- Email: [email protected]
Baseline cyst formation after luteal phase gonadotropin-releasing hormone agonist administration is linked to poor in vitro fertilization outcome*
FERTILITY AND STERILITY Copyright
Vol. 64, No.3, September 1995
1995 American Society for Reproductive Medicine
Printed on acid-free paper in U. S. A.
Baseline cyst formation after luteal phase gonadotropin-releasing hormone agonist administration is linked to poor in vitro fertilization outcome*
Martin D. Keltz, M.D. t+ Ervin E. Jones, Ph.D., M.D. t Antoni J. Duleba, M.D.t
Tibor Polcz, M.D.§ Karen Kennedy, M.D.II David L. Olive, M.D.t
Yale University School of Medicine, New Haven, and Bridgeport Hospital, Bridgeport, Connecticut
Objective: To investigate the prognostic significance of baseline ovarian cysts after luteal phase GnRH agonist (GnRH-a) administration for IVF-ET. Design: All nondonor IVF-ET cycles in one program in which luteal phase GnRH-a was administered between July 1993 and January 1994 were assessed for the formation of baseline ovarian cysts defined as a mean diameter 2: 15 mm. Outcome data from the IVF cycles were compared between patients with and without baseline ovarian cysts. Results: Of 78 IVF cycles, baseline cysts 2: 15 mm were noted in 26 cycles. Cycles in which cysts were formed were associated with significantly older patients with significantly higher baseline FSH values. Cycles in which cysts were present demonstrated fewer follicles, retrieved oocytes, and embryos. Cyst cycles also demonstrated a lower peak E2 level, implantation rate, and clinical pregnancy rate (PR) per initiated cycle (7.7% versus 32.7%). Cyst cycles also demonstrated a higher cancellation rate. Logistic regression modeling, accounting for age, confirmed significantly lower clinical PRs in cycles with a baseline cyst. Conclusions: Baseline cyst formation after luteal phase GnRH-a administration is both a marker for poor responders and a reliable predictor of poor stimulation and low PRs in a given IVF-ET cycle. Fertil SteriI1995;64:568-72 Key Words: Cyst, IVF-ET, GnRH-a
There has been considerable interest in the prognostic significance of baseline ovarian cysts for IVFET. This issue initially was addressed for IVF-ET cycles that did not use GnRH agonists (GnRH-a) for suppression. Thatcher et al. (1) noted that cystic structures seen during ultrasound (US) on the 3rd menstrual day before IVF-ET were associated with
Received October 19, 1994; revised and accepted March 13, 1995. * Presented at the 50th Annual Meeting of The American Fertility Society, San Antonio, Texas, November 5 to 10, 1994. t Department of Obstetrics and Gynecology, Yale University School of Medicine. t Reprint requests: Martin D. Keltz, M.D., Yale University School of Medicine, Department of Obstetrics and Gynecology, 333 Cedar Street, P.O. Box 208063, New Haven, Connecticut 06520 (FAX: 203-785-7134). § Department of Obstetrics and Gynecology, Bridgeport Hospital. II Department of Pediatrics, Yale University Schoor of Medicine.
568
Keltz et al.
Cysts after GnRH-a and IVF outcome
poorer stimulation. Yet it was subsequently reported that, when comparing the same patient in cycles with and without baseline cystic structures, there are no differences in the quality of stimulation or pregnancy rates (PRs) (2). Concern over ovarian cysts before gonadotropin stimulation for IVF-ET has been compounded by the finding that GnRH-a results in cyst formation in 10% to 29% of cycles (3, 4). Gonadotropin-releasing hormone agonists, used for gonadotropin and ovarian suppression, have gained widespread use in IVF-ET as they significantly reduce the number of cancelled cycles due to premature luteinization, thereby increasing the per cycle PR (5, 6). Yet they have concomitantly increased the rate of cyst formation before initiation of IVF-ET (6). Numerous studies have investigated early follicular phase GnRH-a administration and follicular cyst formation. These studies generally have reported no difference in outcomes between IVF-ET cycles with Fertility and Sterility
follicular cyst formation after GnRH-a administration and those without cyst formation (3, 4, 7). Many IVF -ET programs, however, have begun using luteal phase starts for GnRH-a administration before IVFET, as fewer cysts and lower baseline E 2 levels have been reported (8), along with a lower rate of spontaneous abortions after successful IVF-ET cycles (9). There have been few studies assessing the prognostic significance of cystic structures after luteal phase administration for IVF-ET. One large retrospective study evaluated the finding of ~30 mm cysts after midluteal GnRH-a and 5 days of gonadotropin stimulation and noted adverse cycle outcome only in those cyst cycles with an elevated E2 before gonadotropin stimulation (10). Another study evaluated both early follicular and midluteal administration of GnRH-a for IVF-ET and found no difference in the eventual PR of the patients forming cysts (~15 mm) versus those without a cyst (11). While using midluteal phase GnRH-a, we noted that baseline cysts seemed to occur more commonly in expected poor responders, as well as in poor stimulation cycles for IVF-ET. As the significance of baseline cysts is unresolved in the literature, a review of recent IVF-ET cycles using luteal phase GnRH-a was initiated. MATERIALS AND METHODS
All IVF cycles from the Yale IVF -ET program between July 1993 and January 1994 were reviewed. Seventy-eight cycles in which patients received luteal phase GnRH-a between cycle days 19 and 28 were included in the study. Patients included in this study were given 1.0 mg SC leuprolide acetate (LA) starting the first Friday after day 21 of their menstrual cycle for pituitary down-regulation. The patients received LA daily for 1 week. At the end of the week, they returned for a baseline transvaginal US and serum E2 level. If the E2 level was <50 pg/ mL (conversion factor to SI unit, 3.671), stimulation with hMG, FSH, or both was initiated 2 days later, and the dose of LA was decreased to 0.5 mg. Ifthe E2 level was elevated, LA administration was continued for another week and patients returned again for a vaginal US and E2 level. Patients were followed with US exams and serum E2 levels at least every 3 days and more frequently as folliculogenesis progressed. When folliculogenesis resulted in at least two follicles > 16 mm average diameter and E2 levels were judged to be adequate, 10,000 IU 1M hCG was administered. Approximately 34 hours later, oocyte retrieval with transvaginal US guidance was performed. Oocytes were incubated with prepared sperm and some number of embryos was transferred approximately 48 hours after oocyte retrieval. PosiVol. 64, No.3, September 1995
tive pregnancies were defined as a serum ,B-hCG of ~ 10 mIUhnL (conversion factor to SI unit, 1.00) ~ 14 days after hCG administration, with a second ,B-hCG showing a rise in value. Clinical pregnancies demonstrated at least one gestational sac on transvaginal US. Statistics were performed using Systat (Systat Inc. Evanston, IL), a computerized statistical program. Univariate analyses were performed with the t-test for continuous data and Fisher's exact test for categorical data. Logistic regression analysis was carried out by modeling clinical pregnancy as a function of age, FSH, and the presence or absence of a baseline cyst ~ 15 mm in diameter. X 2 analysis was performed for discrete levels of cyst size and PR. Modified receiver operating characteristic (ROC) analysis was performed, testing cystic structures from 10 mm until >20 mm, at I-mm increments, to determine the ideal threshold for PRs (12). RESULTS
Of78 IVF cycles with luteal phase GnRH-a administration, 26 (33.3%) demonstrated a cystic structure ~ 15 mm at the time of baseline US. The cycles in which these cysts were demonstrated were associated with older patients, 37.9 ± 3.3 versus 34.7 ± 4.0 years of age (P < 0.001). Cyst cycles also were associated with higher FSH values, 12.4 ± 6.8 versus 8.8 ± 3.5 (conversion factor to SI unit, 1.00) (P = 0.001). There was no difference in the percent of patients undergoing a first IVF -ET cycle between the cyst and no cyst groups (50.0% versus 53.8%). The percent of patients with infertility categorized as tuboperitoneal, unexplained, male factor, endometriosis, and oligo-ovulation displayed no significant differences between the cyst and no cyst groups. At the time of baseline US, cycles with cysts did have a significantly higher baseline E2 level, 202.2 versus 36 pg/mL (conversion factor to SI unit, 3.671; P = 0.007). Yet among cyst cycles, there were no outcome differences between the 16 cycles with an elevated baseline E2 level and the 10 cycles with a suppressed baseline E 2 level. The P levels, however, were no different, and there was no difference in the luteal phase day in which GnRH -a was administered between cycles with and without a baseline cyst. Baseline P levels of >3 ng/mL (conversion factor to SI unit, 3.180) were, however, significantly correlated with GnRH-a administration earlier in the luteal phase, luteal day 22.4 versus 24.3, P < 0.03. Cyst cycles demonstrated fewer follicles > 12 mm mean diameter on the day of hCG administration, lower peak E2 levels, fewer oocytes retrieved, and fewer total embryos, and a higher cancellation rate. There were no significant differences in fertilization Keltz et al.
Cysts after GnRH-a and IVF outcome
569
Table 1 Cycle Outcome Variables
Table 3
Progressive Baseline Cyst Diameter and Clinical PR
Outcome
With cyst
Without cyst
P value
Cyst size
Clinical PR*
Peak E2* No. offollicles >12 mm Cancellation ratet Oocytes retrieved* Fertilization rate* (%) Total number of embryos* (%) Percent grade 1 and 2 embryos per transfer cycle* (%) Total PR per startt Clinical PR per startt Implantation ratet Clinical PR per start for persistent cystst§
650.7 :!: 427.3
1257.4 :!: 905.9
<0.001
15/41 (36.7) 2/11 (18.8)
4.7 :!: 3.5 8/26 (30.8) 6.4 :!: 5.2
7.2 :!: 3.5 5/52 (9.6) 11.3 :!: 7.7
0.005 0.026 0.01
65.9 :!: 32.7
61.0 :!: 32.2
NS:/:
P
4.6 :!:
2.1
7.0 :!:
5.4
0.020
49.3 :!: 27.6 3/26 (11.5)
53.4 :!: 31.4 23/52 (44.2)
NS 0.005
2/26 (7.7) 2/71 (2.8)
17/52 (32.7) 29/186 (12.9)
0.038 0.019
0/18 (0,0)
19/60 (32)
0.004
* Values are means:!: SD. t Values in parentheses are percentages. :/: NS, not significant. § Persistent cyst, cyst;=: 15 mm when gonadotropins were initiated.
rates or embryo quality. Total PRs and clinical PRs were lower per cycle start, retrieval, and transfer for cycles with a baseline cyst and were even lower in cycles in which gonadotropins were initiated when a 20: 15 mm cyst was still present. Implantation rates also were lower in cyst cycles (Table 1). Logistic regression modeling verified the prognostic significance of baseline ovarian cysts independent of age. When accounting for day 3 FSH values, the odds ratio was unchanged, however, the 95% confidence interval was much broader as analysis could be completed on only 46 of 78 cycles and statistical significance was not achieved (Table 2). Among the 26 cycles with a baseline cyst 20: 15 mm, 8 no longer had a cyst 20: 15 mm when gonadotropin stimulation was started, either because the cyst decreased in size during the delay because of an elevated baseline E 2 , as occurred in 6 cases, or because of a cyst aspiration, as was performed in 2 cases. Among cycles with a baseline cyst, cycles without a
Table 2 The Correlation of Baseline Cyst, Age, and FSH with Clinical PR Variable
Odds ratio
Cyst* Age* Cystt FSHt
0.195 0.960 0.162 1.009
95% confidence interval 0.039 0.835 0.015 0.840
to to to to
0.975 1.103 1.800 1.212
* Seventy-eight cycles analyzed for cyst and a~e. t Forty-six cycles and analyzed for cyst, FSH, and age. 570
Keltz et al.
Cysts after GnRH-a and IVF outcome
=
119 (11.1)
1/17 (5.9)
0.038.
* Values in parentheses are percentages.
cyst when gonadotropins were initiated had a significantly higher PR than cycles that still had an ovarian cyst 20: 15 mm (37_5% versus 0.0%, P = 0.022). A progressive worsening of clinical pregnancy outcomes was seen with progressively larger baseline cysts by grouping the cystic structures into < 10 mm, 10 to 14 mm, 15 to 19 mm, and 20:22 mm groups. X2 analysis demonstrated the dependence of clinical PR on cyst size (Table 3). When we performed a ROC analysis (12) of cyst size and pregnancy outcome with our data, this confirmed that the best threshold excluded cystic structures :5 14 mm and included structures 20: 15 mm as cysts. DISCUSSION
Our study demonstrates that ovarian cyst production after GnRH-a administration during the luteal phase is associated with a marked reduction in PRs in the ensuing NF-ET cycle. In the cycles in which cysts were formed, a succession of signs of poor folliculogenesis led to the poor PR, including decreased follicle production, increased cancellation rate, fewer oocytes retrieved, and fewer total embryos per retrieval. Interestingly, although there was no significant difference in the embryo quality noted between cycles with and without cysts, the implantation rate was reduced markedly in the patients with ovarian cysts. This reduction in implantation rate may be due to a number of factors associated with the cyst cycles, including older patient age, differences in embryo quality that are not assessed adequately by grading, and possible deleterious affects these cysts or their steroidogenesis may have had on endometrial receptivity. This study demonstrated a relatively high rate, 33.3%, of baseline ovarian cysts. This likely is due to a number of variables, including patient age and the cutoff for the cyst's diameter. Our patient population had a median age of 36 years, which is considerably older than other studies assessing baseline cysts (3,10). As this study demonstrated, cyst formation is more frequent with advancing age. Based on our ROC analysis, we used a cutoff of 20: 15 mm. Fertility and Sterility
Other investigators have used larger mean cystic diameter to define a baseline cyst, which reduces the incidence of these cysts (3,8, 10). Finally, the protocol for GnRH-a administration is not standard throughout the literature, and daily doses of GnRHa as opposed to long-acting GnRH-a may affect the rate of cyst formation (3-11). The reduction in PRs in cycles with baseline cysts may be attributable to two potential factors. The first factor involves the propensity of patients with expected poor ovarian response to form cysts to luteal phase GnRH-a administration. The cycles in which cysts were formed were associated with older patients and patients with higher FSH levels, which suggests that cystic production is not random and may be associated with patients at risk for poor response cycles. Although this study did not demonstrate a reduced PR with increasing age or day 3 FSH level, these factors previously have been demonstrated to be important predictors ofIVF-ET outcome (13,14). In our study, 90% of the 46 cycles that had documented levels had a day 3 FSH < 15 mIUI mL; because of the lack of variability in FSH level in this study, there was insufficient statistical power to demonstrate the impact of FSH on PRs. For patients with an acceptably low day 3 FSH, baseline cyst formation in combination with age may increase the sensitivity of predicting a poor IVF-ET outcome before initiating gonadotropins. The second factor is a negative impact of ovarian cysts on folliculogenesis and IVF-ET outcome. Our data suggest that the cysts themselves have a direct impact on IVF-ET outcome. In all the study cycles, E 2 1evels were <50 pg/mL before initiating stimulation, yet cycles with baseline cysts were associated with a marked reduction in pregnancy. Also, those cycles in which a cyst was present when gonadotropins were initiated had an even lower PR than cycles in which the cyst was reduced in size to < 15 mm or aspirated before initiating stimulation. In a number of the studies (7, 8,11) in which baseline cysts did not appear to impact on the PRs, those cysts were gone before stimulation. In two such studies, cysts were followed with continued GnRH-a administration until they were < 15 mm in diameter before initiation of gonadotropins and, in a third study, all cysts were aspirated before continued stimulation (7, 8, 11). There are also indications in the literature that baseline ovarian cysts have a negative impact on folliculogenesis. Although Ron-El et al. (7) found no difference in PRs, there were fewer oocytes retrieved in cycles in which a baseline ovarian cyst had been found. Goldberg et al. (15) found a higher cancellation rate and lower peak E2 among patients with a baseline ovarian cyst > 12 mm in IVF and GIFT cycles. Jenkins et al. (10) found that Vol. 64, No.3, September 1995
large cysts >30 mm after luteal phase GnRH-a administrat10n were associated with a poor IVF outcome when in combination with an elevated baseline E2 level. This study suggests that the formation of baseline cysts are indicative of patients likely to have poor response cycles. It also suggests that cysts that persist despite suppressed E 2 1evels have some deleterious effect on folliculogenesis and implantation. The study's limitations include inadequate sample size to demonstrate the predictive value of a baseline cyst for clinical PRs independent of day 3 FSH level, as well as its retrospective design, which prevents the evaluation of various interventions once a baseline cyst is diagnosed. With further study it should be possible to use the formation of baseline ovarian cysts after GnRH-a administration prognostically, in conjunction with age and day 3 FSH level, when counseling patients about continuing a cycle. Although this study suggests that there may be an advantage in delaying gonadotropin stimulation until a follicular cyst either has diminished in size or has been aspirated, defining the best course of action once a cyst is identified will require further study. REFERENCES 1. Thatcher SS, Jones E, DeCherney AH. Ovarian cysts decrease the success of controlled ovarian stimulation and in vitro fertilization. Fertil Steril 1989;52:812-6. 2. Penzias AS, Jones EE, Seifer DB, Grifo JA, Thatcher SS, DeCherney AH. Baseline ovarian cysts do not affect clinical response to controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 1992;57:1017 -21. 3. Sampaio M, Serra B, Miro F, Calatayud C, Castellvi R, Pellicer A. Development of ovarian cysts during gonadotropin releasing hormone agonists administration. Hum Reprod 1991;6:194-7. 4. Feldberg D, Ashkenazi J, Dicker D, Yeshaya A, Goldman GA, Goldman JA. Ovarian cyst formation: a complication of gonadotropin releasing hormone agonist therapy. Fertil Steril 1989;51:42-5. 5. Meldrum DR, Wisot A, Hamilton F, Gutlay AL, Kempton W, Huynh D. Routine pituitary suppression leuprolide before ovarian stimulation for oocyte retrieval. Fertil Steril 1989; 51:455-9. 6. Berg Van De-Helder A, Helmerhorst F, Blankhart A, Brand R, Waegemaekers C, N aaktgeboren N. Comparison of ovarian stimulation regimens for in vitro fertilization with and without a gonadotropin-releasing hormone agonist: results of a randomized study. J In Vitro Fert Embryo Transf 1990; 7:358-64. 7. Ron-El R, Herman A, Golan A, Raziel A, Soffer Y, Caspi E. Follicle cyst formation following long-acting gonadotropin-releasing hormone analog administration. Fertil Steril 1989;52:1063-6. 8. Ben-Rafael Z, Bider D, Menashe Y, Maymon R, Zolti M, Mashiach S. Follicular and luteal cysts after treatment with gonadotropin-releasing hormone analog for in vitro fertilization. Fertil Steril 1990;53:1091-4. 9. San Roman GA, Surrey ES, Judd HL, Kerin JF. A prospective randomized comparison ofluteal phase versus concurrent fol-
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licular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization. Fertil Steril1992;58:744-9. 10. Jenkins J, Davies D, Anthony F, Wood P, Gadd S, Watson R, et al. The detrimental influence of functional ovarian cyst during in-vitro fertilization cycles. Hum Reprod 1992;7: 776-80. 11. Herman A, Ron-El R, Golan A, Nahum H, Soffer Y, Caspi E. Follicle cysts after menstrual versus midluteal administration of gonadotropin-releasing hormone analog in in vitro fertilization. Fertil Steril 1990;53:854-8. 12. Silverberg K, Burns W, Olive D, Riehl R, Schenken R. Serum progesterone levels predict success of in vitro fertilization! embryo transfer in patients stimulated with leuprolide ace-
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tate and human menopausal gonadotropins. J Clin Endocrinol Metab 1993;73:797-803. 13. Tan S, Steer C, Royston P, Rizk B, Mason B, Campbell S. Conception rates and in vitro fertilization [letterl. Lancet 1990;335:229. 14. Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651-4. 15. Goldberg JM, Miller FA, Friedman CI, Dodds WG, Kim MH. Effects of baseline ovarian cysts on in vitro fertilization and gamete intrafallopian transfer cycles. Fertil Steril 1991; 55:319-23.
Fertility and Sterility
Vol. 64, No.3, September 1995
1995 American Society for Reproductive Medicine
Printed on acid-free paper in U. S. A.
Baseline cyst formation after luteal phase gonadotropin-releasing hormone agonist administration is linked to poor in vitro fertilization outcome*
Martin D. Keltz, M.D. t+ Ervin E. Jones, Ph.D., M.D. t Antoni J. Duleba, M.D.t
Tibor Polcz, M.D.§ Karen Kennedy, M.D.II David L. Olive, M.D.t
Yale University School of Medicine, New Haven, and Bridgeport Hospital, Bridgeport, Connecticut
Objective: To investigate the prognostic significance of baseline ovarian cysts after luteal phase GnRH agonist (GnRH-a) administration for IVF-ET. Design: All nondonor IVF-ET cycles in one program in which luteal phase GnRH-a was administered between July 1993 and January 1994 were assessed for the formation of baseline ovarian cysts defined as a mean diameter 2: 15 mm. Outcome data from the IVF cycles were compared between patients with and without baseline ovarian cysts. Results: Of 78 IVF cycles, baseline cysts 2: 15 mm were noted in 26 cycles. Cycles in which cysts were formed were associated with significantly older patients with significantly higher baseline FSH values. Cycles in which cysts were present demonstrated fewer follicles, retrieved oocytes, and embryos. Cyst cycles also demonstrated a lower peak E2 level, implantation rate, and clinical pregnancy rate (PR) per initiated cycle (7.7% versus 32.7%). Cyst cycles also demonstrated a higher cancellation rate. Logistic regression modeling, accounting for age, confirmed significantly lower clinical PRs in cycles with a baseline cyst. Conclusions: Baseline cyst formation after luteal phase GnRH-a administration is both a marker for poor responders and a reliable predictor of poor stimulation and low PRs in a given IVF-ET cycle. Fertil SteriI1995;64:568-72 Key Words: Cyst, IVF-ET, GnRH-a
There has been considerable interest in the prognostic significance of baseline ovarian cysts for IVFET. This issue initially was addressed for IVF-ET cycles that did not use GnRH agonists (GnRH-a) for suppression. Thatcher et al. (1) noted that cystic structures seen during ultrasound (US) on the 3rd menstrual day before IVF-ET were associated with
Received October 19, 1994; revised and accepted March 13, 1995. * Presented at the 50th Annual Meeting of The American Fertility Society, San Antonio, Texas, November 5 to 10, 1994. t Department of Obstetrics and Gynecology, Yale University School of Medicine. t Reprint requests: Martin D. Keltz, M.D., Yale University School of Medicine, Department of Obstetrics and Gynecology, 333 Cedar Street, P.O. Box 208063, New Haven, Connecticut 06520 (FAX: 203-785-7134). § Department of Obstetrics and Gynecology, Bridgeport Hospital. II Department of Pediatrics, Yale University Schoor of Medicine.
568
Keltz et al.
Cysts after GnRH-a and IVF outcome
poorer stimulation. Yet it was subsequently reported that, when comparing the same patient in cycles with and without baseline cystic structures, there are no differences in the quality of stimulation or pregnancy rates (PRs) (2). Concern over ovarian cysts before gonadotropin stimulation for IVF-ET has been compounded by the finding that GnRH-a results in cyst formation in 10% to 29% of cycles (3, 4). Gonadotropin-releasing hormone agonists, used for gonadotropin and ovarian suppression, have gained widespread use in IVF-ET as they significantly reduce the number of cancelled cycles due to premature luteinization, thereby increasing the per cycle PR (5, 6). Yet they have concomitantly increased the rate of cyst formation before initiation of IVF-ET (6). Numerous studies have investigated early follicular phase GnRH-a administration and follicular cyst formation. These studies generally have reported no difference in outcomes between IVF-ET cycles with Fertility and Sterility
follicular cyst formation after GnRH-a administration and those without cyst formation (3, 4, 7). Many IVF -ET programs, however, have begun using luteal phase starts for GnRH-a administration before IVFET, as fewer cysts and lower baseline E 2 levels have been reported (8), along with a lower rate of spontaneous abortions after successful IVF-ET cycles (9). There have been few studies assessing the prognostic significance of cystic structures after luteal phase administration for IVF-ET. One large retrospective study evaluated the finding of ~30 mm cysts after midluteal GnRH-a and 5 days of gonadotropin stimulation and noted adverse cycle outcome only in those cyst cycles with an elevated E2 before gonadotropin stimulation (10). Another study evaluated both early follicular and midluteal administration of GnRH-a for IVF-ET and found no difference in the eventual PR of the patients forming cysts (~15 mm) versus those without a cyst (11). While using midluteal phase GnRH-a, we noted that baseline cysts seemed to occur more commonly in expected poor responders, as well as in poor stimulation cycles for IVF-ET. As the significance of baseline cysts is unresolved in the literature, a review of recent IVF-ET cycles using luteal phase GnRH-a was initiated. MATERIALS AND METHODS
All IVF cycles from the Yale IVF -ET program between July 1993 and January 1994 were reviewed. Seventy-eight cycles in which patients received luteal phase GnRH-a between cycle days 19 and 28 were included in the study. Patients included in this study were given 1.0 mg SC leuprolide acetate (LA) starting the first Friday after day 21 of their menstrual cycle for pituitary down-regulation. The patients received LA daily for 1 week. At the end of the week, they returned for a baseline transvaginal US and serum E2 level. If the E2 level was <50 pg/ mL (conversion factor to SI unit, 3.671), stimulation with hMG, FSH, or both was initiated 2 days later, and the dose of LA was decreased to 0.5 mg. Ifthe E2 level was elevated, LA administration was continued for another week and patients returned again for a vaginal US and E2 level. Patients were followed with US exams and serum E2 levels at least every 3 days and more frequently as folliculogenesis progressed. When folliculogenesis resulted in at least two follicles > 16 mm average diameter and E2 levels were judged to be adequate, 10,000 IU 1M hCG was administered. Approximately 34 hours later, oocyte retrieval with transvaginal US guidance was performed. Oocytes were incubated with prepared sperm and some number of embryos was transferred approximately 48 hours after oocyte retrieval. PosiVol. 64, No.3, September 1995
tive pregnancies were defined as a serum ,B-hCG of ~ 10 mIUhnL (conversion factor to SI unit, 1.00) ~ 14 days after hCG administration, with a second ,B-hCG showing a rise in value. Clinical pregnancies demonstrated at least one gestational sac on transvaginal US. Statistics were performed using Systat (Systat Inc. Evanston, IL), a computerized statistical program. Univariate analyses were performed with the t-test for continuous data and Fisher's exact test for categorical data. Logistic regression analysis was carried out by modeling clinical pregnancy as a function of age, FSH, and the presence or absence of a baseline cyst ~ 15 mm in diameter. X 2 analysis was performed for discrete levels of cyst size and PR. Modified receiver operating characteristic (ROC) analysis was performed, testing cystic structures from 10 mm until >20 mm, at I-mm increments, to determine the ideal threshold for PRs (12). RESULTS
Of78 IVF cycles with luteal phase GnRH-a administration, 26 (33.3%) demonstrated a cystic structure ~ 15 mm at the time of baseline US. The cycles in which these cysts were demonstrated were associated with older patients, 37.9 ± 3.3 versus 34.7 ± 4.0 years of age (P < 0.001). Cyst cycles also were associated with higher FSH values, 12.4 ± 6.8 versus 8.8 ± 3.5 (conversion factor to SI unit, 1.00) (P = 0.001). There was no difference in the percent of patients undergoing a first IVF -ET cycle between the cyst and no cyst groups (50.0% versus 53.8%). The percent of patients with infertility categorized as tuboperitoneal, unexplained, male factor, endometriosis, and oligo-ovulation displayed no significant differences between the cyst and no cyst groups. At the time of baseline US, cycles with cysts did have a significantly higher baseline E2 level, 202.2 versus 36 pg/mL (conversion factor to SI unit, 3.671; P = 0.007). Yet among cyst cycles, there were no outcome differences between the 16 cycles with an elevated baseline E2 level and the 10 cycles with a suppressed baseline E 2 level. The P levels, however, were no different, and there was no difference in the luteal phase day in which GnRH -a was administered between cycles with and without a baseline cyst. Baseline P levels of >3 ng/mL (conversion factor to SI unit, 3.180) were, however, significantly correlated with GnRH-a administration earlier in the luteal phase, luteal day 22.4 versus 24.3, P < 0.03. Cyst cycles demonstrated fewer follicles > 12 mm mean diameter on the day of hCG administration, lower peak E2 levels, fewer oocytes retrieved, and fewer total embryos, and a higher cancellation rate. There were no significant differences in fertilization Keltz et al.
Cysts after GnRH-a and IVF outcome
569
Table 1 Cycle Outcome Variables
Table 3
Progressive Baseline Cyst Diameter and Clinical PR
Outcome
With cyst
Without cyst
P value
Cyst size
Clinical PR*
Peak E2* No. offollicles >12 mm Cancellation ratet Oocytes retrieved* Fertilization rate* (%) Total number of embryos* (%) Percent grade 1 and 2 embryos per transfer cycle* (%) Total PR per startt Clinical PR per startt Implantation ratet Clinical PR per start for persistent cystst§
650.7 :!: 427.3
1257.4 :!: 905.9
<0.001
15/41 (36.7) 2/11 (18.8)
4.7 :!: 3.5 8/26 (30.8) 6.4 :!: 5.2
7.2 :!: 3.5 5/52 (9.6) 11.3 :!: 7.7
0.005 0.026 0.01
65.9 :!: 32.7
61.0 :!: 32.2
NS:/:
P
4.6 :!:
2.1
7.0 :!:
5.4
0.020
49.3 :!: 27.6 3/26 (11.5)
53.4 :!: 31.4 23/52 (44.2)
NS 0.005
2/26 (7.7) 2/71 (2.8)
17/52 (32.7) 29/186 (12.9)
0.038 0.019
0/18 (0,0)
19/60 (32)
0.004
* Values are means:!: SD. t Values in parentheses are percentages. :/: NS, not significant. § Persistent cyst, cyst;=: 15 mm when gonadotropins were initiated.
rates or embryo quality. Total PRs and clinical PRs were lower per cycle start, retrieval, and transfer for cycles with a baseline cyst and were even lower in cycles in which gonadotropins were initiated when a 20: 15 mm cyst was still present. Implantation rates also were lower in cyst cycles (Table 1). Logistic regression modeling verified the prognostic significance of baseline ovarian cysts independent of age. When accounting for day 3 FSH values, the odds ratio was unchanged, however, the 95% confidence interval was much broader as analysis could be completed on only 46 of 78 cycles and statistical significance was not achieved (Table 2). Among the 26 cycles with a baseline cyst 20: 15 mm, 8 no longer had a cyst 20: 15 mm when gonadotropin stimulation was started, either because the cyst decreased in size during the delay because of an elevated baseline E 2 , as occurred in 6 cases, or because of a cyst aspiration, as was performed in 2 cases. Among cycles with a baseline cyst, cycles without a
Table 2 The Correlation of Baseline Cyst, Age, and FSH with Clinical PR Variable
Odds ratio
Cyst* Age* Cystt FSHt
0.195 0.960 0.162 1.009
95% confidence interval 0.039 0.835 0.015 0.840
to to to to
0.975 1.103 1.800 1.212
* Seventy-eight cycles analyzed for cyst and a~e. t Forty-six cycles and analyzed for cyst, FSH, and age. 570
Keltz et al.
Cysts after GnRH-a and IVF outcome
=
119 (11.1)
1/17 (5.9)
0.038.
* Values in parentheses are percentages.
cyst when gonadotropins were initiated had a significantly higher PR than cycles that still had an ovarian cyst 20: 15 mm (37_5% versus 0.0%, P = 0.022). A progressive worsening of clinical pregnancy outcomes was seen with progressively larger baseline cysts by grouping the cystic structures into < 10 mm, 10 to 14 mm, 15 to 19 mm, and 20:22 mm groups. X2 analysis demonstrated the dependence of clinical PR on cyst size (Table 3). When we performed a ROC analysis (12) of cyst size and pregnancy outcome with our data, this confirmed that the best threshold excluded cystic structures :5 14 mm and included structures 20: 15 mm as cysts. DISCUSSION
Our study demonstrates that ovarian cyst production after GnRH-a administration during the luteal phase is associated with a marked reduction in PRs in the ensuing NF-ET cycle. In the cycles in which cysts were formed, a succession of signs of poor folliculogenesis led to the poor PR, including decreased follicle production, increased cancellation rate, fewer oocytes retrieved, and fewer total embryos per retrieval. Interestingly, although there was no significant difference in the embryo quality noted between cycles with and without cysts, the implantation rate was reduced markedly in the patients with ovarian cysts. This reduction in implantation rate may be due to a number of factors associated with the cyst cycles, including older patient age, differences in embryo quality that are not assessed adequately by grading, and possible deleterious affects these cysts or their steroidogenesis may have had on endometrial receptivity. This study demonstrated a relatively high rate, 33.3%, of baseline ovarian cysts. This likely is due to a number of variables, including patient age and the cutoff for the cyst's diameter. Our patient population had a median age of 36 years, which is considerably older than other studies assessing baseline cysts (3,10). As this study demonstrated, cyst formation is more frequent with advancing age. Based on our ROC analysis, we used a cutoff of 20: 15 mm. Fertility and Sterility
Other investigators have used larger mean cystic diameter to define a baseline cyst, which reduces the incidence of these cysts (3,8, 10). Finally, the protocol for GnRH-a administration is not standard throughout the literature, and daily doses of GnRHa as opposed to long-acting GnRH-a may affect the rate of cyst formation (3-11). The reduction in PRs in cycles with baseline cysts may be attributable to two potential factors. The first factor involves the propensity of patients with expected poor ovarian response to form cysts to luteal phase GnRH-a administration. The cycles in which cysts were formed were associated with older patients and patients with higher FSH levels, which suggests that cystic production is not random and may be associated with patients at risk for poor response cycles. Although this study did not demonstrate a reduced PR with increasing age or day 3 FSH level, these factors previously have been demonstrated to be important predictors ofIVF-ET outcome (13,14). In our study, 90% of the 46 cycles that had documented levels had a day 3 FSH < 15 mIUI mL; because of the lack of variability in FSH level in this study, there was insufficient statistical power to demonstrate the impact of FSH on PRs. For patients with an acceptably low day 3 FSH, baseline cyst formation in combination with age may increase the sensitivity of predicting a poor IVF-ET outcome before initiating gonadotropins. The second factor is a negative impact of ovarian cysts on folliculogenesis and IVF-ET outcome. Our data suggest that the cysts themselves have a direct impact on IVF-ET outcome. In all the study cycles, E 2 1evels were <50 pg/mL before initiating stimulation, yet cycles with baseline cysts were associated with a marked reduction in pregnancy. Also, those cycles in which a cyst was present when gonadotropins were initiated had an even lower PR than cycles in which the cyst was reduced in size to < 15 mm or aspirated before initiating stimulation. In a number of the studies (7, 8,11) in which baseline cysts did not appear to impact on the PRs, those cysts were gone before stimulation. In two such studies, cysts were followed with continued GnRH-a administration until they were < 15 mm in diameter before initiation of gonadotropins and, in a third study, all cysts were aspirated before continued stimulation (7, 8, 11). There are also indications in the literature that baseline ovarian cysts have a negative impact on folliculogenesis. Although Ron-El et al. (7) found no difference in PRs, there were fewer oocytes retrieved in cycles in which a baseline ovarian cyst had been found. Goldberg et al. (15) found a higher cancellation rate and lower peak E2 among patients with a baseline ovarian cyst > 12 mm in IVF and GIFT cycles. Jenkins et al. (10) found that Vol. 64, No.3, September 1995
large cysts >30 mm after luteal phase GnRH-a administrat10n were associated with a poor IVF outcome when in combination with an elevated baseline E2 level. This study suggests that the formation of baseline cysts are indicative of patients likely to have poor response cycles. It also suggests that cysts that persist despite suppressed E 2 1evels have some deleterious effect on folliculogenesis and implantation. The study's limitations include inadequate sample size to demonstrate the predictive value of a baseline cyst for clinical PRs independent of day 3 FSH level, as well as its retrospective design, which prevents the evaluation of various interventions once a baseline cyst is diagnosed. With further study it should be possible to use the formation of baseline ovarian cysts after GnRH-a administration prognostically, in conjunction with age and day 3 FSH level, when counseling patients about continuing a cycle. Although this study suggests that there may be an advantage in delaying gonadotropin stimulation until a follicular cyst either has diminished in size or has been aspirated, defining the best course of action once a cyst is identified will require further study. REFERENCES 1. Thatcher SS, Jones E, DeCherney AH. Ovarian cysts decrease the success of controlled ovarian stimulation and in vitro fertilization. Fertil Steril 1989;52:812-6. 2. Penzias AS, Jones EE, Seifer DB, Grifo JA, Thatcher SS, DeCherney AH. Baseline ovarian cysts do not affect clinical response to controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 1992;57:1017 -21. 3. Sampaio M, Serra B, Miro F, Calatayud C, Castellvi R, Pellicer A. Development of ovarian cysts during gonadotropin releasing hormone agonists administration. Hum Reprod 1991;6:194-7. 4. Feldberg D, Ashkenazi J, Dicker D, Yeshaya A, Goldman GA, Goldman JA. Ovarian cyst formation: a complication of gonadotropin releasing hormone agonist therapy. Fertil Steril 1989;51:42-5. 5. Meldrum DR, Wisot A, Hamilton F, Gutlay AL, Kempton W, Huynh D. Routine pituitary suppression leuprolide before ovarian stimulation for oocyte retrieval. Fertil Steril 1989; 51:455-9. 6. Berg Van De-Helder A, Helmerhorst F, Blankhart A, Brand R, Waegemaekers C, N aaktgeboren N. Comparison of ovarian stimulation regimens for in vitro fertilization with and without a gonadotropin-releasing hormone agonist: results of a randomized study. J In Vitro Fert Embryo Transf 1990; 7:358-64. 7. Ron-El R, Herman A, Golan A, Raziel A, Soffer Y, Caspi E. Follicle cyst formation following long-acting gonadotropin-releasing hormone analog administration. Fertil Steril 1989;52:1063-6. 8. Ben-Rafael Z, Bider D, Menashe Y, Maymon R, Zolti M, Mashiach S. Follicular and luteal cysts after treatment with gonadotropin-releasing hormone analog for in vitro fertilization. Fertil Steril 1990;53:1091-4. 9. San Roman GA, Surrey ES, Judd HL, Kerin JF. A prospective randomized comparison ofluteal phase versus concurrent fol-
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tate and human menopausal gonadotropins. J Clin Endocrinol Metab 1993;73:797-803. 13. Tan S, Steer C, Royston P, Rizk B, Mason B, Campbell S. Conception rates and in vitro fertilization [letterl. Lancet 1990;335:229. 14. Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651-4. 15. Goldberg JM, Miller FA, Friedman CI, Dodds WG, Kim MH. Effects of baseline ovarian cysts on in vitro fertilization and gamete intrafallopian transfer cycles. Fertil Steril 1991; 55:319-23.
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