Introduction: How Low Should We Goµ

Oral contraceptives are one of the most commonly prescribed medications in the United States today, with 10.4 million users and approximately 70 million prescriptions annually. However, the patient's ability to tolerate these medications has become an important issue that has repercussions for both physicians and patients. Discontinuation of oral contraceptives due to side effects can be as high as 50 percent in the first year of use. This not only leads to wasted and unscheduled consultation time, but also leads to the risk of unintended pregnancies.

The dose of estrogen has been reduced over the last four decades, from an initial daily dose of 150 µg in 1960 to 20 µg in today's lowest of low-dose pills. Two reasons for this reduction are the search for more tolerable oral contraceptives, as well as indications that lower estrogen doses reduce the risk of cardiovascular disease.

Today's 20 µg formulations were initially used for high-risk patients, but clinical practice is gradually shifting in the direction of using them as first- line therapy. However, the 20 µg products currently represent only eight percent of oral contraceptive prescriptions, with 30/35 µg products making up the balance. The apparent reluctance to use lower doses of estrogen is due in part to a perception that slightly higher doses benefit patients by providing more stable cycle control and greater anti-androgenic effects, such as acne resolution. Until now, direct comparisons between 20 µg and 30/35 µg products in literature were limited. Two recent studies attempt to shed light on this perception by comparing higher and lower estrogen doses, and reporting the cycle control, side effects, and clinical outcomes associated with each.

Low Dose as First-Line

Today, researchers are beginning to provide evidence-based justification for first-line use of 20 µg estrogen formulations. Rosenberg, Meyers, and Roy demonstrated that cycle control and pregnancy rates were similar for two 20 µg products and a 35 µg product.1 However, side effects such as bloating, breast tenderness, and nausea were approximately 50 percent more common in women using the 35 µg formulation.

The randomized, open-label trial took place across 15 sites in the United States. A total of 463 sexually active women ages 18-50, with regular menstrual cycles of 21-38 days, were randomized to one of three OC products: Alesse® (20 µg ethinyl estradiol and 100 µg of the progestin levonorgestrel for days 1-21, followed by seven hormone-free days); Mircette® (20 µg ethinyl estradiol and 150 µg desogestrel, followed by two hormone-free days, then five days of 10 µg of ethinyl estradiol); or Tri-Cyclen® (35 µg of ethinyl estradiol daily and escalating 180-250 µg doses of norgestimate, followed by seven hormone-free days). The effects of the OC products were studied over six cycles.

The study found that contraceptive efficacy did not differ significantly between treatment groups. Cycle control throughout the trial was similar for all women who had switched from another brand of oral contraceptive to one of the three trial products ("switchers"). Control differences were seen in the first two cycles in women who were new to oral contraceptives ("starters"), with more breakthrough bleeding experienced with Alesse®. By the third cycle, however, control was similar for all products.

Side effects related to estrogen were seen in all users, but were approximately 50 percent more common in 35 µg users when compared to 20 µg users. In women on the 35 µg product, bloating was 40 percent more common (p = 0.000), breast tenderness 50 percent more common (p = 0.000), and nausea 60 percent more common (p = 0.004). In addition, self-reported acne decreased for women taking the 20 µg products (19 percent in Alesse® and 43 percentin Mircette®) in the starter group. In contrast, acne increased by 22 percent in starters using Tri- Cyclen®. Switchers reported less change in their acne, with Mircette® users demonstrating the greatest decrease (16 percent) and Tri-Cyclen® users experiencing a 22 percent increase. Alesse® users experienced no change in their acne when switching from another product.

Equally Effective, Fewer Side Effects

Rosenberg et al., concluded, "In this three-way comparison, we found fewer estrogenic side effects, and equivalent cycle control and contraceptive efficacy in users of two 20 µg ethinyl estradiol preparations as compared to women using a 35 µg ethinyl estradiol oral contraceptive."

The power of this study, the authors said, is that previous head-to-head trials involved only a single comparison and were performed post-marketing. "In contrast, this investigation was performed as a phase III study under rigorous United States Food and Drug Administration regulations," they said, "thus ensuring a greater level of attention and follow-up than is often found in post- marketing studies."

Acne Control as a Treatment Goalµ*

In accordance with Rosenberg et al., a study conducted by Thorneycroft, Stanczyk, Bradshaw, Ballagh, Nichols, and Weber focused on the effect of OC in clinical outcomes and androgen levels. It showed that lower-dose (20 µg) oral contraceptives reduced circulating androgens and acne lesions, as assessed by independent observers, and did not cause weight gain.2

The multi-center, open-label, randomized study compared clinical outcomes, such as acne and weight gain, and biochemical androgen profiles associated with two oral contraceptives containing the same amounts of ethinyl estradiol (20 µg) but different progestin amounts: levonorgestrel (100µg) and norethindrone acetate (1000 µg). Fifty-eight regularly cycling women ages 18-28, with or without acne, received one of two products for three cycles of treatment: Alesse® (100 µg levonorgestrel/20 µg ethinyl estradiol) or Loestrin® (1000 µg norethindrone acetate/20 µg ethinyl estradiol, plus 75 mg of ferrous fumarate on nonhormonal days).

The researchers found that both Alesse® and Loestrin® produced a significant reduction in total acne lesions compared to baseline (p = 0.049 and 0.036, respectively). In a subset of women most severely affected by acne at the start of the study (>15 lesions), there was a 56 percent reduction in total lesion count, with 20.9 + 16.5 fewer lesions at the end of the study, compared to a mean baseline count of 37.2 + 14.4. Neither Alesse® nor Loestrin® caused significant weight gain among study participants.

Although the beneficial effects on acne were similar for the two products, the progestin component of the medications appeared to affect secondary markers differently. Both products increased the level of sex hormone-binding globulin (SHBG) produced. However, levonorgestrel (in Alesse®) reduced adrenal, ovarian, and peripheral androgen levels, while norethindrone acetate (in Loestrin®) reduced only adrenal and peripheral androgens.

The authors commented that theirs was one of the few studies to evaluate the relationship between androgenic markers and acne changes after 20 µg oral contraceptive use. They concluded: "Both treatments reduced bioavailable testosterone and total acne lesion counts without causing weight gain."

Summary

The results of Rosenberg et al., served to alter the perception that oral contraceptives containing 20 µg of estrogen are less effective than the more common 30/35 µg. Common side effects, such as bloating, breast tenderness, and nausea, were found to be more common among 35 µg users. All users, however, had similar cycle control and pregnancy rates.

Thorneycroft et al., credited varying progestin levels in 20 µg oral contraceptives with reducing androgens and increasing SHBG, which effects clinical outcomes, such as acne. The results of this study show the positive effect of oral contraceptives on acne. The study also highlights the ability of oral contraceptives to provide cycle control and pregnancy prevention, without causing significant weight gain.

Footnotes: *Low-dose oral contraceptives are not indicated for the treatment of acne

References:

1. Rosenberg M.J., Meyers A., Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 µg and 35 µg estrogen preparations. Contraception 2000;60:321-329.

2. Thorneycroft I.H., Stanczyk F.Z., Bradshaw K.D., Ballagh S.A., Nichols M., Weber M.E. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception 1999;60:255-262.