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ORIGINAL RESEARCH |
From the Tripler Army Medical Center, Honolulu, Hawaii.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Prospective cohort trial of 84 infertility patients undergoing ovulation induction with clomiphene citrate. Patients with basal ovarian cysts of 10 mm or greater (n = 42) were compared with patients without ovarian cysts (n = 42). The main outcome measure was ovulation determined by menstrual cycle day 21 progesterone level. Each patients with an ovarian cyst was also evaluated for persistence or resolution of the cyst in association with ovulation and cyst size. Pretreatment and posttreatment transvaginal ultrasound examinations were performed on all patients.
RESULTS: Demographic data were similar among the groups. The mean ovarian cyst size was 17.4 ± 5.8 mm. Patients in the ovarian cyst group were significantly less likely to ovulate (80.9% versus 97.6%, P < .05), but did not differ in pregnancy rate compared with patients without baseline ovarian cysts (4.8% versus 11.9%, P = .43). Persistent ovarian cysts occurred in 36.7% of the patients. The initial size of the cyst did not predict cyst persistence.
CONCLUSION: According to these data, basal ovarian cysts significantly reduce ovulatory events in patients treated with clomiphene citrate.
LEVEL OF EVIDENCE: II-2
A recent study concluded that basal ovarian cysts are difficult to predict but are a common finding in patients presenting for ovulation induction, with an overall incidence of 17.8%.5 We could find only one study in the literature documenting an effect of pretreatment basal ovarian cysts during clomiphene citrate ovulation induction cycles. Opsahl et al,6 in an analysis of 19 patients, found that 7 patients with ovarian cysts had spontaneous regression during treatment. This observation was a secondary outcome measure of the study. Evaluation of cycle response was not documented, but the patients with baseline ovarian cysts did not experience any adverse occurrence caused by the ovarian cyst.
Protocols for ovulation induction vary among institutions. Some providers routinely perform baseline ultrasound screening before starting medication therapy, whereas others perform ultrasound examinations on a less routine if not irregular basis. If data from the controlled ovarian hyperstimulation and IVF literature are extrapolated to clomiphene citrate ovulation induction, an argument can be made for baseline ultrasound screening. It is important to determine if patients with pretreatment ovarian cysts can be treated with clomiphene citrate and undergo normal ovulation or if clomiphene citrate should be withheld in these patients. The present study was designed to define the effects of pretreatment ovarian cysts on the ability of clomiphene citrate to induce ovulation and to evaluate the effects of clomiphene citrate on simple basal ovarian cysts.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Controlling for probability of a type 1 error at 
= 0.05 and a power of 0.80, a sample of 84 patients (42 in each group) was needed to detect a 30% change in ovulation rates. Previous data suggest ovulation rates of approximately 80% with the use of clomiphene citrate.7 Because the ovulation rate of patients with basal ovarian cysts is unknown, an ovulation rate of 50% within the cyst group was assumed for the power analysis.
Patients were between the ages of 19 and 40 years and had completed routine infertility evaluation and testing to include basal day 3 hormone levels (follicle-stimulating hormone [FSH], luteinizing hormone [LH], estradiol), prolactin, thyroid-stimulating hormone, hysterosalpingogram, and semen analysis. All patients underwent a transvaginal ultrasound examination (ATL Ultramark HDI 3000; Philips Medical Systems, Bothell, WA) with a 7 MHz vaginal transducer to assess ovarian status on menstrual day 3 before starting clomiphene citrate. The presence of a basal ovarian cyst with a mean diameter of 10 mm or greater made the patient eligible for this study. The term basal is defined as occurring in the pretreatment phase of the ovulation induction cycle on days 2 through 5 of the patient’s menstrual cycle.
Ovarian cyst size was measured by viewing the cyst via transvaginal ultrasonography in its largest cross-section and averaging the 2 perpendicular diameter measurements. Patients with complex or solid ovarian cysts were excluded from the study. In addition, patients were excluded if they refused ultrasound monitoring, had an elevated FSH greater than 12 mIU/mL, had a complex mass, or had a simple cyst greater than 5 cm. Controls (patients without pretreatment ovarian cysts 
10 mm) were recruited during the same time period.
All patients received clomiphene citrate for 5 days, starting on cycle day 3, 4, or 5. Patients were started on 50 mg of clomiphene citrate for all diagnoses except for patients with unexplained infertility who were started on 100 mg of clomiphene citrate. For patients who had previously take clomiphene citrate, the documented ovulatory dose was used. Ovulation was predicted with a urinary LH-ovulation predictor kit and confirmed with a serum day 21 progesterone level. No patient received human chorionic gonadotropin for ovulation induction. Timed intercourse or intrauterine insemination was recommended as appropriate per the semen analysis results.
The main outcome measure was ovulation with clomiphene citrate as determined by measuring a serum progesterone level on day 21 of the treatment cycle. Ovulation was defined as a serum progesterone level greater than 3 ng/dL on day 21. A secondary outcome assessed for resolution or persistence of the ovarian cyst. Cyst persistence was defined as the continued presence of the cyst ( 10 mm) at repeat ultrasound examination 4 weeks after the initial ultrasound screening. Additional secondary outcome measures included age, basal serum estradiol, day 3 FSH, day 3 LH, diagnosis, dosage of clomiphene citrate, and number of clomiphene citrate cycles.
All patients with pretreatment ovarian cysts were compared with patients undergoing clomiphene citrate ovulation induction without pretreatment cysts. All patients included in this trial were evaluated in the course of only one cycle. The t test was used to compare means between 2 groups whose data were normally distributed. A Mann-Whitney rank sum test based on normality was used to compare means between 2 groups whose data were not normally distributed. Differences in outcome rates were analyzed using a 
2 or 2-tailed Fisher exact test where appropriate. An error of 0.05 was considered significant for all comparisons. Relative risk and 95% confidence intervals are displayed where appropriate. All data are reported as means or medians with their associated standard deviations.
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RESULTS |
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When comparing the patients with cysts to those without baseline cysts, there was a significantly greater number of prior clomiphene citrate cycles in the cyst group (median 1.0 ± 1.0 versus 0.0 ± 1.3, respectively; P < .01) as well as greater clomiphene citrate dose (median 100 ± 23.5 mg versus 75 ± 27.6 mg; P < .05). There was also an earlier initiation of clomiphene citrate treatment. Within the cyst group, treatment was started on mean day 3.5 ± 0.8 compared with day 4.0 ± 1.0 within the control group (P < .05). There were no significant differences in age, gravidity, parity, day 3 FSH, day 3 LH, or the number of years attempting conception (Table 1).
Table 2 further compares the cyst group and the control group. The cyst group had a significantly higher rate of prior cysts by history compared with the control group (33.3% versus 2.4%; P < .001). The main outcome measure, ovulation, was significantly lower in the cyst group. Within the cyst group, 80.9% of patients ovulated, compared with 97.6% of patients within the control group (P < .05). There was no significant difference noted in pregnancy rates between the 2 groups (4.8% in cyst group versus 11.9% in control group). The current study had a power of 20.4% to detect a difference in pregnancy rates. To meet statistical significance for pregnancy rates, 445 patients would be needed to demonstrate a significant difference.
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To determine whether the presence of a basal ovarian cyst affected the serum progesterone concentration, day 21 progesterone levels were evaluated in all ovulatory patients. For the day 21 progesterone levels, patients who did not ovulate were excluded (n = 9) from the analysis because their values of less than 3 ng/dL would have artificially lowered the serum progesterone levels. For those patients who ovulated, there was no significant difference in day 21 progesterone levels (30.8 ± 19.5 ng/dL in cyst group versus 33.2 ± 22.5 ng/dL in the control group; Table 2). This suggests that, if ovulation occurs, the presence of a basal ovarian cyst does not affect progesterone production by the granulosa cells of the corpus luteum.
A subanalysis of the patients with basal ovarian cysts is shown in Table 3. The patients with a pretreatment basal ovarian cyst were further divided into 2 groups: those with a persistent cyst noted on ultrasound examination at 4 weeks after treatment and those noted to have resolution of the pretreatment cyst. Twelve patients failed to return for the 4-week follow-up ultrasound evaluation. Two of the 12 were pregnant, and the remaining 10 either refused or were unable to get the transvaginal ultrasonography at the appropriate time. Of the 30 patients who had a repeat ultrasound examination at 4 weeks, 36.7% (11/30) had a persistent cyst. There was no significant difference between these 2 groups with respect to age, mean baseline cyst size, ovulatory rates, or day 21 progesterone levels. Ovulation rates appeared to trend toward significance. The power of the study to detect a difference in ovulation rates in the subanalysis was 30%. Power analysis revealed the need for 78 patients with pretreatment ovarian cysts to demonstrate a significant difference in ovulation rates. The initial size of the cyst did not seem to predict cyst persistence. Of note, the patient with the largest cyst in the study (3.9 cm) did ovulate on clomiphene citrate and did not have a persistent cyst.
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DISCUSSION |
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The ovulation rate for the overall patient population and for the cyst group was greater than 80%. This ovulation rate is consistent with the prior literature on clomiphene citrate ovulation induction cycles.7 For those patients who did ovulate, the progesterone levels were not affected by the presence of the basal ovarian cyst. These data suggest that patients with a cyst can receive clomiphene citrate with expectation of good ovulation rates and adequate progesterone production. The functionality of the basal ovarian cyst was not evaluated with an estradiol level at the initiation of the treatment cycle. An area of future research may further evaluate basal ovarian cysts to determine whether functional ovarian cysts affect ovulation.
Although significantly lower ovulation rates were noted in the group with pretreatment basal ovarian cysts, it is unclear whether there is any clinical significance since the ovulation rates were greater than 80%. It is anticipated that the differences in ovulation rates ultimately will impact pregnancy rates. Because pregnancy rate was not the main outcome for our study, the number of patients (n = 445) needed to demonstrate a significant difference in pregnancy rates was not obtained. The pregnancy rates in this study agree with the published literature. Previous literature supports pregnancy rates up to 8% in patients with unexplained infertility treated with empiric clomiphene citrate, and from 8.5% to 9.5% in patients treated with clomiphene citrate with intrauterine insemination compared with those with no treatment.
Although it is possible that a menstrual cycle can be prolonged with ovulation occurring after cycle day 21, clomiphene citrate therapy stimulates a more normal cycle length. All of our patients experienced menses within 30 days of their prior menses. Therefore, for this study population, a cycle day 21 progesterone should have adequately determined ovulation.
A follow-up ultrasound examination was unable to be performed on 12 of the 42 women in the cyst group. A follow-up ultrasound evaluation was not performed in 2 patients because the patients became pregnant. The remaining 10 patients either refused or were unable to get the ultrasound evaluation during the allotted time period. The high dropout rate of 28.6% (10/42) could have biased the data acquired for the cyst group. Many of these patients did have subsequent clomiphene citrate cycles and ultrasound evaluations, but the follow-up ultrasound data were only included if the follow-up occurred with the patient’s subsequent menses.
Patients with cysts were found to be more likely to have a persistence of the cyst. Our study found a 36.7% incidence of cyst persistence. These data agree with our previous retrospective cohort study involving 466 clomiphene citrate treatment cycles, which found a 48.2% incidence of persistent cysts.5 The cysts observed in the follow-up ultrasonography did share similar characteristics of location and size to the prior ultrasound evaluation. Although it is impossible to state as an absolute fact, it can be concluded that the cysts that were viewed on ultrasonography in this study were persistent cysts and not newly developed cysts.
Based on these data, we recommend routine ultrasound screening in patients undergoing clomiphene citrate induction cycles for 2 groups of patients: 1) those with history of prior cysts, as they are more likely to have a current cyst, and 2) those not ovulating on clomiphene citrate. Because we found a significant difference in ovulation rates, physician discretion should be used to determine whether clomiphene citrate should be withheld in patients with a basal ovarian cyst. It is unknown whether ovulation can be enhanced by increasing the medication dose in these patients. In addition, women who fail to conceive after ovulation induced by clomiphene citrate may be included for the use of routine ultrasonography.
In summary, patients with a history of an ovarian cyst are more likely to have a pretreatment ovarian cyst before clomiphene citrate ovulation induction. Although other studies have shown a negative effect of ovarian cysts on ovulation induction in IVF and controlled ovarian hyperstimulation cycles, our data provide evidence for a significant negative effect on ovulation induction with clomiphene citrate as well. Although ovulation rates are decreased in patients with a pretreatment ovarian cyst, ovulation rates remain at acceptable levels (> 80%), and if ovulation occurs, serum progesterone levels are not affected. A larger study population would be required to determine the ultimate effect on pregnancy rates.
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Footnotes |
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The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.
Corresponding author: John L. Frattarelli, MD, Reproductive Endocrinology and Infertility Division, Department of Obstetrics and Gynecology, Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 95859-5000; e-mail: john.frattarelli{at}amedd.army.mil.
doi:10.1097/01.AOG.0000217695.95139.1e
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REFERENCES |
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