Oral contraceptives: Does formulation matter?

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