Oral contraceptives: Does formulation matter?

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; eschaff@aol.com