Contraceptive Technology Reports

An examination of Cyclessa — Efficacy, cycle control, and side effects

Author: Lynn Borgatta, MD, MPH, Associate Professor, Obstetrics and Gynecology, Boston University School of Medicine, Boston.
Peer Reviewer: Steven J. Sondheimer, MD, Professor of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia.


Cyclessa (Organon, West Orange, NJ) is a new triphasic oral contraceptive containing ethinyl estradiol (EE) and desogestrel. The dosing and schedule of both components are new to the United States. The dose of EE is 25 mcg for 21 days; other pills on the market have doses of 35, 30, or 20 mcg EE, and some phasic pills have 40 mcg during part of the cycle. All but one of the phasic pills previously available have mean EE doses of at least 30 mcg throughout the active cycle.

Cyclessa is the first phasic oral contraceptive containing desogestrel in the United States. The other phasic pills, which are all triphasic schedules, are listed in a table enclosed in this issue. Desogestrel is used in several monophasic pills with 20 mcg EE (Mircette) or 30 mcg EE (Orthocept/Desogen and others), but the dose of desogestrel is 150 mcg for all. The desogestrel dose in Cyclessa increases from 50 mcg in the first week, to 100 mcg, to 150 mcg in the final week of active pills.

As both the estrogen dose and the progestin dose have been decreased simultaneously, there may be some concern about efficacy as well as anticipation about beneficial effects on cycle control and the incidence of side effects. There are only a few papers published about tricyclic desogestrel-containing pills, so direct comparisons are limited, but evaluations of similar combinations is helpful.


Kaunitz compared Cyclessa to Ortho-Novum 7/7/7 (EE 30 mcg/phasic norethindrone) using a randomized, open-label design.1 This multicenter trial enrolled 5,654 women for a six-month period. There were 12 pregnancies among Cyclessa users and nine among Ortho-Novum users; the estimated pregnancy rate over six months was 0.5% for Cyclessa and 0.4% for Ortho-Novum, which is not a significant difference.

Another phasic desogestrel-containing formulation, not available in the United States, contains the same amount and pattern of desogestrel as does Cyclessa. The EE dose, however, is higher: 35 mcg the first week and 30 mcg for the second two weeks. In a single-agent series of 2,070 women and 10,408 treatment cycles, there were only two pregnancies, a Pearl index (pregnancies per hundred woman-years) of 0.25.2

Other trials have evaluated pregnancy rates among other contraceptives using less than 30 mcg EE. These contraceptives are listed in a table enclosed in this issue. Two monophasic combinations using 150 mcg of desogestrel are widely used; Mircette is available in the United States and is unique among existing oral contraceptives in having EE 10 mcg during days 23-28. In a randomized, open-label trial of Mircette, Ortho-Novum TriCyclen (35 mcg EE and phasic norgestimate), and Alesse (20 mcg EE and levonorgestrel 100 mcg), 463 women were enrolled.3 Although the Pearl indices were 0, 4.4, and 1.5 respectively for Mircette, Alesse, and Ortho-Novum, these pregnancy rates do not significantly differ among the groups; there were only four pregnancies in the entire cohort. Mercilon (20 mcg EE and 150 mcg of desogestrel for 21 days) is used widely outside of the United States. Compared to Meliane, a 20 mcg EE mono-phasic pill containing gestodene (a progestin not available in the United States) in a randomized trial, the one-year Pearl index was 1.06 (per hundred woman-years) for gestodene and 0.53 for desogestrel.4 Finally, the relationship of different EE doses (20 and 30 mcg EE) with 150 mcg desogestrel and contraceptive failure was evaluated in another large European study. There was no significant difference in rates, and there were only two pregnancies in 4,543 cycles, consistent with a Pearl rate of about 0.5.5

In each study, the efficacy for all studied pills is similar. However, the rates of pregnancy differ from study to study. An extraordinarily low Pearl index reported by Ferguson6 in a large series, 0.25, is half that (0.53) of another study,4 for example. The rates in the Kaunitz study probably would be consistent with a Pearl index around 1. Since the Kaunitz and Ferguson studies were conducted with different designs, different preparations, and different populations, their pregnancy rates cannot be compared directly. A large (1,143) series of women using Mircette showed a Pearl index of 1,7 in contrast to the observed rate of zero for Mircette in a much smaller study.3 Pearl indices and life table estimates of contraceptive failure represent a "best guess" and are not accompanied by confidence intervals. With the range of comparisons for oral contraceptives containing between 20 and 35 mcg, there is no consistent evidence to show superior efficacy of one pill over another.

The evaluation of efficacy according to progestational agent and dose is more complex because of the number of different progestins and the number of phasic preparations, but the conclusions are similar: There is no consistent evidence to show superiority of one progestin agent over another, or of one dosing schedule another. The phasic dosing of desogestrel (50, 100, and 150 mcg), which reduces the total dose of desogestrel, has not been compared directly to the existing oral contraceptives containing monophasic desogestrel at 150 mcg for 21 days.

Indirect support for the equivalent efficacy of oral contraceptives in the interval of 20-35 mcg is provided by a European oral contraceptive with a decrease in both the EE dose and progestin dose compared to other marketed oral contraceptives. The combination of 15 mcg of EE and 60 mcg of gestodene represents a 25% and 20% decrease, respectively, for each component. It was formulated with either a 21- or 24-day active cycle, and the 24-day packet has been marketed as Minesse.8 A small trial of 58 women showed that with either schedule, ovulation was suppressed;9 only one ovulatory cycle occurred by ultrasound criteria, and that was accompanied by a progesterone level that was too low to be likely to support pregnancy. Apparently this combination with 15 mcg of EE is enough to prevent ovulation, which implies that 20 or 25 mcg is likely to be enough, even with a different progestin.

Cycle Control

Cycle control is extremely important to women using oral contraceptives. Deviations from perfect cycle control, including amenorrhea and midcycle bleeding or spotting, generally are unrelated to contraceptive efficacy bur are reasons for dissatisfaction and discontinuation.

In the Kaunitz study of Cyclessa and Ortho-Novum, 18.4% of women in each group discontinued their oral contraceptive before the six-month mark.1 In that study, 4.4% of Cyclessa users and 3.9% of Ortho-Novum users discontinued because of side effects, and the proportion of women discontinuing because of bleeding was the same in each group: 0.8%. Despite the low rate of discontinuation for bleeding, there were some differences between Cyclessa and Ortho-Novum in bleeding patterns. Lack of withdrawal bleeding in a cycle was more common for Ortho-Novum than Cyclessa (5.1% vs. 2.9%, p = 0.001). Breakthough bleeding or spotting or both occurred in more cycles with Ortho-Novum than Cyclessa (15.5% vs. 11.0%, p = 0.001); however, the mean number of total bleeding or spotting days during the six-month period was similar: 17% vs. 17.8%. As expected, the incidence of bleeding and spotting decreased from the first cycle to the sixth. For Cylessa users, the rate for bleeding went from 4% to 3.5%, and the rate for spotting went from 10% to 8%. Rates of bleeding by month were higher initially for Ortho-Novum, but decreased more during the study period.

For desogestrel and gestodene pills containing 20 mcg EE, recorded bleeding rates are higher than in the Kaunitz study, although they are similar for desogestrel (150 mcg for 21 days) and gestodene.10 This study showed bleeding or spotting in the desogestrel cohort occurred in 24.6% initially, decreasing to 9.4% by six months, and the rates for gestodene were 19.7% and 8.6%. Rates of amenorrhea ranged from 1% to 2.8% throughout the study, and the mean rate for both agents was 2% per cycle. Comparing the same formulations over a 12-month period, one study4 found a similar pattern: The desogestrel combination has slightly more bleeding initially, whether measured by total spotting or bleeding days. The difference between the agents decreased with continued use.

When 20 mcg EE and either levonorgestrel (Alesse) or desogestrel (Mircette) combinations are compared, bleeding rates are similar during the first half of the cycle, but Alesse had more bleeding in the second half of the cycle (Day 12 and beyond).3 Mircette has 10 mcg EE on days 23-28, and the additional estrogen might make a difference in bleeding pattern. In the same study, Ortho-Novum TriCyclen has bleeding patterns that are similar to Mircette. While EE dose has a relationship to cycle control when identical progestins are used, this study and others show that the dose of EE is not the sole determinant of cycle control. While 150 mcg desogestrel in combination with 20 mcg had significantly more bleeding or spotting days than desogestrel /30 mcg EE, (24% more during the first cycle and 38% during the sixth cycle),5 Gestodene with the same dose of EE had better cycle control than either desogestrel combination.5,11

Finally, another study by Rosenberg confirms the adverse effect of smoking on cycle control; the effect of smoking was larger than the effect of different progestins.12

Weight Gain

Weight gain is feared by many women and is cited as a reason for discontinuing oral contraceptives. In the Cyclessa study1 the baseline mean body weight was similar for both Cyclessa and Ortho-Novum groups, and women over 130% of ideal body weight were excluded from enrollment. The mean weight change for Cyclessa users was a loss of 0.2 kg, and the mean weight change for Ortho-Novum users was a gain of 0.1 kg. This is numerically significant (p = 0.0002), but may not be clinically noticeable.

Drospirenone, a new contraceptive progestin with structural similarities to desogestrel, has anti-mineralocorticoid properties that might result in weight loss. It is marketed with 30 mcg EE as Yasmin. Froidart, comparing 30 mcg EE with either 3 mg drospirenone or 150 mcg desogestrel, found a slight weight loss for drospirenone users compared to a slight weight gain for desogestrel users, over the course of a year.13 However, a study of Yasmin users alone showed a weight loss of 0.5 kg at six months and a net gain of 0.5 at 12 months.14 Both gestodene 75 mcg EE and desogestrel 150 mcg EE in combination with 20 mcg EE had a mean weight change of zero after one year.10 One study found that users of desogestrel with 30 mcg EE had a slight weight gain over a year, while desogestrel with 20 mcg EE resulted in a slight weight loss.5 When 30-40 mcg EE were used, phasic desogestrel and levonorgestrel users had a statistically significant increase in body mass index (2% and 4%).15 It’s questionable whether any of the oral contraceptives currently on the market have a large effect on body weight, but users of 20 mcg EE preparations appear to have slightly less weight gain. Desogestrel appears to be the equivalent or better than other progestins in this respect.

Other Side Effects

Other side effects, probably related to estrogen, also can be distressing and lead to discontinuation. Comparing Ortho-Novum 7/7/7 to both 20 mcg EE pills, Rosenberg found common symptoms of bloating (30%-80%), nausea (5%-40%), and breast tenderness (20%-60%) were more common with 35 mcg EE than with 20 mcg EE (RR about 1.5 for each symptom, p < .005 for each symptom).3 Other investigators have found lower baseline rates: Ferguson found the baseline rate for breast tenderness, 5%, fell to 1.6% after continuous use of phasic desogestrel with 30-35 mcg EE; nausea also fell, from 2.1% to 0.9%.2 In contrast, with equivalent desogestrel doses, women using 20 mcg EE had more side effects than the 30 mcg EE users although the incidence was low overall. Users of 20 mcg EE were more likely to discontinue pills.5 One study found that women using 20 mcg EE had the same incidence and pattern of side effects whether they used gestodene or desogestrel.4 The side effect rates for both groups, before and after treatment, were higher than those of Ferguson, but much lower than those of Rosenberg.3,11 This limits ability to compare studies, as it appears that the population and research techniques have a large effect on reported rates, while the difference between formulations is generally modest.

One study found that dysmenorrhea resolved for 53% and 70% of women using desogestrel or gestodene with 20 mcg EE.10 The incidence of premenstrual syndrome (defined as water retention, mood changes, and breast pain) decreased from 20%-26% at baseline to 12% in both groups.

Oral contraceptives can be used to treat acne, and new-onset acne may be an unwanted side effect. Ortho-Tricyclen (phasic norgestimate with 35 mcg EE) was effective in treating mild and moderate acne; this study used a placebo control group.16 Gestodene and desogestrel with 30 mcg EE had equivalent beneficial effects on pre-existing acne.17 It’s possible that any EE-containing oral contraceptive might have comparable effectiveness in treating acne. There was no difference in the occurrence of acne in 20 mcg compared to 35 mcg EE.3

Effects on bone density are a long-term concern, and as the dosage of EE decreases, the protective effect on bone density might decrease. A literature review18 concluded that there was good evidence for a protective effect even with very low EE preparations, and a subsequent study19 showed that bone density increased in perimenopausal women taking 20 mcg EE and 150 mcg desogestrel. Cyclessa and all other current oral contraceptives can be expected to maintain or increase bone density.

Cardiovascular Risks

Oral contraceptives have complex effects on serum markers associated with cardiovascular disease. In 1995, several European papers, including Jick,20 reported an association between progestin compound and the occurrence of venous thromboembolic disease, with "third-generation" progestins such as gestodene and desogestrel having the highest rates. Furthermore, it appeared as if lower doses of EE (20 mcg as opposed to higher doses) also were associated with increased rates of thromboembolism. Subsequent re-analysis indicated that the EE dose probably was unrelated to rates; prescribing bias occurred as practitioners used the lowest does of EE for women at higher risk for thromboembolism.21 One study22 concluded that an association Sof progestin type and thromboembolism could not be supported. The earlier reports could have been a result of prescribing bias, healthy user effect, and confounding variables.

Hemostatic parameters probably are related to risk of venous thromboembolism. One study15 compared phasic desogestrel in doses identical to Cyclessa, but with 30-35 mcg EE, was to phasic levonorgestrel with 30-40 mcg EE (Triphasil) over a six-month period. Measures of multiple compounds such as anti-thrombin III and Protein C were similar, while Factor V and free Protein S decreased with desogestrel and increased slightly with levonorgestrel. As the factors have opposite effects on the clotting cascade, the clinical effect is probably small or nonexistent. A meta-analysis23 concluded that levonorgestrel, gestodene, and desogestrel showed no differences in serum risk factors for thromboembolism. Clotting parameter data for Cyclessa’s formulation was not studied, but it doesn’t appear as if the patterns would be different.

Clinical Considerations

Contraceptive failure rates are very low for all oral contraceptives, and therefore the choice of oral contraceptive does not need to be made on the basis of efficacy. Although gestodene appears to have a slight advantage over desogestrel in terms of cycle control, the differences are small. Phasic and monophasic desogestrel have similar or better cycle control compared to each other. Therefore, Cyclessa can be expected to have cycle control similar to, or better than, other oral contraceptives available in the United States. "Nuisance" side effects such as bloating/water retention, breast tenderness, and premenstrual symptoms have the same, or lower, incidence.

As Cyclessa lowers the total hormone dose without detriment to efficacy, and with similar or better side effect profiles, it is suited for new starts and may be useful for women who have had problems with cycle control on another oral contraceptive.


1. Kaunitz AM. Efficacy, cycle control, and safety of two triphasic oral contraceptives: Cyclessa (desogestrel/ethinyl estradiol) to Ortho-Novum 7/7/7 (norethindrone/ ethinyl estradiol): A randomized clinical trial. Contraception 2000; 61:295-302.

2. Ferguson H, Vree ML, Wilpshaar J, et al. Multicenter study of the efficacy, cycle control, and tolerability of a phasic desogestrel-containing oral contraceptive. Eur J Contraception and Repro Health Care 2000; 5:35-45.

3. Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: A randomized trial of 20 mcg and 35 mcg estrogen preparations. Contraception 1999; 60:321-329.

4. Endrikat B, Dusterberg B, Ruebig A, et al. Comparison of efficacy, cycle control, and tolerability of two low-dose oral contraceptives in a multicenter clinical study. Contraception 1999; 60:269-274.

5. Akerlund M, Rode A, Westergaard J. Comparative profiles of reliability, cycle control, and side effects of two oral contraceptive formulations containing 150 micrograms desogestrel and either 30 mcg or 20 mcg ethinyl oestradiol. Brit J Obstet Gynaecol 1993; 100:832-838.

6. Ferguson H, Vree ML, Wilpshaar J, et al. Multicenter study of the efficacy, cycle control, and tolerability of a phasic desogestrel-containing oral contraceptive. E Eur J Contraception and Repro Health Care 2000; 5:35-45.

7. The Mircette Study Group. An open-label, multicenter, noncomparative safety and efficacy study of Mircette, a low-dose estrogen-progestin oral contraceptive. Am J Obstet Gynecol 1998; 179:S2-S8.

8. Using oral contraceptives. Population Reports 2000; 28:1-7.

9. Sullivan H, Furniss H, Spona J, et al. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 mcg) and ethinyl estradiol (15 mcg) on ovarian activity. Fertil Steril 1999; 72:115-120.

10. Serfaty D, Vree ML. A comparison of the cycle control and tolerability of two ultra low-dose oral contraceptives containing 20 mcg ethinylestradiol and either 150 mcg desogestrel or 75 mcg gestodene. Eur J Contraception and Repro Health Care 1998; 3:179-189.

11. Rosenberg MJ, Waugh MS, Higgins JE. The effect of desogestrel, gestodene, and other factors on spotting and bleeding. Contraception 1996; 53:85-90.

12. Rosenberg MJ, Waugh MS, Stevens CM. Smoking and cycle control among oral contraceptive users. Am J Obstet Gynecol. 1996; 174:628-632.

13. 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 Contraception and Repro Health Care 2000; 5:124-134.

14. Parsey KS, Pong A. An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen. Contraception 2000; 61:105-112.

15. 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.

16. 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.

17. Halbe HW, de Melo NR, Bahamondes L, et al. Efficacy and acceptability of two monophasic oral contraceptives containing ethinylestradiol and either desogestrel or gestodene. Eur J Contraception and Repro Health Care 1998; 3:113-120.

18. Kuohung W, Borgatta L. Low-dose oral contraceptives and bone mineral density: An evidence-based analysis. Contraception 2000; 61:77-82.

19. Giambacciani M, Ciaponi M, Cappagli B, et al. Longitudinal evaluation of perimenopausal femoral bone loss: Effects of a low-dose oral contraceptive preparation on bone mineral density and metabolism. Osteoporosis International 2000; 11:544-548.

20. Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thomboembolism in women using oral contraceptives with differing progestogen components. Lancet 1995; 346:1,589-1,593.

21. Farmer RD, Lawrenson RA. Oral contraceptives and venous thromboembolic disease: The findings from database studies in the United Kingdom and Germany. Am J Obstet Gynecol 1998; 179:S78-S86).

22. Lawrenson R, Farmer R. Venous thromboembolism and combined oral contraceptives: Does the type of progestogen make a difference? Contraception 2000; 62:S21-S28.

23. Winkler U. Hemostatic effects of third- and second-generation oral contraceptives: Absence of a causal mechanism for a difference in risk of venous thromboembolism. Contraception 2000; 62:S11-S20.