Advances in Contraception. 1992;8(Suppl 1):35-45. ~) 1992 Kluwer Academic Publishers. Printed in the Netherlands
Oral contraceptives and cycle control: A critical review of the literature M.J. ROSENBERG, MD, and S.C. LONG Health Decisions, lnc., PO Box 4151, Chapel Hill, North Carolina, 27515, USA
Dr Michael J. Rosenberg is currently president at Health Decisions, Inc., of Chapel Hill, North Carolina, and clinical associate professor in the departments of epidemiology and obstetrics and gynecology of the University of North Carolina, Chapel Hill. Dr Rosenberg was formerly the Executive Director of the American Social Health Association (ASHA), a 75-year-old organization devoted to the eradication of sexuallytransmitted diseases. Under his leadership, ASHA initiated a variety of educational programs in schools and the workplace to increase the public's awareness of sexuallytransmitted diseases, including the National AIDS Hotline. Before joining ASHA, Dr Rosenberg was director of the Reproductive Epidemiology Division for Family Health International He conducted international studies on sexually-transmitted diseases and contraception. The author or co-author of more than 50 clinical papers, Dr Rosenberg holds a membership in several prestigious associations, such as the American Association for the Advancement of Science, American College of Physicians, American Public Health Association, and the Society for Epidemiological Research. In addition, he is a Fellow of the American College of Physicians, the American College of Preventive Medicine, and the American College of Epidemiology. A native of California, Dr Rosenberg received his MD from the University of California, Davis, California. In 1987, Dr Rosenberg received a master's degree in Public Health from Harvard University, Cambridge, Massachusetts. Ms Sharon C. Long is research associate at Health Decisions, Inc., of Chapel Hill.
Abstract Control of spotting and breakthrough bleeding and absence of withdrawal bleeding, collectively termed cycle control, is the single most important determinant of whether a new user of oral contraceptives (OCs) will continue this method. However, information about different OC preparations and how they affect such problems, including the effects of progestogen and estrogen phasing and the components of these hormones, is scant and confusing. Studies cited in this report reveal highly variable rates of bleeding problems in women taking OCs: after 6 months of OC use, the prevalence of spotting varied between 0% and 8.5%; of breakthrough bleeding, 0% and 12.2%; and of amenorrhea, 0%
36
Rosenberg and Long
and 5.8%. At least some of this variation is attributable to differing study populations and cultures, study designs, and the manner in which data were collected and reported. However, methodologic weaknesses were common, often involving lack of randomization and blinding, and attrition rates were high. Despite these limitations, it is clear that the frequency of bleeding problems decreases with continuing use of OCs, emphasizing the need for patient reassurance about the transient nature of these problems. In addition, gestodene-containing preparations appear to offer better cycle control than do desogestrel-containing preparations and levonorgestrel-containing preparations better control than norethindrone-contalning preparations. However, the strongest lesson to emerge is the need for more rigorous studies to adequately address questions of comparative bleeding problems, particularly with newer triphasic formulations. These conclusions underscore the importance of counseling new OC users about the possibility of bleeding problems, reassuring them that most such problems are temporary, and, that if compliance is maintained, these will not impair contraceptive efficacy.
Introduction
Approximately half of the women who begin using oral contraceptives (OCs) will not be using them i year later, and problems with cycle control are probably the single most important reason for OC discontinuation [1,2]. Cyde control problems include spotting (generally defined as bleeding that does not require use of pads or tampons), breakthrough bleeding (bleeding that requires sanitary protection), and amenorrhea (absence of withdrawal bleeding). Cycle control factors are also important considerations in a provider's initial choice of OCs and in choosing an alternative preparation should side effects occur [1]. Part of the rationale for development of triphasic preparations as well as the newer progestins - desogestrel, gestodene and norgestimate - is improved cycle control. In an attempt to darlfy and provide a current perspective to this issue, we present a summary and critical assessment of available information on cycle control.
Methods
Multiple MEDLINE (US Library of Medicine) searches were conducted, with additional studies selected by review of the references identified in the MEDLINE search, by ongoing review of journal articles, and by contact with experts in the field.
Results
Twenty-five studies were identified that include information on cycle control (Table 1) [4-29]; additional papers were reviewed but did not contain detailed information on
Oral Contraceptives and Cycle Control
37
cycle control. All preparations studied included the estrogen ethinyl estradiol (EE) in fixed doses of 20-35 #g or in doses that varied twice during a cycle. The progestogens included in these studies were gestodene, levonorgestrel, norethindrone, norgestrel, desogestrel, and norgestimate; the doses of these were also either fixed or varied two or three times during a cycle. The number of women in a study ranged from 17 to over 95 000, and study duration from 3 to 48 cycles. Ten of the 25 studies were randomized, two were double-blind, and 18 were conducted in more than one clinical center. Patient follow-up rates varied greatly. In the studies for which follow-up data were available, fewer than half the women starting the study remained at its conclusion. Two studies provided detailed information about reasons for discontinuation [4,23], but many did not differentiate between patients lost to follow-up or those who terminated participation at the request of the patient or investigator. The most common reason cited for loss of patient participation was OC discontinuation. Few studies included descriptions of data collection methods, such as when data were collected, by whom, and wording of questions. In addition, few studies dearly defmed reported outcomes. No studies reported measures of validity such as problems among or characteristics of persons who dropped out or were lost to follow-up, or test-retest agreement on questionnaires. Most studies provided meager descriptions of methodology, omitting details as to whether women in the study were first-time OC users or were switching from another preparation to the study preparation. Some studies lacked details of how the study was conducted. The evaluated studies indicated a wide range in frequency of bleeding problems: for example, after 6 months of OC use, 0%-8.5% of women experienced spotting, 0%-12.2% had breakthrough bleeding, and 0%-5.8% had amenorrhea. The frequency of problems changed with the duration of OC use. However, considerable variation was still observed (Figure 1). Even further limitation of data to a single outcome for a single preparation showed considerable interstudy variation. For example, the prevalence of spotting, the most commonly reported outcome, varied four- to fivefold for a single preparation (from 1.3% to 5.9%). Comparisons of other preparations, outcomes, and time intervals indicate a similarly wide range of reported values. Study results consistently demonstrated a reduction in the prevalence of bleeding problems with continued OC use, a trend most clearly evident in studies that include follow-up beyond 6 months. For example, Hoppe indicated a progressive decrease in spotting and breakthrough bleeding over 24 cycles, with rate of bleeding by f'mal cycle being approximately half that at the first [14]. A similar trend was reflected in the studies that provide more limited follow-up (Table 1). These studies also indicate that the most marked reduction in frequency of bleeding problems occurred over the first few months and tended to plateau after 6 months of use. The most useful information in assessing the effect of the progestogen component comes from well-designed, well-conducted studies that directly compare different formulations. Results of two such studies suggest that the progestogen component may affect cycle control. In the first study, women taking levonorgestrel consistently had the lowest incidence of spotting and breakthrough bleeding [23]. Although the
38
Rosenberg and Long
16 14
2 0
~
~
o
Reference No: 8 20 22 4
LNG+EEtdphasic
BTB
•
Spotting
~ ~"
5 29
]
~
~
°o.
22 27 4 29
6 13 16 18 5
150LNG+30EE
150DSG+30EE
14 15 19 24 27
18
18 20
75GTD+30EE GTD+EE NET+35 triphasic triphasi~
Figure 1 Spotting and breakthrough bleeding (BTB) for oral contraceptive preparations at month 6 (DSG = desogestrel; E E = ethinyl estradiol; GTD = gestodene; LNG = levonorgestrel)
incidence was significantly lower only for breakthrough bleeding, the reduced frequency with levonorgestrel was consistent for all comparisons. This study involved 313 women randomized to the use of one of three preparations: a phased estrogen plus phased levonorgestrel, an unphased estrogen (35 ~zg/d) with phased norethindrone, or an unphased estrogen (35/zg/d) with phased norethindrone in a dose slightly lower than that contained in the second preparation. Strengths of this study include clearly defined methodology and outcomes, a reasonably large number of subjects, and analysis only of women who did not miss any pills. The findings from this study are consistent with those of another that compared the same three formulations [20] as well as with two others that found fewer bleeding problems with levonorgestrel- than with norethindrone-containing preparations [21,22]. The second report summarized three studies that used the same protocol in a total of 867 women. Here, Christie reported that gestodene was associated with approximately half the spotting frequency and fewer than half as many problems with breakthrough bleeding as desogestrel or norethindrone-containing preparations [18]. These studies involved use of phased estrogen and gestodene, monophasic estrogen (EE, 30 /zg) and monophasic desogestrel (150 #g), or a preparation containing monophasic estrogen (35 /zg) and phased norethindrone. The prevalence of both spotting and breakthrough bleeding was substantially lower with the gestodene preparation than with either of the other two preparations (spotting at cycle 6, 4.5% compared with 8.5% and 8.5%, respectively). Study strengths included a large sample size and multiple sites in geographically distinct areas. However, methodologic details
193
Cullberg, 1982 [5]
17
317
235
176
Fioretti, 1987 [7]
Hanson, 1991 [8]
Nevinny-Stickel, 1987 [9]
Rabe, 1987 [10]
185
208
Wiseman, 1984 [6]
199
235 254
No. of patients
Zador, 1979 [4]
Author, y e a r
6 cycles
Cycle 6, 70.0 Cycle 12, 50.8 Cycle 24, 28.1 Cycle 36, 3.5
Cycle 3, 88.2 Cycle 6, 82.4
57.7
LNG triphasic, 83.9 DSG, 80.4
LNG, 84.7 LNG triphasic, 85.8
Follow-up rate* (%)
GTD, 93.2 LNG, 86.0
Up to 32 cycles Cycle 3, 96.2 Cycle 6, 89.8 Cycle 12, 72.8 Cycle 18, 66.0 Cycle 24, 54.0
36 cycles
Randomized 6 cycles Multicenter
Open label Multieenter
Multicenter
Single center 6 cycles
Multicenter
Randomized 6 months Malticenter
Randomized 6 months Multicenter
Study ctmracteristics Design Duration
Table 1 Studies of oral contraceptive cycle control
150 LNG + 30 EE
75 GTD + 30 EE
150 DSG + 20 EE
LNG + EE triphasic
150 DSG + 20 EE
150 DSG + 30 EE
150 DSG + 30 EE
LNG + EE triphasic
150 LNG + 30 EE LNG + EE triphasic
OC formulation t
6 1-6 6 1-6
3 6 12 18 24
12 1-36
3 6
9.1~
10.0~:
7.1 7.6 7.6 5.8 3.9
10.7 8.3 4.5 3.7 4.4t
7.1
6 1
12.5
3
3 6
9.5 5.8
8.2 4.4
6
14.1
1
12.9 12.0 5.6
ll.0t 6.6t
3
1 3 6
1-6 1-6
3.1~
1.8~:
2.2 1.9 0.0 2.6 1.6
6.9 9.8 3.2 1.2 3.25
7.1
0.0
0.0
7.1 5.2 2.3 2.6 2.4
0.6:1:
1.9 0.5
0.0
5.9
2.5 6.25
8.8 5.8
2.3t 0.9:1:
5.0
12.1 8.1
10.1
9.8 12.1 9.2
4.7 331t
Spotting Spotting BTB Amenorrhea Cycle (%) & BTB (%) (%) (%)
O
13 290
1095
239
1613
378 384
Hoppe, 1988 [14]
Privrel, 1988 [15]
Rekers, 1988 [16]
Benagiano, 1989 [17]
3546
Woutersz, 1987 [12]
Bilotta, 1988 [13]
295
No. of patients
van Kets, 1987 [11]
Author, year
Table 1 (continued)
Follow-up rate* (%)
6 cycles
24 cycles
6 cycles
3-48 cycles
Multicenter
Multicenter
Open label Multicenter
Multicenter
Open label 6 cycles Randomized Multicenter
24 cycles
6
150 DSG + 30 EE
Cycle 6, 77.1 Cycle 12, 51.8 Cycle 24, 23.7 Cycle 36, 9.4 Cycle 48, 4.6
75 GTD + 30 EE 150 DSG + 30 EE
3 6
75 GTD + 30 EE
78.2
85.2 85.4
1
1-6 1-6
24
6 24
75 GTD + 30 EE
Cycle 6, 88.6 Cycle 12, 61.0 Cycle 18, 32.2 Cycle 24, 24.6
7.0I 8.05
4.0 2.4
8.2 5.9
6.7 4.1 3.7
6.7 2.8
8.2
3
3 6
6.2 5.1 2.7 0.0 1.9
3 6 12 24
10.4 8.0
0.8 0.9 0.0
2.0~ 2.0I
5.2 1.9
2.7 2.1
1.2 0.9 0.0
0.4 0.1
6.6
5.5 3.6 1.9 1.5 0.9
0.5~t 0.95
0.0 1.6
0.4 0.5 0.0
5.5 5.8 3.5 1.5 2.8
Spotting Spotting BTB Amenorrhea C~cle (%) & BTB (%) (%) (%)
150 DSG + 30 EE
LNG + EE tdphasic
150 DSG + 20 EE
OC formulation t
87.3
At 12 months: 31.3 At 24 months: 10.2
Up to 48 cycles Cycle 12, 87.1 Cycle 24, 46.1 Cycle 36, 36.3 Cycle 48, 12.5
Multicenter
Open label Multicenter
Study characteristics Design Duration
,.n
cr
133
Edg~n, 1989 [21]
Schilling, 1989 [23]
Ramos, 1989 [22]
206
Dr~mueller, 129120]
107 97 109
601
600
599
135
685
Open, randomized Multicenter
4 cycles
LNG triphasic, 83.2 NET1, 82.5 NET2, 81.7
LNG triphasic, 72.5
LNG, 74.8
NET, 68.1
300 NGL + 30 EE
NGL, 37.0
Double blind 8-14 months Randomized Multicenter
50 NET + 35 EE
LNG + EE triphasic NET + 35 EE triphas. NET + 35 EE triphas.
LNG + EE triphasic
150 LNG + 30 EE
400 NET + 35 EE
NET + 35 EE triphasic
NET + 35 EE triphasic
NET, 36.8
LNG + EE triphasic
75 GTD + 30 EE
Randomized 12 months Multicenter
85.0
86.6
6cycles
NET + 35 EE triphasic
GTD + EE triphasic
150 DSG + 30 EE
OC formulationt
Randomized 3 & 6 months
Open label Multicenter Two studies
NET, 66.2
639
136
Follow-up rate* (%)
Up to 14 cycles At cycle 6: Open label Multicenter DSG, 78.3 Three studies GTD, 58.4
Study characteristics Design Duration
92
No. of patients
de Andrade, 19891191
Christie, 1989 [18]
Author, year
Table 1 (continued)
1-4 1-4 1-4
6 12 6 12 6 12
6 12 6 i2
6 1-6 6 1-6 6 1-6
6 1-6
1 3 6 1 3 6 1 3 6
14.95 34.9J; 40.8t
1.7 0.2 0.7 0.2 0.2 0.2
0.0 3.35 4.9 8.91; 2.6 5.41;
4.3 8.11;
11.9 11.0 8.5 5.6 3.6 4.5 10_5 10.0 8.5 1.7 1.8t
3.6 2.7 0.0 1.8 1.9 1.4 10.5 6.0 7.0
33.0§ 24.0~ 28.0~ 18.0§
23.95 28.8t
8.7t
3.1 0.4 0.4 0.4 0.9 0.2
5.0§ 5.0 7.1§1; 3.81; 14.6§ 12.2 24.6~1; 18.8~: 5.3§ 2.6 12.0~t 7.91;
2.6 3.31;
8.3 5.5 1.7 2.5 2.1 1.0 11.3 3.0 7.0
2.3~ 3.41; 6.3~
0.4 0.51;
2.01;
0.31;
0.71;
Spotting Spotting BTB Amenorrhea Cycle (%) &BTB (%) (%) (%)
e~
!
O
736
Corson, 1990 [26]
278 277
1921
362 377
227
229
Multicenter
6 cycles
Phase 3, 24 months
Phase 2, 6 months
Double blind Up to 6 cycles Randomized Multicenter
Multicenter Two studies
81.6
Follow-up rate* (%)
LNG 84.5
At 6 months: LNG, 92-5 GTD, 90.2 At 24 months: 87.4
LNG, 84.6
LNG + EE triphasic LNG + EE
LNG + EE triphasic 75 GTD + 30 EE
150 LNG + 30 EE
75 GTD + 30 EE
300 NGL + 30 EE
NGL, 26.1 GTD, 87.8
250 NGM + 35 EE
75 GTD + 30 EE
75 GTD + 30 EE
OC formulationt
NGM, 26.9
Up to 18 cycles Cycle 6, 91.8 Cycle 12, 56.6 Cycle 18, 33.4
6 cycles
Randomized 24 cycles Multicenter Two studies
Multicenter
Multicenter
Study clmracteristics Design Duration
6 6
24
1-6 1-6 12
6 1-6 6 1-6
1-6 7-12 1-6 7-12
1-3 4-6 1-18
1 6
6.4%~t 16.5%~t
11.15 7.65
5.0 21.0~t 6.0 19.05
15.95 2.1~t
11.5 1.3
2.2§
3.7§
11.3§~; 6.6§~t 10.6§t 7.3§$
16.7 2.6
1.2%~t 2.8%t
1.5 5.0t 2.5 8.05
8.3~t 1.6~t
5.2 1.3
0.2%5 0.9%~
1.1t 1-5it
1.0t
0.95
0.8t
Spotting Spotting BTB Amenorrhea Cycle (%) & BTB (%) (%) (%)
*Indicates percentage of patients for whom information was collected through the end of the study unless otherwise indicated lNumbers in formulations are in micrograms ,Cumulative incidence §Spotting and/or breakthrough bleeding BTB = breakthrough bleeding; DSG = desogestrel; EE = ethinyl estradiol; GTD = gestodene; LNG = levonorgestrel; OC = oral contraceptive; NET = norethindrone; NGL = norgestrel; NGM = norgestimate; NR - not reported
Lachnit-Fixon [29]
Skouby, 1987 [28]
Loudon, 1990 [27]
3267
Brill, 1990 [25]
737
95 906
No. of patients
Brill, 1990 [24]
Author, year
Table 1 (continued)
t~
o
,.
to
Oral Contraceptivesand CycleControl
43
and statistical evaluation were lacking. Other studies reported rates of spotting and breakthrough bleeding for gestodene similar to that found by Christie [14,19,25,27], although one reported a higher rate [25]. Other studies also reported rates of spotting and breakthrough bleeding with gestodene that are the same or more favorable than those for levonorgestrel [10,14]. Cross-study comparisons indicate that desogestrelcontaining preparations may cause a slightly lower incidence of bleeding problems than levonorgestrel-contalning preparations [6,8,9,11,12]; however, other comparisons indicate the opposite [7,8,28]. Collectively, these studies suggest that use of gestodene preparations results in fewer bleeding problems than use of desogestrel- and possibly levonorgestrel-containing preparations [30]. Studies of triphasics are few, and previously noted differences preclude conclusions. Only four published studies compared triphasic with monophasic preparations, and only one of these studies compared a triphasic and a monophasic preparation containing the same progestin - levonorgestrel [4]. Three other studies compared the effects of triphasic and monophasic compounds containing different progestins [5,28,18]. One large study found triphasics to provide superior cycle control to that of monophasics [29], while one did not [22].
Discussion
When cycle control studies are compared, the most striking feature is the marked variation reported in the incidence of bleeding problems, even for the same preparation. Considering these limitations, however, two tentative conclusions emerge: (1) the occurrence of bleeding problems decreased with continued OC use, regardless of preparation; and (2) gestodene provided better cycle control than did desogestrel, and levonorgestrel was better than norethindrone. The latter point is tempered by the considerable variability in the design, conduction, and reporting methods of the studies as well as by common methodologic weaknesses. The most important message from this literature is that more rigorous studies are needed to adequately address questions about the effects of different OC compositions and phasing on cycle control. The observed variation in rates of bleeding problems frequently precluded definitive study conclusions. These differences might be attributable to the varying approaches of the investigators and might easily obscure the effects of either phasing or preparation composition, if such differences exist. In addition, the outcomes of the investigations were based on subjective parameters such as age, culture, and other factors that are difficult to define. Measuring each of these variables is a precondition to adequate assessment of the independent effect of phasing or formulation. Research could be improved by adopting a standardized definition of spotting, breakthrough bleeding, and amenorrhea and with clear definition of how data are to be collected. Studies should also be designed so that they are of adequate size (after losses to follow-up) to detect a postulated difference in bleeding problems. For studies that fail to demonstrate such a difference, if one exists, detection limits should be explicitly noted. Standardization in reporting intervals (for example, 3-, 6-, and
44
RosenbergandLong
12-month intervals) and d e a r l y differentiating cumulative prevalence from monthly (or other) prevalence would also facilitate comparisons. Analysis of data should account for the degree of O C compliance and might include the ratio of an o u t c o m e with one preparation as c o m p a r e d with another, a measure of relative risk. This technique, with confidence intervals to indicate the degree of statistical reliability, is m o r e informative than statistical significance alone [31]. Comparison of different progestogens is of particular interest, especially the newer formulations. T h e c o m p a r a t i v e studies f o u n d that r e g a r d i n g cycle control, levonorgestrel p r o d u c e d better results than did norethindrone, and gestodene better than desogestrel and possibly levonorgestrel. These tentative conclusions are based on a single large study that directly c o m p a r e d different progestogens; however, they are c o n s i s t e n t w i t h m u l t i p l e s m a l l e r studies. Clearly, better-designed and better-conducted studies to directly compare these different preparations are needed. These findings emphasize the importance of informing new patients that bleeding problems m a y occur with O C use. Even greater is the importance of providing reassurance about the usually transient nature of such problems. G o o d compliance also must be stressed, as erratic use of low-dose OCs may induce bleeding problems. T h e likelihood of bleeding problems also suggests that a first follow-up visit might suitably be scheduled within the first few months after O C initiation, in contrast to the practice of some physicians to follow up at yearly intervals.
References 1. Hatcher RA, Stewart F, Trussell J, et al., editors. Contraceptive Technology, 1990-1992. 15th ed. New York: Irvington Publishers, 1990. 2. De Lia JE, Emery MG. Clinical pharmacology and common minor side effects of oral contraceptives. Clin Obstet Gynecol. 1981;24:879-92. 3. Upton GV. The phasic approach to oral contraception: the triphasic concept and its clinical application. Int J Fertil. 1983;28:121-40. 4. Zador G. Fertility regulation using "triphasic" administration of ethinyl estradiol and levonorgestrel in comparison with the 30 plus 150 v-g fixed dose regime. Acta Obstet Gynecol Stand. 1979;88(suppl):43-8. 5. CuUbergG, Samsioe (3, Andersen RF, el al. Two oral contraceptives, efficacy, serum proteins, and lipid metabolism. Contraception. 1982;26:229-43. 6. Wiseman A, Bowie J, CogsweUD, et al. Marvelon: clinical experience in the UK. Br J Fam Plann. 1984;10:38-42. 7. Fioretti P, Fruzzetti F, Navalesi R, et al. Clinical and metabolic study of a new pill containing 20 mcg ethinylestradiol plus 0.150 mg desogestrel. Contraception. 1987;35:229-43. 8. Hanson MS, Stewart GK, Bechtel RC, Turan ES. Planned Parenthood experience with Triphasil. J Reprod Med. 1987;32:592-6. 9. Nevinny-Stickel J. German trial of an oral contraceptive containing 0.150 mg desogestrel plus 0.020 mg ethinylestradiol. Acta Obstet Gynecol Scand. 1987;144(suppl):19-21. 10. Rabe T, Runnebaum B, Kohlmeier M, Harenberg J, Weicker H, Unger R. Clinical and metabolic effects of gestodene on levonorgestrel. Int J Fertil. 1987;32(suppl):29-44. 11. van Kets HE. Belgian trial of an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. Acta Obstet Gynecol Scand. 1987;144(suppl):13-7. 12. Woutersz TB, Butler AJ, Cohen M, Korba VD, Canavan RC. A low-dose triphasic oral contraceptive. Fertil Steril. 1987;47:425-30. 13. Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinylestradiol/desogestrel-containing oral contraceptive. Drug Res. 1988;38:932-4. 14. Hoppe G. Gestoden, an innovative progestogen. Contraception. 1988;37:493-501.
Oral Contraceptives and Cycle Control
45
15. Privrel T, Daubenfeld O. Clinical experience in Switzerland with the new monophasic oral contraceptive Minulet (75 meg gestodene, 30 mcg ethinyl oestradiol). Br J Clin Pract. 1988;42:292-8. 16. Rekers H. Muiticenter trial of a monophasic oral contraceptive containing ethinyl estradiol and desogestrei. Aeta Obstet Gynecol Seand. 1988;67:171-4. 17. Benagiano G. Comparison of two monophasic oral contraceptives: gestodene/ethinyl estradiol versus desogestrel/ethinyl estradiol. Int J Fertil. 1989;34(suppl)31-9. 18. Christie T. A clinical overview of a new triphasic contraceptive containing gestodene. Int J Fertil. 1989;34(suppl):40-9. 19. de Andrade RP. A muiticenter clinical evaluation of a new monophasic combination: Minulet (gestodene and ethinyl estradiol). Int J Fertil. 1989;34(suppl):22-30. 20. Droegemueller W, Katta LR, Bright TG, Bowes WA Jr. Triphasic randomized clinical trial: comparative frequency of intermenstrual bleeding. Am J Obstet Gynecoi. 1989;161:1407-11. 21. Edgren RA, Nelson JH, Gordon RT, Kiefer WS Jr. Bleeding patterns with low-dose, monophasic oral contraceptives. Contraception. 1989;40:285-97. 22. Ramos R, Apelo R, Osteria T~ Vilar E. A comparative analysis of three different dose combinations of oral contraceptives. Contraception. 1989;39:165-77. 23. Schilling LH, Bolding OT, Chenault CB, et al. Evaluation of the clinical performance of three triphasic oral contraceptives: a multicenter, randomized comparative trial. Am J Obstet Gynecol. 1989;160:1264-8. 24. Brill K, Norpoth T, Schnitker J, Albring M. Clinical experience with a modern low-dose oral contraceptive in almost 100,000 users. Contraception. 1991;43:101-10. 25. Brill K, Schnitker J, Albring M. Long-term experience with a low-dose oral contraceptive. Gynecol Endocrinol. 1990;4:277-86. 26. Corson SL. Efficacy and clinical profile of a new oral contraceptive containing norgcstimate: U.S. clinical trials. Acta Obstet Gynecol Scand. 1990;152(suppl):25-31. 27. Loudon NB, Kirkman RJE, Dewsbury JA. A double-blind comparison of the efficacy and acceptability of Femodene and Microgynon-30. Eur J Obstet Gynecol Reprod Biol. 1990;34:257-66. 28. Skouby So. Oral contraception with a triphasic combination of gestodene and ethinyl estradiol: results of a multicentel" clinical study. Int J Fertil. 1987;32(suppl):45-8. 29. Lachnit-Fixon U, Aydinlik S, Lehnert J. Clinical comparison between a monophasic preparation and a triphasic preparation. Advances in Fertility Control and Treatment of Sterility. Lancaster, U ~ MTP Press, 1984:71-79. 30. Chez RA. Clinical aspects of three new progestogens: desogestrel, gestodene, and norgestimate. Am J Obstet GynecoL 1989;160:1296-300. 31. Rothman KJ. Modern epidemiology. Boston: Little, Brown and Company;, 1986:81.
Oral contraceptives and cycle control: A critical review of the literature M.J. ROSENBERG, MD, and S.C. LONG Health Decisions, lnc., PO Box 4151, Chapel Hill, North Carolina, 27515, USA
Dr Michael J. Rosenberg is currently president at Health Decisions, Inc., of Chapel Hill, North Carolina, and clinical associate professor in the departments of epidemiology and obstetrics and gynecology of the University of North Carolina, Chapel Hill. Dr Rosenberg was formerly the Executive Director of the American Social Health Association (ASHA), a 75-year-old organization devoted to the eradication of sexuallytransmitted diseases. Under his leadership, ASHA initiated a variety of educational programs in schools and the workplace to increase the public's awareness of sexuallytransmitted diseases, including the National AIDS Hotline. Before joining ASHA, Dr Rosenberg was director of the Reproductive Epidemiology Division for Family Health International He conducted international studies on sexually-transmitted diseases and contraception. The author or co-author of more than 50 clinical papers, Dr Rosenberg holds a membership in several prestigious associations, such as the American Association for the Advancement of Science, American College of Physicians, American Public Health Association, and the Society for Epidemiological Research. In addition, he is a Fellow of the American College of Physicians, the American College of Preventive Medicine, and the American College of Epidemiology. A native of California, Dr Rosenberg received his MD from the University of California, Davis, California. In 1987, Dr Rosenberg received a master's degree in Public Health from Harvard University, Cambridge, Massachusetts. Ms Sharon C. Long is research associate at Health Decisions, Inc., of Chapel Hill.
Abstract Control of spotting and breakthrough bleeding and absence of withdrawal bleeding, collectively termed cycle control, is the single most important determinant of whether a new user of oral contraceptives (OCs) will continue this method. However, information about different OC preparations and how they affect such problems, including the effects of progestogen and estrogen phasing and the components of these hormones, is scant and confusing. Studies cited in this report reveal highly variable rates of bleeding problems in women taking OCs: after 6 months of OC use, the prevalence of spotting varied between 0% and 8.5%; of breakthrough bleeding, 0% and 12.2%; and of amenorrhea, 0%
36
Rosenberg and Long
and 5.8%. At least some of this variation is attributable to differing study populations and cultures, study designs, and the manner in which data were collected and reported. However, methodologic weaknesses were common, often involving lack of randomization and blinding, and attrition rates were high. Despite these limitations, it is clear that the frequency of bleeding problems decreases with continuing use of OCs, emphasizing the need for patient reassurance about the transient nature of these problems. In addition, gestodene-containing preparations appear to offer better cycle control than do desogestrel-containing preparations and levonorgestrel-containing preparations better control than norethindrone-contalning preparations. However, the strongest lesson to emerge is the need for more rigorous studies to adequately address questions of comparative bleeding problems, particularly with newer triphasic formulations. These conclusions underscore the importance of counseling new OC users about the possibility of bleeding problems, reassuring them that most such problems are temporary, and, that if compliance is maintained, these will not impair contraceptive efficacy.
Introduction
Approximately half of the women who begin using oral contraceptives (OCs) will not be using them i year later, and problems with cycle control are probably the single most important reason for OC discontinuation [1,2]. Cyde control problems include spotting (generally defined as bleeding that does not require use of pads or tampons), breakthrough bleeding (bleeding that requires sanitary protection), and amenorrhea (absence of withdrawal bleeding). Cycle control factors are also important considerations in a provider's initial choice of OCs and in choosing an alternative preparation should side effects occur [1]. Part of the rationale for development of triphasic preparations as well as the newer progestins - desogestrel, gestodene and norgestimate - is improved cycle control. In an attempt to darlfy and provide a current perspective to this issue, we present a summary and critical assessment of available information on cycle control.
Methods
Multiple MEDLINE (US Library of Medicine) searches were conducted, with additional studies selected by review of the references identified in the MEDLINE search, by ongoing review of journal articles, and by contact with experts in the field.
Results
Twenty-five studies were identified that include information on cycle control (Table 1) [4-29]; additional papers were reviewed but did not contain detailed information on
Oral Contraceptives and Cycle Control
37
cycle control. All preparations studied included the estrogen ethinyl estradiol (EE) in fixed doses of 20-35 #g or in doses that varied twice during a cycle. The progestogens included in these studies were gestodene, levonorgestrel, norethindrone, norgestrel, desogestrel, and norgestimate; the doses of these were also either fixed or varied two or three times during a cycle. The number of women in a study ranged from 17 to over 95 000, and study duration from 3 to 48 cycles. Ten of the 25 studies were randomized, two were double-blind, and 18 were conducted in more than one clinical center. Patient follow-up rates varied greatly. In the studies for which follow-up data were available, fewer than half the women starting the study remained at its conclusion. Two studies provided detailed information about reasons for discontinuation [4,23], but many did not differentiate between patients lost to follow-up or those who terminated participation at the request of the patient or investigator. The most common reason cited for loss of patient participation was OC discontinuation. Few studies included descriptions of data collection methods, such as when data were collected, by whom, and wording of questions. In addition, few studies dearly defmed reported outcomes. No studies reported measures of validity such as problems among or characteristics of persons who dropped out or were lost to follow-up, or test-retest agreement on questionnaires. Most studies provided meager descriptions of methodology, omitting details as to whether women in the study were first-time OC users or were switching from another preparation to the study preparation. Some studies lacked details of how the study was conducted. The evaluated studies indicated a wide range in frequency of bleeding problems: for example, after 6 months of OC use, 0%-8.5% of women experienced spotting, 0%-12.2% had breakthrough bleeding, and 0%-5.8% had amenorrhea. The frequency of problems changed with the duration of OC use. However, considerable variation was still observed (Figure 1). Even further limitation of data to a single outcome for a single preparation showed considerable interstudy variation. For example, the prevalence of spotting, the most commonly reported outcome, varied four- to fivefold for a single preparation (from 1.3% to 5.9%). Comparisons of other preparations, outcomes, and time intervals indicate a similarly wide range of reported values. Study results consistently demonstrated a reduction in the prevalence of bleeding problems with continued OC use, a trend most clearly evident in studies that include follow-up beyond 6 months. For example, Hoppe indicated a progressive decrease in spotting and breakthrough bleeding over 24 cycles, with rate of bleeding by f'mal cycle being approximately half that at the first [14]. A similar trend was reflected in the studies that provide more limited follow-up (Table 1). These studies also indicate that the most marked reduction in frequency of bleeding problems occurred over the first few months and tended to plateau after 6 months of use. The most useful information in assessing the effect of the progestogen component comes from well-designed, well-conducted studies that directly compare different formulations. Results of two such studies suggest that the progestogen component may affect cycle control. In the first study, women taking levonorgestrel consistently had the lowest incidence of spotting and breakthrough bleeding [23]. Although the
38
Rosenberg and Long
16 14
2 0
~
~
o
Reference No: 8 20 22 4
LNG+EEtdphasic
BTB
•
Spotting
~ ~"
5 29
]
~
~
°o.
22 27 4 29
6 13 16 18 5
150LNG+30EE
150DSG+30EE
14 15 19 24 27
18
18 20
75GTD+30EE GTD+EE NET+35 triphasic triphasi~
Figure 1 Spotting and breakthrough bleeding (BTB) for oral contraceptive preparations at month 6 (DSG = desogestrel; E E = ethinyl estradiol; GTD = gestodene; LNG = levonorgestrel)
incidence was significantly lower only for breakthrough bleeding, the reduced frequency with levonorgestrel was consistent for all comparisons. This study involved 313 women randomized to the use of one of three preparations: a phased estrogen plus phased levonorgestrel, an unphased estrogen (35 ~zg/d) with phased norethindrone, or an unphased estrogen (35/zg/d) with phased norethindrone in a dose slightly lower than that contained in the second preparation. Strengths of this study include clearly defined methodology and outcomes, a reasonably large number of subjects, and analysis only of women who did not miss any pills. The findings from this study are consistent with those of another that compared the same three formulations [20] as well as with two others that found fewer bleeding problems with levonorgestrel- than with norethindrone-containing preparations [21,22]. The second report summarized three studies that used the same protocol in a total of 867 women. Here, Christie reported that gestodene was associated with approximately half the spotting frequency and fewer than half as many problems with breakthrough bleeding as desogestrel or norethindrone-containing preparations [18]. These studies involved use of phased estrogen and gestodene, monophasic estrogen (EE, 30 /zg) and monophasic desogestrel (150 #g), or a preparation containing monophasic estrogen (35 /zg) and phased norethindrone. The prevalence of both spotting and breakthrough bleeding was substantially lower with the gestodene preparation than with either of the other two preparations (spotting at cycle 6, 4.5% compared with 8.5% and 8.5%, respectively). Study strengths included a large sample size and multiple sites in geographically distinct areas. However, methodologic details
193
Cullberg, 1982 [5]
17
317
235
176
Fioretti, 1987 [7]
Hanson, 1991 [8]
Nevinny-Stickel, 1987 [9]
Rabe, 1987 [10]
185
208
Wiseman, 1984 [6]
199
235 254
No. of patients
Zador, 1979 [4]
Author, y e a r
6 cycles
Cycle 6, 70.0 Cycle 12, 50.8 Cycle 24, 28.1 Cycle 36, 3.5
Cycle 3, 88.2 Cycle 6, 82.4
57.7
LNG triphasic, 83.9 DSG, 80.4
LNG, 84.7 LNG triphasic, 85.8
Follow-up rate* (%)
GTD, 93.2 LNG, 86.0
Up to 32 cycles Cycle 3, 96.2 Cycle 6, 89.8 Cycle 12, 72.8 Cycle 18, 66.0 Cycle 24, 54.0
36 cycles
Randomized 6 cycles Multicenter
Open label Multieenter
Multicenter
Single center 6 cycles
Multicenter
Randomized 6 months Malticenter
Randomized 6 months Multicenter
Study ctmracteristics Design Duration
Table 1 Studies of oral contraceptive cycle control
150 LNG + 30 EE
75 GTD + 30 EE
150 DSG + 20 EE
LNG + EE triphasic
150 DSG + 20 EE
150 DSG + 30 EE
150 DSG + 30 EE
LNG + EE triphasic
150 LNG + 30 EE LNG + EE triphasic
OC formulation t
6 1-6 6 1-6
3 6 12 18 24
12 1-36
3 6
9.1~
10.0~:
7.1 7.6 7.6 5.8 3.9
10.7 8.3 4.5 3.7 4.4t
7.1
6 1
12.5
3
3 6
9.5 5.8
8.2 4.4
6
14.1
1
12.9 12.0 5.6
ll.0t 6.6t
3
1 3 6
1-6 1-6
3.1~
1.8~:
2.2 1.9 0.0 2.6 1.6
6.9 9.8 3.2 1.2 3.25
7.1
0.0
0.0
7.1 5.2 2.3 2.6 2.4
0.6:1:
1.9 0.5
0.0
5.9
2.5 6.25
8.8 5.8
2.3t 0.9:1:
5.0
12.1 8.1
10.1
9.8 12.1 9.2
4.7 331t
Spotting Spotting BTB Amenorrhea Cycle (%) & BTB (%) (%) (%)
O
13 290
1095
239
1613
378 384
Hoppe, 1988 [14]
Privrel, 1988 [15]
Rekers, 1988 [16]
Benagiano, 1989 [17]
3546
Woutersz, 1987 [12]
Bilotta, 1988 [13]
295
No. of patients
van Kets, 1987 [11]
Author, year
Table 1 (continued)
Follow-up rate* (%)
6 cycles
24 cycles
6 cycles
3-48 cycles
Multicenter
Multicenter
Open label Multicenter
Multicenter
Open label 6 cycles Randomized Multicenter
24 cycles
6
150 DSG + 30 EE
Cycle 6, 77.1 Cycle 12, 51.8 Cycle 24, 23.7 Cycle 36, 9.4 Cycle 48, 4.6
75 GTD + 30 EE 150 DSG + 30 EE
3 6
75 GTD + 30 EE
78.2
85.2 85.4
1
1-6 1-6
24
6 24
75 GTD + 30 EE
Cycle 6, 88.6 Cycle 12, 61.0 Cycle 18, 32.2 Cycle 24, 24.6
7.0I 8.05
4.0 2.4
8.2 5.9
6.7 4.1 3.7
6.7 2.8
8.2
3
3 6
6.2 5.1 2.7 0.0 1.9
3 6 12 24
10.4 8.0
0.8 0.9 0.0
2.0~ 2.0I
5.2 1.9
2.7 2.1
1.2 0.9 0.0
0.4 0.1
6.6
5.5 3.6 1.9 1.5 0.9
0.5~t 0.95
0.0 1.6
0.4 0.5 0.0
5.5 5.8 3.5 1.5 2.8
Spotting Spotting BTB Amenorrhea C~cle (%) & BTB (%) (%) (%)
150 DSG + 30 EE
LNG + EE tdphasic
150 DSG + 20 EE
OC formulation t
87.3
At 12 months: 31.3 At 24 months: 10.2
Up to 48 cycles Cycle 12, 87.1 Cycle 24, 46.1 Cycle 36, 36.3 Cycle 48, 12.5
Multicenter
Open label Multicenter
Study characteristics Design Duration
,.n
cr
133
Edg~n, 1989 [21]
Schilling, 1989 [23]
Ramos, 1989 [22]
206
Dr~mueller, 129120]
107 97 109
601
600
599
135
685
Open, randomized Multicenter
4 cycles
LNG triphasic, 83.2 NET1, 82.5 NET2, 81.7
LNG triphasic, 72.5
LNG, 74.8
NET, 68.1
300 NGL + 30 EE
NGL, 37.0
Double blind 8-14 months Randomized Multicenter
50 NET + 35 EE
LNG + EE triphasic NET + 35 EE triphas. NET + 35 EE triphas.
LNG + EE triphasic
150 LNG + 30 EE
400 NET + 35 EE
NET + 35 EE triphasic
NET + 35 EE triphasic
NET, 36.8
LNG + EE triphasic
75 GTD + 30 EE
Randomized 12 months Multicenter
85.0
86.6
6cycles
NET + 35 EE triphasic
GTD + EE triphasic
150 DSG + 30 EE
OC formulationt
Randomized 3 & 6 months
Open label Multicenter Two studies
NET, 66.2
639
136
Follow-up rate* (%)
Up to 14 cycles At cycle 6: Open label Multicenter DSG, 78.3 Three studies GTD, 58.4
Study characteristics Design Duration
92
No. of patients
de Andrade, 19891191
Christie, 1989 [18]
Author, year
Table 1 (continued)
1-4 1-4 1-4
6 12 6 12 6 12
6 12 6 i2
6 1-6 6 1-6 6 1-6
6 1-6
1 3 6 1 3 6 1 3 6
14.95 34.9J; 40.8t
1.7 0.2 0.7 0.2 0.2 0.2
0.0 3.35 4.9 8.91; 2.6 5.41;
4.3 8.11;
11.9 11.0 8.5 5.6 3.6 4.5 10_5 10.0 8.5 1.7 1.8t
3.6 2.7 0.0 1.8 1.9 1.4 10.5 6.0 7.0
33.0§ 24.0~ 28.0~ 18.0§
23.95 28.8t
8.7t
3.1 0.4 0.4 0.4 0.9 0.2
5.0§ 5.0 7.1§1; 3.81; 14.6§ 12.2 24.6~1; 18.8~: 5.3§ 2.6 12.0~t 7.91;
2.6 3.31;
8.3 5.5 1.7 2.5 2.1 1.0 11.3 3.0 7.0
2.3~ 3.41; 6.3~
0.4 0.51;
2.01;
0.31;
0.71;
Spotting Spotting BTB Amenorrhea Cycle (%) &BTB (%) (%) (%)
e~
!
O
736
Corson, 1990 [26]
278 277
1921
362 377
227
229
Multicenter
6 cycles
Phase 3, 24 months
Phase 2, 6 months
Double blind Up to 6 cycles Randomized Multicenter
Multicenter Two studies
81.6
Follow-up rate* (%)
LNG 84.5
At 6 months: LNG, 92-5 GTD, 90.2 At 24 months: 87.4
LNG, 84.6
LNG + EE triphasic LNG + EE
LNG + EE triphasic 75 GTD + 30 EE
150 LNG + 30 EE
75 GTD + 30 EE
300 NGL + 30 EE
NGL, 26.1 GTD, 87.8
250 NGM + 35 EE
75 GTD + 30 EE
75 GTD + 30 EE
OC formulationt
NGM, 26.9
Up to 18 cycles Cycle 6, 91.8 Cycle 12, 56.6 Cycle 18, 33.4
6 cycles
Randomized 24 cycles Multicenter Two studies
Multicenter
Multicenter
Study clmracteristics Design Duration
6 6
24
1-6 1-6 12
6 1-6 6 1-6
1-6 7-12 1-6 7-12
1-3 4-6 1-18
1 6
6.4%~t 16.5%~t
11.15 7.65
5.0 21.0~t 6.0 19.05
15.95 2.1~t
11.5 1.3
2.2§
3.7§
11.3§~; 6.6§~t 10.6§t 7.3§$
16.7 2.6
1.2%~t 2.8%t
1.5 5.0t 2.5 8.05
8.3~t 1.6~t
5.2 1.3
0.2%5 0.9%~
1.1t 1-5it
1.0t
0.95
0.8t
Spotting Spotting BTB Amenorrhea Cycle (%) & BTB (%) (%) (%)
*Indicates percentage of patients for whom information was collected through the end of the study unless otherwise indicated lNumbers in formulations are in micrograms ,Cumulative incidence §Spotting and/or breakthrough bleeding BTB = breakthrough bleeding; DSG = desogestrel; EE = ethinyl estradiol; GTD = gestodene; LNG = levonorgestrel; OC = oral contraceptive; NET = norethindrone; NGL = norgestrel; NGM = norgestimate; NR - not reported
Lachnit-Fixon [29]
Skouby, 1987 [28]
Loudon, 1990 [27]
3267
Brill, 1990 [25]
737
95 906
No. of patients
Brill, 1990 [24]
Author, year
Table 1 (continued)
t~
o
,.
to
Oral Contraceptivesand CycleControl
43
and statistical evaluation were lacking. Other studies reported rates of spotting and breakthrough bleeding for gestodene similar to that found by Christie [14,19,25,27], although one reported a higher rate [25]. Other studies also reported rates of spotting and breakthrough bleeding with gestodene that are the same or more favorable than those for levonorgestrel [10,14]. Cross-study comparisons indicate that desogestrelcontaining preparations may cause a slightly lower incidence of bleeding problems than levonorgestrel-contalning preparations [6,8,9,11,12]; however, other comparisons indicate the opposite [7,8,28]. Collectively, these studies suggest that use of gestodene preparations results in fewer bleeding problems than use of desogestrel- and possibly levonorgestrel-containing preparations [30]. Studies of triphasics are few, and previously noted differences preclude conclusions. Only four published studies compared triphasic with monophasic preparations, and only one of these studies compared a triphasic and a monophasic preparation containing the same progestin - levonorgestrel [4]. Three other studies compared the effects of triphasic and monophasic compounds containing different progestins [5,28,18]. One large study found triphasics to provide superior cycle control to that of monophasics [29], while one did not [22].
Discussion
When cycle control studies are compared, the most striking feature is the marked variation reported in the incidence of bleeding problems, even for the same preparation. Considering these limitations, however, two tentative conclusions emerge: (1) the occurrence of bleeding problems decreased with continued OC use, regardless of preparation; and (2) gestodene provided better cycle control than did desogestrel, and levonorgestrel was better than norethindrone. The latter point is tempered by the considerable variability in the design, conduction, and reporting methods of the studies as well as by common methodologic weaknesses. The most important message from this literature is that more rigorous studies are needed to adequately address questions about the effects of different OC compositions and phasing on cycle control. The observed variation in rates of bleeding problems frequently precluded definitive study conclusions. These differences might be attributable to the varying approaches of the investigators and might easily obscure the effects of either phasing or preparation composition, if such differences exist. In addition, the outcomes of the investigations were based on subjective parameters such as age, culture, and other factors that are difficult to define. Measuring each of these variables is a precondition to adequate assessment of the independent effect of phasing or formulation. Research could be improved by adopting a standardized definition of spotting, breakthrough bleeding, and amenorrhea and with clear definition of how data are to be collected. Studies should also be designed so that they are of adequate size (after losses to follow-up) to detect a postulated difference in bleeding problems. For studies that fail to demonstrate such a difference, if one exists, detection limits should be explicitly noted. Standardization in reporting intervals (for example, 3-, 6-, and
44
RosenbergandLong
12-month intervals) and d e a r l y differentiating cumulative prevalence from monthly (or other) prevalence would also facilitate comparisons. Analysis of data should account for the degree of O C compliance and might include the ratio of an o u t c o m e with one preparation as c o m p a r e d with another, a measure of relative risk. This technique, with confidence intervals to indicate the degree of statistical reliability, is m o r e informative than statistical significance alone [31]. Comparison of different progestogens is of particular interest, especially the newer formulations. T h e c o m p a r a t i v e studies f o u n d that r e g a r d i n g cycle control, levonorgestrel p r o d u c e d better results than did norethindrone, and gestodene better than desogestrel and possibly levonorgestrel. These tentative conclusions are based on a single large study that directly c o m p a r e d different progestogens; however, they are c o n s i s t e n t w i t h m u l t i p l e s m a l l e r studies. Clearly, better-designed and better-conducted studies to directly compare these different preparations are needed. These findings emphasize the importance of informing new patients that bleeding problems m a y occur with O C use. Even greater is the importance of providing reassurance about the usually transient nature of such problems. G o o d compliance also must be stressed, as erratic use of low-dose OCs may induce bleeding problems. T h e likelihood of bleeding problems also suggests that a first follow-up visit might suitably be scheduled within the first few months after O C initiation, in contrast to the practice of some physicians to follow up at yearly intervals.
References 1. Hatcher RA, Stewart F, Trussell J, et al., editors. Contraceptive Technology, 1990-1992. 15th ed. New York: Irvington Publishers, 1990. 2. De Lia JE, Emery MG. Clinical pharmacology and common minor side effects of oral contraceptives. Clin Obstet Gynecol. 1981;24:879-92. 3. Upton GV. The phasic approach to oral contraception: the triphasic concept and its clinical application. Int J Fertil. 1983;28:121-40. 4. Zador G. Fertility regulation using "triphasic" administration of ethinyl estradiol and levonorgestrel in comparison with the 30 plus 150 v-g fixed dose regime. Acta Obstet Gynecol Stand. 1979;88(suppl):43-8. 5. CuUbergG, Samsioe (3, Andersen RF, el al. Two oral contraceptives, efficacy, serum proteins, and lipid metabolism. Contraception. 1982;26:229-43. 6. Wiseman A, Bowie J, CogsweUD, et al. Marvelon: clinical experience in the UK. Br J Fam Plann. 1984;10:38-42. 7. Fioretti P, Fruzzetti F, Navalesi R, et al. Clinical and metabolic study of a new pill containing 20 mcg ethinylestradiol plus 0.150 mg desogestrel. Contraception. 1987;35:229-43. 8. Hanson MS, Stewart GK, Bechtel RC, Turan ES. Planned Parenthood experience with Triphasil. J Reprod Med. 1987;32:592-6. 9. Nevinny-Stickel J. German trial of an oral contraceptive containing 0.150 mg desogestrel plus 0.020 mg ethinylestradiol. Acta Obstet Gynecol Scand. 1987;144(suppl):19-21. 10. Rabe T, Runnebaum B, Kohlmeier M, Harenberg J, Weicker H, Unger R. Clinical and metabolic effects of gestodene on levonorgestrel. Int J Fertil. 1987;32(suppl):29-44. 11. van Kets HE. Belgian trial of an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. Acta Obstet Gynecol Scand. 1987;144(suppl):13-7. 12. Woutersz TB, Butler AJ, Cohen M, Korba VD, Canavan RC. A low-dose triphasic oral contraceptive. Fertil Steril. 1987;47:425-30. 13. Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinylestradiol/desogestrel-containing oral contraceptive. Drug Res. 1988;38:932-4. 14. Hoppe G. Gestoden, an innovative progestogen. Contraception. 1988;37:493-501.
Oral Contraceptives and Cycle Control
45
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