for women who cannot or should not take estrogen in OCs, and women who are breastfeeding. The advantages of POPs include a simplified and fixed regimen. Disadvantages include irregular bleeding and menstrual cycle length. A 2010 Cochrane review examined various POP formulations in 6 different trials and concluded that there is not sufficient research to compare POPs in terms of efficacy, acceptability, and continuation rates.12
Monophasic vs multiphasic OCs. Biphasic and triphasic OCs were introduced in an effort to decrease the amount of hormone and the side effects. Their phasic nature also attempts to mimic the pattern of rising and falling estrogen and progesterone levels seen during a normal menstrual cycle. Cochrane reviews in 200913 and 201014 compared the cycle control and side effects of biphasic vs monophasic, and triphasic vs monophasic formulations of OCs, respectively. The 2009 review comparing biphasic and monophasic OCPs was limited to one study of 533 women using biphasic pills and 481 women using monophasic pills. No differences were found in intermenstrual bleeding, amenorrhea, or discontinuation due to intermenstrual bleeding.
The 2011 review comparing triphasic and monophasic OCs included 21 studies, and found no significant difference in discontinuation due to medical reasons, cycle disturbance, intermenstrual bleeding, or adverse events. Both of the Cochrane reviews concluded that monophasic pills should be the first choice for women starting OCs given the lack of advantage in using multiphasic formulations, and the larger number of studies showing the safety and efficacy of monophasic pills.
The 2009 Cochrane review compared biphasic and triphasic OCPs in terms of cycle control and side effects.13The first trial examined in this review included 458 women and compared 2 biphasic pills and one triphasic pill, all containing LNG and EE. It found no important differences between all 3 formulations, but found that 252 women of the initial 458 (55%) discontinued the study for various reasons.
The second trial included 469 women (169 of whom withdrew from the study or 36%), and compared a biphasic pill containing norethindrone with 2 triphasic pills, one containing LNG and the other containing norethindrone. This study showed no differences between the biphasic and triphasic pills containing norethindrone, but inferior cycle control in the biphasic pill containing norethindrone compared with the triphasic containing LNG. The review concluded that the choice of progestin type (LNG preferred over norethindrone) might be more important than the choice of phasic regimen.13
Monthly vs extended cycle OCs. When OCs were first introduced, researchers believed that women would prefer a 21-day formulation followed by a 7-day pill free time that mimicked an average woman’s menstrual cycle because the withdrawal bleeding would be an indicator that she was not pregnant. Extending the time between menses has garnered increased interest. Extended-cycle preparations are available for durations ranging from 84 to 365 days.15
A study of 99 women evaluated the impact of omitting the first 3 combined OC pills (second and third generation) on ovulation during a 28-day cycle. While none of the women experienced ovulation, follicle-stimulating hormone reached a maximal serum concentration in most women during the first 7 pill-free days, indicating complete pituitary recovery. Additionally, the researchers detected increases in serum estradiol, indicating that follicular growth up to preovulatory size is common in women missing the first one to 3 pills of their contraceptive cycle.16 Non-adherence often occurs during transitions between successive packs of Ocs.17 It has been reported that 47% of women using OCPs miss one pill and 22% miss 2 pills per cycle.18 Ovulation and pregnancy are more likely to occur if pills are missed in the first week after menses.
Extended-cycle OCs prevent hormonal fluctuations and provide continuous suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH), decreasing the likelihood of ovulation and, therefore, pregnancy. Since the extended-cycle regimen decreases the number of transitions between packs of OCs, one might expect a reduction in the risk associated with non-adherence at the beginning of a cycle. However, extended cycles have a greater risk of breakthrough bleeding, which can decrease adherence and increase discontinuation of the method and, thereby, increase the risk of pregnancy.
A multicenter RCT of 682 women examined the efficacy and safety of the extended-cycle OC Seasonale (30 mcg EE/150 mcg LNG) compared with a traditional cycle OC Nordette-28 (30 mcg EE/150 mcg LNG). Women received either 4, 91-day extended cycles (n=456) or 13, 28-day regular cycle (n=226) regimens over the course of one year. On average, 38% of women in the extended cycle group reported unscheduled (breakthrough) bleeding, while 18% of women in the conventional cycle group reported unscheduled bleeding. Breakthrough bleeding decreased with each successive cycle of the extended regimen, from a median of 12 days with the first cycle, to a median of 4 days during the fourth and final cycle. This study also reported no significant differences in side effects between the extended and traditional cycle regimens, including changes in lipids, body weight, blood pressure, or endometrial hyperplasia.19
Another RCT examined the difference in bleeding patterns, side effects, and acceptability between a standard 28-day cycle OC and an extended regimen 168-day cycle OC in 32 women. Both OCs contained 20 mcg EE and 100 mcg LNG, and the study was conducted over 6 months. Women in the extended cycle regimen reported significantly fewer days of bloating (0.7 vs 11.1 days; P=0.04), and menstrual pain (1.9 vs 13.3 days; P<0.01). There was no significant difference in reported headache, breast tenderness, nausea, depression, or premenstrual symptoms. Women in the extended cycle group also reported significantly fewer bleeding days that required sanitary pads (18.4 vs 33.8 days; P<0.01). However, there was no statistically significant difference in the total number of days where any degree of bleeding occurred (34.9 days in the monthly cycle group, 25.9 days in the extended cycle group; P=0.33).20
In a study of 126-day extended-cycle OCs with 30 mcg EE and 3 mg drospirenone, the bleeding profile improved over time and endometrial biopsies revealed no hyperplasia.21 Another benefit of the extended cycle is personal preference, ie, controlling the timing of one’s menses,22 for example, in athletes during training and competition.
Continuous use of OCs prevents the cyclic fluctuations of serum levels of EE and progestogen and, hence, the cyclic variations of related serum-based metabolic parameters. Extended cycle OCs can make it easier to titrate other medications affected by hormonal fluctuations. Another study of extended cycle drospirenone OCs compared with monthly OCs over 6 months showed no difference in lipid, carbohydrate, and coagulation markers.23
Six RCTs were reviewed in a Cochrane review of monthly vs extended cycle combined pills. It found no significant differences in efficacy, adherence, discontinuation rates, and patient satisfaction. The only difference was improvement of menstrual-associated symptoms of “headaches, genital irritation, tiredness, bloating and menstrual pain” with the extended cycle regimen.24
OCs effect on weight, BP, and premenstrual symptoms
Weight gain. A 2008 Cochrane review examined 3 placebo-controlled RCTs and concluded that the available evidence was insufficient to determine the effect of combined hormonal contraceptives on weight, and that larger doses of estrogen were not shown to cause larger weight gain.25
One RCT examined the effects of OCs on variations of total body water, fat mass, and fat-free mass throughout the menstrual cycle to determine if different doses of estrogen (15 mcg vs 30 mcg EE) or different types of progestins (gestodene 60 mcg vs drospirenone 3 mg) impact weight gain. This study only included 80 women randomized to the 2 treatment groups and an additional control group using male condoms. No differences were found in total body water or fat mass. There was, however, a significant increase in the fat-free mass in women of the EE/gestodene group when compared to controls, indicating a possible effect of the androgenic properties of gestodene compared with drospirenone (which has anti-androgen properties) in increasing muscle mass.26
In a 6 month study of drospirenone compared with LNG, mean body weight fell by 0.8 to 1.7 kg in women treated with drospirenone compared with a 0.7 kg weight gain in the LNG group (P < 0.05).27 A multicenter RCT comparing OCs with EE 30 mcg/drospirenone 3 mg, and EE 30 mcg/desogestrel 150 mcg, concluded that EE/drospirenone has a more favorable effect on body weight than EE/desogestrel. This finding may have resulted from the antimineralocorticoid, mild diuretic effects of drospirenone.28
Hypertension. In a review of progestin-only OCs in normotensive women, the authors could find no evidence to show a statistically significant increase in blood pressure.29
In a study of 120 women randomized to drospirenone/EE or LNG/EE, the drospirenone group had a mean decrease in systolic blood pressure from 107 to 103 mm Hg, and a significantly lower group mean blood pressure compared with the LNG group.30 Another study of 80 women over 6 months randomized into 3groups each having 3 mg of drospirenone with either a 30-, 20-, or 15-mcg dose of EE found that systolic blood pressure decreased by 1 to 4 mm Hg compared with an elevation of blood pressure of 4 mm Hg in the LNG/EE group.27
In women with well-controlled blood pressure who were less than 35 years old, non-smokers and otherwise healthy, the American College of Obstetricians and Gynecologists (ACOG) recommends31 a trial of OCs with monitoring of their blood pressure.
Acne. One Cochrane review looked at studies that compared combined OCs to placebo, and found OCs improved the condition. However, there was insufficient evidence regarding the difference in effectiveness of various formulations of OCs in treating the disease.32 There was no difference between first and second generation progestins,33 between second and third generations,34 or third generation vs drospirenone.35
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) OCs46,47 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
Bone mineral density (BMD). A 2000 study compared 2 OCs with the same dose of progestin (gestodene 75 mcg) and 2 doses of EE (20 vs 30 mcg) to determine if there was a correlation between dose of estrogen and loss of BMD in young post-adolescent women taking OCs. It concluded that pills with 20 and 30 mcg of estrogen were associated with the same reduction in BMD.54
However a 2009 Cochrane review concluded that combined OCs do not affect bone health, ie, fracture rate, BMD, or biochemical markers of bone change. Thirteen RCTs were reviewed and researchers concluded that the relationship between OC use and fracture risk cannot be determined from the limited data currently available.55
Cancer. Research does not support the notion that OCs contribute to cancer. In fact, reduced endometrial and ovarian cancers have been shown among users of OCs containing 50 mcg EE.56-58 Low-dose formulations (≤35 mg EE) have been less studied but also confer a substantial risk reduction.59
Data are conflicting regarding a slight increase in risk for breast cancer in current or recent users of OC from older, higher-estrogen doses; that risk returns to normal over time.60 The World Health Organization recognizes this slight risk, but has concluded that the benefits of OCs outweigh the risks. 61
Evidence-based guidelines are lacking
There is a paucity of RCTs with sufficient duration and sample size that compare different OC formulations to provide evidence-based guidance for physicians. While some pharmaceutical companies market their product for particular benefits, these finding too often come from non-comparative trials, ie, their product vs placebo.
So here’s what we know...
No OC formulation is more effective at preventing pregnancy than any others. Cycle control, ie, less intermenstrual bleeding, is improved with 30 to 35 mcg EE formulations compared with ultra-low dose (20 mcg) EE. There are no advantages to choosing a multiphasic formulation over a monophasic OC. While extended-cycle formulations have more breakthrough bleeding than monthly cycles, overall they have fewer days of menstrual bleeding, which tend to decrease even further in successive cycles. Extended-cycle formulations have decreased days of bloating and menstrual cramping.
There is no evidence that different doses of estrogen or progestin affect weight gain or total body water. DRSP leads to a more favorable lean body mass profile than LNG and desogestrel, which may be related to its anti-mineralocorticoid effect. While both second and third generation progestin formulations have been shown to improve acne, there is no evidence to indicate a preference.
There is also little evidence to recommend a particular OC to avoid adverse events such as CAD or VTE; in fact the evidence is often contradictory. Epidemiologic studies confirm that venous thromboembolic disease is similar for 20 and 30 mcg EE. There may be an increase in VTE with desogestrel, but recent evidence finds no significant increase. The clinical significance that DRSP increases triglyceride levels while it decreases LDL and HDL, and the significance of LDL reduction by desogestrel requires further investigation.
There is no evidence that OCs affect bone health indices such as fracture rate, BMD, or biochemical markers of bone change. OC formulations with While extended-cycle formulations have more breakthrough bleeding than monthly cycles, they have overall fewer days of menstrual bleeding.higher doses of estrogen have been shown to reduce ovarian and endometrial cancer, presumably due to fewer ovulatory cycles. However, similar reductions should therefore be observed with lower EE dose formulations as well.
Clearly, the literature indicates that there is little evidence to recommend one OC formulation over another. All currently marketed OCs have low dose EE. However, when counseling patients, keep in mind that extended cycle formulations decrease some side effects and generic formulations reduce costs.
CORRESPONDENCE
Eric A. Schaff, MD, Philadelphia Women’s Center, 777 Appletree Street, #7, Philadelphia, PA 19106; [email protected]
1. Chandra A, Martinez GM, Mosher WD, et al. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat. 2005;25:1-160.
2. Keam SJ, Wagstaff AJ. Ethinyl estradiol/drospirenone: a review of its use as an oral contraceptive. Treatments Endocrinol. 2003;2:49-70.
3. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception. 2000;62:29-38.
4. Maitra NN, Kulier R, Bloemenkamp K, et al. Progestogens in combined oral contraceptives for contraception. Cochrane Database Syst Rev. 2004, Issue 3.
5. Oral Contraceptives at Drugstore.com. http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?search=oral+contraceptive [accessed January 24, 2011]
6. Society of Obstetricians and Gynaecologists of Canada Statement on Generic Contraceptions. J Obstet Gynecol Canada. 2008;30:271-272.
7. Coney P, Washenik K, Langley RG, et al. Weight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials. Contraception. 2001;63:297-302.
8. O’Connell K, Davis AR, Kerns J. Oral contraceptives: side effects and depression in adolescent girls. Contraception. 2007;75:299-304.
9. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol. 1997;89:615-622.
10. Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse and discontinuation of oral contraceptives. J Reprod Med. 1995;40:355-360.
11. Endrikat J, Muller U, Dusterberg B. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, with respect to efficacy, cycle control, and tolerance. Contraception. 1997;55:131-137.
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.
14. Grimes DA, Lopez LM, Schulz KF et al. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev. 2009, Issue 2.
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.
18. Rosenberg M, Waugh MS. Causes and consequences of oral contraceptive noncompliance. Am J Obstet Gynecol. 1999;180:S276-279.
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.
58. LaVecchia C, Franceschi S, Decarli A. Oral contraceptive use and the risk of epithelial ovarian cancer. Br J Cancer. 1984;50:31-34.
59. Royar J, Becher H, Chang-Claude J. Low-dose oral contraceptives: protective effect on ovarian cancer risk. Int J Cancer. 2001;95:370-374.
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.
1. Chandra A, Martinez GM, Mosher WD, et al. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat. 2005;25:1-160.
2. Keam SJ, Wagstaff AJ. Ethinyl estradiol/drospirenone: a review of its use as an oral contraceptive. Treatments Endocrinol. 2003;2:49-70.
3. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception. 2000;62:29-38.
4. Maitra NN, Kulier R, Bloemenkamp K, et al. Progestogens in combined oral contraceptives for contraception. Cochrane Database Syst Rev. 2004, Issue 3.
5. Oral Contraceptives at Drugstore.com. http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?search=oral+contraceptive [accessed January 24, 2011]
6. Society of Obstetricians and Gynaecologists of Canada Statement on Generic Contraceptions. J Obstet Gynecol Canada. 2008;30:271-272.
7. Coney P, Washenik K, Langley RG, et al. Weight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials. Contraception. 2001;63:297-302.
8. O’Connell K, Davis AR, Kerns J. Oral contraceptives: side effects and depression in adolescent girls. Contraception. 2007;75:299-304.
9. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol. 1997;89:615-622.
10. Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse and discontinuation of oral contraceptives. J Reprod Med. 1995;40:355-360.
11. Endrikat J, Muller U, Dusterberg B. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, with respect to efficacy, cycle control, and tolerance. Contraception. 1997;55:131-137.
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.
14. Grimes DA, Lopez LM, Schulz KF et al. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev. 2009, Issue 2.
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.
18. Rosenberg M, Waugh MS. Causes and consequences of oral contraceptive noncompliance. Am J Obstet Gynecol. 1999;180:S276-279.
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.
58. LaVecchia C, Franceschi S, Decarli A. Oral contraceptive use and the risk of epithelial ovarian cancer. Br J Cancer. 1984;50:31-34.
59. Royar J, Becher H, Chang-Claude J. Low-dose oral contraceptives: protective effect on ovarian cancer risk. Int J Cancer. 2001;95:370-374.
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.