A randomized, double-blind, placebo-controlled comparison of the impact of low-dose and triphasic oral contraceptives on follicular development Ronald L. Young, MD, Michael C. Snabes, MD, PhD, Margaret L. Frank, PhD, and Maryanne Reilly, RN Houston, Texas OBJECTIVE: This investigation tests the hypothesis that triphasic oral contraceptives are associated with the development of large, persistent ovarian cysts. STUDY DESIGN: Weekly vaginal ultrasonography was used in a randomized, double-blind, placebo-controlled, parallel-group, single-center study that compared the incidence, risk, size, and time to resolution of ovarian follicles in healthy women who took Estrostep or Loestrin oral contraceptives (manufactured by Parke-Davis) or a placebo during three consecutive menstrual cycles. RESULTS: Sixty-three percent of placebo-treated subjects developed follicles >18 mm, compared with 39% and 23% in the Estrostep and Loestrin groups. The risks for each group of developing a large fOllicle during a single cycle were not different. No dominant follicle persisted for >2 weeks for any subject. CONCLUSION: These results demonstrate that follicular development continues during treatment with oral contraceptives. In addition, the findings fail to support the hypothesis that triphasic oral contraceptives result in persistent ovarian cysts. (AM J OBSTET GVNECOL 1992;167:678-82.)
Key words: Oral contraceptives, follicular development Triphasic oral contraceptives have been available in the United States since 1984 and now are the most frequently prescribed oral contraceptives. In 1987 Caillouette and Koehler' published a report describing seven subjects treated with triphasic oral contraceptives in whom large, persistent ovarian cysts developed and in some cases required surgery. These investigators then suggested that the triphasic oral contraceptives were causally related to cyst development. The study described here investigated this hypothesis by examining follicular development in healthy subjects with normal menstrual cycles who received a placebo, the oral contraceptive Loestrin, or the new triphasic oral contraceptive Estrostep (both manufactured by ParkeDavis) in a randomized, controlled, double-blind trial.
Material and methods Study design. A single site was chosen for this 5month double-blind, placebo-controlled, parallelgroup study. After a 2-;eek screening period, which From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Baylor College of Medicine. Supported by a grant from the Parke-Davis Pharmaceutical Research Division ofWarner-La,mbert Company, Ann Arbor, Michigan. Presented in part at the District VII Annual Meeting of the American College of Obstetricians and Gynecologists, Puerto Vallarla, Mexico, November 1991. Received for publication October 7, 1991; revised March 2, 1992; accepted March 13, 1992. Reprint requests: Ronald L. Young, MD, Baylor College ofMedicine, 1 Baylor Plaza, Houston, TX 77030. 6/1137862
678
was sufficient to collect and evaluate the patient history and physical and laboratory examinations, subjects who had met the inclusion criteria were randomized and began a 4 week control period (cycle I). After completing this period, subjects began a 12-week blinded treatment period. This was followed by a 4-week posttreatment washout cycle. Sample selection. A sample of 48 healthy female volunteers who were between 18 and 35 years old, were post partum or had not used oral contraceptives, and had had normal menstrual cycles (28 ± 3 days) for a minimum of two consecutive months before the study was selected. All subjects initially had a normal pelvic examination, vaginal ultrasonography, and Papanicolaou smear. Each agreed to use barrier contraceptives throughout the study. Subjects were excluded if they had medical contraindications to oral contraceptives, had used oral contraceptives during the preceding 2 months, were pregnant before or became pregnant during the study. In addition, potential subjects who were lactating, had a history of ovarian follicular cysts, or had any significant history of a gynecologic pathologic condition such as pelvic inflammatory disease, endometriosis, dysfunctional uterine bleeding, or uterine abnormalities were excluded. Concurrent medications that could conceivably decrease contraceptive efficacy were disallowed. Subjects were withdrawn from the study if they experienced an adverse event, had an interfering intercurrent illness, did not tolerate the drug, failed to comply, or simply desired to withdraw.
Follicular development and oral contraceptives
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679
Table I. Risk of experiencing a large follice (> 18 mm) during a single cycle Treatment group
Risk per 1000 cycles
Attributable risk
Relative risk
95% Confidence interval
Control Loestrin Estrostep
157.1 276.6 190.1
119.5 33.4
1.7607 1.2126
0.7312-4.1518 0.4672-3.2177
Differences between risk levels were not significant, X2 = 2.5373944. Risk associated with control cycles was computed with all five possible cycles for control subjects. When baseline and washout cycles were included for experimental groups, resulting risk was 0.1705. Risk ratios were adjusted for small sample size and logarithmic conversions were used per Haldane. 6
Treatment. The medications used in this study were identical in appearance and packaging. Loestrin 1.5/30 contains 30 /Jog of ethinyl estradiol and 1.5 mg of norethindrone acetate taken for 21 days. Estrostep contains the same progestin dosage with 20, 30, and 35 /Jog of ethinyl estradiol taken on days 1 to 5, 6 to 12, and 13 to 21, respectively. The placebo was taken on days 1 to 21 by subjects randomized to the control group. No subject took study tablets on days 22 to 28. Treatment began with the initial tablet being taken on the first Sunday after the onset of the menstrual period. Seven days after finishing the previous package the subject started a new package. Tablets were taken with fluid at bedtime and recorded in the subject'S diary. The daily diary recorded the time of medication, adverse reactions, or missed pills. Subjects were assigned a treatment by means of a double-blind, balanced randomization scheme supplied by the Biometrics Department, Parke-Davis, Inc., Ann Arbor, Michigan. After the initial history, physical examination, and laboratory tests indicated that a subject met all inclusion criteria, she was enrolled. Blood pressure measurements were taken weekly. In addition, vaginal ultrasonography was performed and diaries were examined for compliance each week over the five cycles, for a total of 20 scans per subject. Vaginal ultrasonography was carried out with a GE3000 (General Electric, Milwaukee) 5.0 MHz vaginal probe with photo documentation. The mean follicular diameter was calculated by averaging the largest transverse and longitudinal diameters!· 3 All follicles> 5 mm were recorded. A pregnancy test was repeated at the end of the control cycle (cycle 1). Before our investigation was begun, this protocol was reviewed and approved by the Baylor College of Medicine, Institutional Review Board for Human Research. Data analysis. If we assume that 30% of subjects taking low-dose oral contraceptives will have ovarian follicles> 18 mm: 10 subjects per group is sufficient to detect a ~65% difference between the multiphasic and monophasic group with 95% confidence. In analyses in which the cycle was the unit of observation, those missing more than one ultrasonography were omitted from calculations. Cycles for which complete data were available for those subjects who were
not studied for the full 5 months were included. (In Fig. 3 the variation in sample size is a result of these acljustments. ) The time to resolution was defined as the number of consecutive weeks from the appearance of one or more follicles > 18 mm to regression of all follicles to < 13 mm. Relative risks were adjusted for small sample size, and logarithmic conversions were used to generate 95% confidence intervals. s. 6 Incidence levels were compared with the X· test for significance, and univariate analyses of variance were used to compare mean numbers and sizes of follicles observed in each treatment group. Results
Subjects were similar in age and medical history, but there were some differences in the past use of oral contraceptives. Eighty-one percent of the placebo group had used oral contraceptives, compared with 46% of the Loestrin and 60% of the Estrostep groups. Forty-eight subjects entered the control cycle. Three subjects withdrew for personal reasons and did not return diaries. Forty-five subjects entered active treatment: 16 received placebo, 14 Loestrin, and 15 Estrostep. Two subjects withdrew for personal reasons, one from the Loestrin and one from the Estrostep group. One Loestrin-treated subject withdrew because of an adverse event (pregnancy). Forty-two subjects completed the study. The most frequently reported gynecologic symptom was amenorrhea, which was reported by two placebotreated subjects, each reporting one episode, and one Loestrin subject reporting two episodes. One Estrostep subject reported an episode of myalgia. Overall, 63% of placebo-treated subjects experienced a follicle > 18 mm. Forty-three percent of Estrosteptreated subjects and 25% of Loestrin-treated subjects had a follicle> 18 mm at some time during the treatment phase. These proportions were not significantly different at an a level of 0.05 (X· == 3.94, df == 2). Table I displays the relative risk of a subject experiencing at least one large follicle (> 18 mm) during a single cycle for each study group. The risk per 1000 cycles was 157 for the control group, 190 for the Estrostep group, and 277 for the Loestrin group. The risk attributable to treatment for the Estrostep subjects
680
Young et al.
September 1992 Am J Obstet Gynecol
Fig. 1. Mean number of follicles of each size by experimental group and month. Average number of large follicles in control group varied from 0 in month 2 to 0.15 in month 3. All variation for two oral contraceptive groups was within that range. Cross-hatched bars, Control group; downward hatched bars, Loestrin group; upward hatched bars, Estrostep group. was 33 per 1000 cycles and 120 per 1000 for the Loestrin group. The relative risks associated with Loestrin and Estrostep were l. 76 and 1.2, respectively. Ninetyfive percent confidence ranges around these ratios included unity. Fig. 1 shows the average number of follicles in each cycle for each of the three treatment groups by cycle. In Fig. 1 (top) the average number of large follicles (> 18 mm) in each cycle is presented. The normal variability in the incidence of large follicles is demonstrated by observing the results in the placebo-treated group. Among the IS subjects receiving placebo, no subject had a large follicle in the second cycle, but an average of 0.15 large follicles were observed in the next (cycle 3). All treatment groups had an incidence of large follicles that was within the range observed for the placebo-treated group. Fig. I (middle and bottom) shows the mean number of medium (10 to 18 mm) and small (6 to 10 mm) follicles among the treatment groups. As with the large follicles, there was no significant effect of hormone treatment on the number of medium or small follicles. Although there was a trend toward an increased number of medium follicles over time for the two treatment groups, this trend was not statistically meaningful. Cycle variability can be observed in Fig. 2, which shows the mean weekly incidence of large (> 18 mm) follicles in the three treatment groups throughout the
study period. These data roughly show the expected patterns of large follicle development in the middle of many of the control cycles. Similarly, it can be observed that there was some continued ovarian activity in both oral contraceptive groups. The largest follicles in the three groups were 41,28, and 43 mm for placebo, Loestrin, and Estrostep-treated subjects, respectively. The mean size oflarge (> 18 mm) follicles among those subjects having large follicles also was similar across groups: 21, 21.5, and 23.8 mm for control, Loestrin, and Estrostep-treated subjects, respectively. Fig. 3 shows the mean size of the largest follicles in a patient month for each cycle in the three treatment groups. There was no significant effect of treatment on the average maximal follicle size. The mean largest follicle values were not significantly different from those in either the Loestrin or Estrostep cycles (F = 1.47, P = 0.2327). Finally, in no subject did an ovarian cystic structure last for >2 weeks in any treatment group. Comment
This investigation used a three-pronged approach to answer this question: Are women exposed to oral contraceptives at greater risk for development of large (> 18 mm) or persistent follicles? Variations across experimental groups were examined for (I) the incidence of at least one large follicle, (2) the risk of a large follicle
Follicular development and oral contraceptives
Volume 167 Number 3
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0.1 0.4 0.3 0.2
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0.2
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Control 1
2
3 Month
Washout 4
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Fig. 2. Average weekly incidence of large (> 18 mm) follicles in three groups. Follicular development continued in both oral contraceptive groups during treatment phase.
in a single cycle, and (3) the average number of large follicles per subject. In addition, differences in maximal follicle size, the distribution of medium and small follicles, and time to resolution of large follicles were measured. The results show the following: (1) the incidence of follicles > 18 mm was not significantly different among the three treatment groups; (2) the risk for development of follicular cysts was not different among the groups; (3) the maximal size of a follicular cyst and the average maximal size of a follicle was not observed to be significantly greater among oral contraceptivetreated subjects than controls; (4) time to resolution of follicles > 18 mm was also not found to be greater in the hormone-treated cycles. Several studies have compared the effects of hormonal contraceptives on ovarian function and follicular activity}·4, 6,7 Grimes and H ughes 8 reviewed the nationwide rate of hospitalization of women with follicular cysts before and after the introduction of triphasic oral contraceptives,8 The number of women using triphasic oral contraceptives increased from 0 to 3 million between 1979 and 1986, but the hospitalization rate for follicular cysts was unchanged. This implies that triphasic oral contraceptives are not associated with more related hospitalizations. Alternatively, Caillouette and Koehler' reported on seven cases of subjects using triphasic contraceptives in whom persistent follicular cysts developed. The data from our study demonstrate that follicular function continues with oral contraceptives
but that the incidence of large follicles is not different when control subjects and those using two types of oral contraceptives are compared. Recently Shoupe et aJ.3 used a similar protocol, involving daily rather than weekly vaginal ultrasonography, to characterize ovarian follicular development with a subcutaneous progestin, the Norplant System levonorgestrel implants (Wyeth-Ayerst, Philadelphia). They noted marked follicular development in many subjects using the progestin-only contraceptive. Our results, in subjects receiving estrogen-progestogen combination oral contraceptives, are similar in that both studies observed continued follicular development in subjects receiving exogenous hormones. The observations of Shoupe et al. of continued follicular development in Norplant users is similar to that of Tayob et al.,7 who noted follicular development in women using progestin-only oral contraceptives. Other investigators have observed similar maximal diameters of dominant follicles in normal ovarian cycles, Queenan et al. 9 observed a maximum follicle size range of 7 to 24 mm within 4 days of ovulation. We noted a follicle size of 10.6 to 16.8 mm in our control group. Our observations of continued follicular development in patients taking oral contraceptives may be explained by the results of Killich et al.,l0 who noted a more pronounced inhibition of ovarian follicular development in subjects taking triphasic oral contracep-
682
Young et al.
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September 1992 Am J abstet Gyneco1
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Fig. 3. Monthly average maximum follicle size in each group. No significant treatment effect was observed. Cross-hatched bars, Control group; downward hatched bars, Loestrin group; upward hatched bars, Estrostep group.
tives when they began on cycle day 1 instead of day 5. The majority of the subjects in the Killich et al. study who had continued follicular development began their pills on cycle day 5. Sunday starts by definition will have some subjects not beginning oral contraceptives on cycle day 1. Thus some follicular development that cannot be inhibited by the oral contraceptives may be occurring by cycle day 5 or 6. However, on the basis of the low incidence of reported symptoms in experimental subjects, there does not appear to be great clinical significance to this continued follicular activity. The low incidence of large follicles and the small sample size compromise the power of the hypothesis tests used in this investigation. Thus, although no differences were detected, there remains the possibility of type II error, which can only be addressed through a more costly investigation that uses a significantly larger sample size. In spite of this limitation, we do not believe that the sample size led to a detection bias, because the observers were blinded to treatment and ovaries were observed in all subjects in all cases and medium and small follicles were observed, measured, and counted in all subjects at each visit. The times chosen for the ultrasonographic measurements and the range of follicular sizes measured in our control population is similar to results seen by Queenan et al. 9 A future study might use a group of subjects who consistently have a monthly dominant follicle before treatment. Given the variability observed
in our control group, a population of this nature may be difficult to find.
REFERENCES 1. CaiIlouette jC, Koehler AL. Phasic contraceptive pills and functional ovarian cysts. AM j OBSTET GYNECOL
1987; 156: 1538-42. 2. Schwinn SR, Lebovic J. Transvaginal pelvic ultrasound: accuracy in follicle and cyst size determination. j Ultrasound Med 1985;4:61-3. 3. Shoupe D, Lacarri M, Horensteinj, Medearis A, Mishell DR. Characterization of ovarian follicular development in Norplant users. Fertil Steril 1991;55:766-70. 4. Van der Vange N. Ovarian activity during low-dose oral contraceptive cycles. In: Chamberlain G, ed. Contemporary obstetrics and gynecology. London: Butterworth, 1988:315-26. 5. Lilienfield AM, Lilienfield DE. Foundations of epidemiology. ed 2. New York: Oxford University Press, 1980:344. 6. Haldane jBS. The estimation an significance of the logarithm of a ratio of frequencies. Ann Hum Genet 1956;2:309-11. 7. Tayob Y, Adams j, jacobs HC, Guillebaud J. Ultrasound demonstration of increased frequency of functional ovarian cysts in women using progestogen-only contraceptives. Br j Obstet Gynaecol 1985;92: 1003-9. 8. Grimes DA, Hughes jM. Use of multiphasic oral contraceptives and hospitalizations of women with functional ovarian cysts in the United States. Obstet Gynecol 1989;73:1037-9. 9. Queenan jT, O'Brien GD, Bains LM, Simpson j, Collins WP, Campbell S. Ultrasound scanning of ovaries to detect ovulation in women. Fertil Steril 1980;34:99-105. 10. Killich S, Eyong E, Elstein M. Ovarian follicular development in oral contraceptive cycles. Fertil Steril 1987;48:409-13.
Key words: Oral contraceptives, follicular development Triphasic oral contraceptives have been available in the United States since 1984 and now are the most frequently prescribed oral contraceptives. In 1987 Caillouette and Koehler' published a report describing seven subjects treated with triphasic oral contraceptives in whom large, persistent ovarian cysts developed and in some cases required surgery. These investigators then suggested that the triphasic oral contraceptives were causally related to cyst development. The study described here investigated this hypothesis by examining follicular development in healthy subjects with normal menstrual cycles who received a placebo, the oral contraceptive Loestrin, or the new triphasic oral contraceptive Estrostep (both manufactured by ParkeDavis) in a randomized, controlled, double-blind trial.
Material and methods Study design. A single site was chosen for this 5month double-blind, placebo-controlled, parallelgroup study. After a 2-;eek screening period, which From the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Baylor College of Medicine. Supported by a grant from the Parke-Davis Pharmaceutical Research Division ofWarner-La,mbert Company, Ann Arbor, Michigan. Presented in part at the District VII Annual Meeting of the American College of Obstetricians and Gynecologists, Puerto Vallarla, Mexico, November 1991. Received for publication October 7, 1991; revised March 2, 1992; accepted March 13, 1992. Reprint requests: Ronald L. Young, MD, Baylor College ofMedicine, 1 Baylor Plaza, Houston, TX 77030. 6/1137862
678
was sufficient to collect and evaluate the patient history and physical and laboratory examinations, subjects who had met the inclusion criteria were randomized and began a 4 week control period (cycle I). After completing this period, subjects began a 12-week blinded treatment period. This was followed by a 4-week posttreatment washout cycle. Sample selection. A sample of 48 healthy female volunteers who were between 18 and 35 years old, were post partum or had not used oral contraceptives, and had had normal menstrual cycles (28 ± 3 days) for a minimum of two consecutive months before the study was selected. All subjects initially had a normal pelvic examination, vaginal ultrasonography, and Papanicolaou smear. Each agreed to use barrier contraceptives throughout the study. Subjects were excluded if they had medical contraindications to oral contraceptives, had used oral contraceptives during the preceding 2 months, were pregnant before or became pregnant during the study. In addition, potential subjects who were lactating, had a history of ovarian follicular cysts, or had any significant history of a gynecologic pathologic condition such as pelvic inflammatory disease, endometriosis, dysfunctional uterine bleeding, or uterine abnormalities were excluded. Concurrent medications that could conceivably decrease contraceptive efficacy were disallowed. Subjects were withdrawn from the study if they experienced an adverse event, had an interfering intercurrent illness, did not tolerate the drug, failed to comply, or simply desired to withdraw.
Follicular development and oral contraceptives
Volume 167 Number 3
679
Table I. Risk of experiencing a large follice (> 18 mm) during a single cycle Treatment group
Risk per 1000 cycles
Attributable risk
Relative risk
95% Confidence interval
Control Loestrin Estrostep
157.1 276.6 190.1
119.5 33.4
1.7607 1.2126
0.7312-4.1518 0.4672-3.2177
Differences between risk levels were not significant, X2 = 2.5373944. Risk associated with control cycles was computed with all five possible cycles for control subjects. When baseline and washout cycles were included for experimental groups, resulting risk was 0.1705. Risk ratios were adjusted for small sample size and logarithmic conversions were used per Haldane. 6
Treatment. The medications used in this study were identical in appearance and packaging. Loestrin 1.5/30 contains 30 /Jog of ethinyl estradiol and 1.5 mg of norethindrone acetate taken for 21 days. Estrostep contains the same progestin dosage with 20, 30, and 35 /Jog of ethinyl estradiol taken on days 1 to 5, 6 to 12, and 13 to 21, respectively. The placebo was taken on days 1 to 21 by subjects randomized to the control group. No subject took study tablets on days 22 to 28. Treatment began with the initial tablet being taken on the first Sunday after the onset of the menstrual period. Seven days after finishing the previous package the subject started a new package. Tablets were taken with fluid at bedtime and recorded in the subject'S diary. The daily diary recorded the time of medication, adverse reactions, or missed pills. Subjects were assigned a treatment by means of a double-blind, balanced randomization scheme supplied by the Biometrics Department, Parke-Davis, Inc., Ann Arbor, Michigan. After the initial history, physical examination, and laboratory tests indicated that a subject met all inclusion criteria, she was enrolled. Blood pressure measurements were taken weekly. In addition, vaginal ultrasonography was performed and diaries were examined for compliance each week over the five cycles, for a total of 20 scans per subject. Vaginal ultrasonography was carried out with a GE3000 (General Electric, Milwaukee) 5.0 MHz vaginal probe with photo documentation. The mean follicular diameter was calculated by averaging the largest transverse and longitudinal diameters!· 3 All follicles> 5 mm were recorded. A pregnancy test was repeated at the end of the control cycle (cycle 1). Before our investigation was begun, this protocol was reviewed and approved by the Baylor College of Medicine, Institutional Review Board for Human Research. Data analysis. If we assume that 30% of subjects taking low-dose oral contraceptives will have ovarian follicles> 18 mm: 10 subjects per group is sufficient to detect a ~65% difference between the multiphasic and monophasic group with 95% confidence. In analyses in which the cycle was the unit of observation, those missing more than one ultrasonography were omitted from calculations. Cycles for which complete data were available for those subjects who were
not studied for the full 5 months were included. (In Fig. 3 the variation in sample size is a result of these acljustments. ) The time to resolution was defined as the number of consecutive weeks from the appearance of one or more follicles > 18 mm to regression of all follicles to < 13 mm. Relative risks were adjusted for small sample size, and logarithmic conversions were used to generate 95% confidence intervals. s. 6 Incidence levels were compared with the X· test for significance, and univariate analyses of variance were used to compare mean numbers and sizes of follicles observed in each treatment group. Results
Subjects were similar in age and medical history, but there were some differences in the past use of oral contraceptives. Eighty-one percent of the placebo group had used oral contraceptives, compared with 46% of the Loestrin and 60% of the Estrostep groups. Forty-eight subjects entered the control cycle. Three subjects withdrew for personal reasons and did not return diaries. Forty-five subjects entered active treatment: 16 received placebo, 14 Loestrin, and 15 Estrostep. Two subjects withdrew for personal reasons, one from the Loestrin and one from the Estrostep group. One Loestrin-treated subject withdrew because of an adverse event (pregnancy). Forty-two subjects completed the study. The most frequently reported gynecologic symptom was amenorrhea, which was reported by two placebotreated subjects, each reporting one episode, and one Loestrin subject reporting two episodes. One Estrostep subject reported an episode of myalgia. Overall, 63% of placebo-treated subjects experienced a follicle > 18 mm. Forty-three percent of Estrosteptreated subjects and 25% of Loestrin-treated subjects had a follicle> 18 mm at some time during the treatment phase. These proportions were not significantly different at an a level of 0.05 (X· == 3.94, df == 2). Table I displays the relative risk of a subject experiencing at least one large follicle (> 18 mm) during a single cycle for each study group. The risk per 1000 cycles was 157 for the control group, 190 for the Estrostep group, and 277 for the Loestrin group. The risk attributable to treatment for the Estrostep subjects
680
Young et al.
September 1992 Am J Obstet Gynecol
Fig. 1. Mean number of follicles of each size by experimental group and month. Average number of large follicles in control group varied from 0 in month 2 to 0.15 in month 3. All variation for two oral contraceptive groups was within that range. Cross-hatched bars, Control group; downward hatched bars, Loestrin group; upward hatched bars, Estrostep group. was 33 per 1000 cycles and 120 per 1000 for the Loestrin group. The relative risks associated with Loestrin and Estrostep were l. 76 and 1.2, respectively. Ninetyfive percent confidence ranges around these ratios included unity. Fig. 1 shows the average number of follicles in each cycle for each of the three treatment groups by cycle. In Fig. 1 (top) the average number of large follicles (> 18 mm) in each cycle is presented. The normal variability in the incidence of large follicles is demonstrated by observing the results in the placebo-treated group. Among the IS subjects receiving placebo, no subject had a large follicle in the second cycle, but an average of 0.15 large follicles were observed in the next (cycle 3). All treatment groups had an incidence of large follicles that was within the range observed for the placebo-treated group. Fig. I (middle and bottom) shows the mean number of medium (10 to 18 mm) and small (6 to 10 mm) follicles among the treatment groups. As with the large follicles, there was no significant effect of hormone treatment on the number of medium or small follicles. Although there was a trend toward an increased number of medium follicles over time for the two treatment groups, this trend was not statistically meaningful. Cycle variability can be observed in Fig. 2, which shows the mean weekly incidence of large (> 18 mm) follicles in the three treatment groups throughout the
study period. These data roughly show the expected patterns of large follicle development in the middle of many of the control cycles. Similarly, it can be observed that there was some continued ovarian activity in both oral contraceptive groups. The largest follicles in the three groups were 41,28, and 43 mm for placebo, Loestrin, and Estrostep-treated subjects, respectively. The mean size oflarge (> 18 mm) follicles among those subjects having large follicles also was similar across groups: 21, 21.5, and 23.8 mm for control, Loestrin, and Estrostep-treated subjects, respectively. Fig. 3 shows the mean size of the largest follicles in a patient month for each cycle in the three treatment groups. There was no significant effect of treatment on the average maximal follicle size. The mean largest follicle values were not significantly different from those in either the Loestrin or Estrostep cycles (F = 1.47, P = 0.2327). Finally, in no subject did an ovarian cystic structure last for >2 weeks in any treatment group. Comment
This investigation used a three-pronged approach to answer this question: Are women exposed to oral contraceptives at greater risk for development of large (> 18 mm) or persistent follicles? Variations across experimental groups were examined for (I) the incidence of at least one large follicle, (2) the risk of a large follicle
Follicular development and oral contraceptives
Volume 167 Number 3
0.4 0.3
...
i• C
-•... a..
0.1 0.4 0.3 0.2
~
0.1
Z
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0.4
~
0.3
•
Control
0.2
.Q
E
681
Estrostep
0.2 0.1
Treatment
Control 1
2
3 Month
Washout 4
5
Fig. 2. Average weekly incidence of large (> 18 mm) follicles in three groups. Follicular development continued in both oral contraceptive groups during treatment phase.
in a single cycle, and (3) the average number of large follicles per subject. In addition, differences in maximal follicle size, the distribution of medium and small follicles, and time to resolution of large follicles were measured. The results show the following: (1) the incidence of follicles > 18 mm was not significantly different among the three treatment groups; (2) the risk for development of follicular cysts was not different among the groups; (3) the maximal size of a follicular cyst and the average maximal size of a follicle was not observed to be significantly greater among oral contraceptivetreated subjects than controls; (4) time to resolution of follicles > 18 mm was also not found to be greater in the hormone-treated cycles. Several studies have compared the effects of hormonal contraceptives on ovarian function and follicular activity}·4, 6,7 Grimes and H ughes 8 reviewed the nationwide rate of hospitalization of women with follicular cysts before and after the introduction of triphasic oral contraceptives,8 The number of women using triphasic oral contraceptives increased from 0 to 3 million between 1979 and 1986, but the hospitalization rate for follicular cysts was unchanged. This implies that triphasic oral contraceptives are not associated with more related hospitalizations. Alternatively, Caillouette and Koehler' reported on seven cases of subjects using triphasic contraceptives in whom persistent follicular cysts developed. The data from our study demonstrate that follicular function continues with oral contraceptives
but that the incidence of large follicles is not different when control subjects and those using two types of oral contraceptives are compared. Recently Shoupe et aJ.3 used a similar protocol, involving daily rather than weekly vaginal ultrasonography, to characterize ovarian follicular development with a subcutaneous progestin, the Norplant System levonorgestrel implants (Wyeth-Ayerst, Philadelphia). They noted marked follicular development in many subjects using the progestin-only contraceptive. Our results, in subjects receiving estrogen-progestogen combination oral contraceptives, are similar in that both studies observed continued follicular development in subjects receiving exogenous hormones. The observations of Shoupe et al. of continued follicular development in Norplant users is similar to that of Tayob et al.,7 who noted follicular development in women using progestin-only oral contraceptives. Other investigators have observed similar maximal diameters of dominant follicles in normal ovarian cycles, Queenan et al. 9 observed a maximum follicle size range of 7 to 24 mm within 4 days of ovulation. We noted a follicle size of 10.6 to 16.8 mm in our control group. Our observations of continued follicular development in patients taking oral contraceptives may be explained by the results of Killich et al.,l0 who noted a more pronounced inhibition of ovarian follicular development in subjects taking triphasic oral contracep-
682
Young et al.
:E
w
September 1992 Am J abstet Gyneco1
20
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-
16 12
Q)
.~
en Q)
-
8
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&
4
c:
as Q)
:E
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2
Treatment 3 Month
4
Fig. 3. Monthly average maximum follicle size in each group. No significant treatment effect was observed. Cross-hatched bars, Control group; downward hatched bars, Loestrin group; upward hatched bars, Estrostep group.
tives when they began on cycle day 1 instead of day 5. The majority of the subjects in the Killich et al. study who had continued follicular development began their pills on cycle day 5. Sunday starts by definition will have some subjects not beginning oral contraceptives on cycle day 1. Thus some follicular development that cannot be inhibited by the oral contraceptives may be occurring by cycle day 5 or 6. However, on the basis of the low incidence of reported symptoms in experimental subjects, there does not appear to be great clinical significance to this continued follicular activity. The low incidence of large follicles and the small sample size compromise the power of the hypothesis tests used in this investigation. Thus, although no differences were detected, there remains the possibility of type II error, which can only be addressed through a more costly investigation that uses a significantly larger sample size. In spite of this limitation, we do not believe that the sample size led to a detection bias, because the observers were blinded to treatment and ovaries were observed in all subjects in all cases and medium and small follicles were observed, measured, and counted in all subjects at each visit. The times chosen for the ultrasonographic measurements and the range of follicular sizes measured in our control population is similar to results seen by Queenan et al. 9 A future study might use a group of subjects who consistently have a monthly dominant follicle before treatment. Given the variability observed
in our control group, a population of this nature may be difficult to find.
REFERENCES 1. CaiIlouette jC, Koehler AL. Phasic contraceptive pills and functional ovarian cysts. AM j OBSTET GYNECOL
1987; 156: 1538-42. 2. Schwinn SR, Lebovic J. Transvaginal pelvic ultrasound: accuracy in follicle and cyst size determination. j Ultrasound Med 1985;4:61-3. 3. Shoupe D, Lacarri M, Horensteinj, Medearis A, Mishell DR. Characterization of ovarian follicular development in Norplant users. Fertil Steril 1991;55:766-70. 4. Van der Vange N. Ovarian activity during low-dose oral contraceptive cycles. In: Chamberlain G, ed. Contemporary obstetrics and gynecology. London: Butterworth, 1988:315-26. 5. Lilienfield AM, Lilienfield DE. Foundations of epidemiology. ed 2. New York: Oxford University Press, 1980:344. 6. Haldane jBS. The estimation an significance of the logarithm of a ratio of frequencies. Ann Hum Genet 1956;2:309-11. 7. Tayob Y, Adams j, jacobs HC, Guillebaud J. Ultrasound demonstration of increased frequency of functional ovarian cysts in women using progestogen-only contraceptives. Br j Obstet Gynaecol 1985;92: 1003-9. 8. Grimes DA, Hughes jM. Use of multiphasic oral contraceptives and hospitalizations of women with functional ovarian cysts in the United States. Obstet Gynecol 1989;73:1037-9. 9. Queenan jT, O'Brien GD, Bains LM, Simpson j, Collins WP, Campbell S. Ultrasound scanning of ovaries to detect ovulation in women. Fertil Steril 1980;34:99-105. 10. Killich S, Eyong E, Elstein M. Ovarian follicular development in oral contraceptive cycles. Fertil Steril 1987;48:409-13.
