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The effects of baseline ovarian cysts on cycle fecundity in controlled ovarian hyperstimulation*
Vol. 59, No, 2, February 1993
FERTILITY AND STERILITY Copyright
Printed on acid-free paper in U.S.A.
1993 The American Fertility Society
The effects of baseline ovarian cysts on cycle fecundity in controlled ovarian hyperstimulation*
James W. Akin, M.D·t Marguerite K. Shepard, M.D. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
Protocols for controlled ovarian hyperstimulation (COH) tend to vary among institutions. Some physicians routinely perform baseline so no grams and serum estradiol (E 2) levels before starting human menopausal gonadotropins (hMG) injections on all patients, whereas others delay sonograms until the E2 has reached a predetermined level. An argument for baseline sonographic screening is determination of any ovarian cysts that might be present. The baseline serum E2 may help identify whether any cysts present are hormonally active. Commonly, physicians performing baseline sonograms cancel the COH cycle if cysts are present. Weare aware of only one prior study to date that addresses the effects of baseline ovarian cysts on COH not associated with in vitro fertilization (IVF) or gamete intrafallopian tube transfer (GIFT). Tummon et al. (1) reported that in 56% of the cycles of patients undergoing superovulation with hMG, residual cysts;::: 14 mm were noted at the start of the next cycle if pregnancy was not achieved. Pregnancy occurred in 4 of 13 (30.8%) women with either anovulation or dysfunctional ovulation who had baseline cysts from a previous COH at the start of hMG stimulation (IVF patients excluded). However, no comparison of cycle fecundity was made to cycles
Received August 21, 1992; revised and accepted October 20, 1992. * Presented at the 48th Annual Meeting of The American Fertility Society Meeting, New Orleans, Louisiana, November 2 to 5,1992. t Reprint requests: James W. Akin, M.D., Department of Obstetrics and Gynecology, Indiana University Hospital, Room 2440, 550 North University Boulevard, Indianapolis, Indiana 462025274. Vol. 59, No.2, February 1993
that did not have a baseline cyst at time of hMG initiation. The purpose of the following study is to determine what effect baseline ovarian cysts have, if any, on the cycle fecundity in COH cycles not associated with either IVF or GIFT. MATERIALS AND METHODS
Over a 12-month period, 57 patients undergoing COH with various diagnoses (minimal or mild endometriosis = 18, unexplained infertility = 29, and polycystic ovarian disease [PCOD] = 29) were prospectively studied in 174 cycles. Diagnostic evaluation of patients included a normal postcoital test, a normal semen analysis (sperm count> 20 X 106 , motility and morphology> 50%), and a laparoscopy demonstrating bilateral patent tubes without adhesions. Patients with endometriosis were treated with the CO 2 laser at time of the laparoscopy and had been trying timed intercourse unsuccessfully for at least 12 months postoperatively. Patients with PCOD had either failed to achieve ovulation or pregnancy on clomiphene citrate before beginning the hMG. Each patient underwent a baseline vaginal sonogram and serum E2 level on menstrual cycle day 3. Previous IVF and GIFT studies (2-4) concerning the effects of baseline cysts on cycle fecundity defined baseline cysts as structures from> 10 mm to >14 mm in mean diameter. For purposes of the present study, a baseline ovarian cyst was defined as an echolucent structure> 10 mm in mean diameter. Patients received daily hMG injections until a follicle of 18 mm mean diameter was seen on vaginal sonogram in association with an appropriate E2 level Akin and Shepard
Communications-in-brief
453
at which time human chorionic gonadotropin (hCG) was given by injection to stimulate ovulation. The patients underwent either timed intercourse or intrauterine insemination (lUI) based on physician and patient preference. Pregnancy was defined as a delay in menses and a positive pregnancy test with subsequent sonographic evidence of a gestational sac. Patients not becoming pregnant underwent consecutive treatment cycles to a maximum of six. Serum E 2 levels were obtained in the early morning hours and assays run daily by the Indiana University Hospital Clinical Chemistry Laboratory. A radioimmunoassay by Diagnostics Products Corporation (Los Angeles, CA) was used. The interassay and intra-assay coefficients of variation were each <10%. Cycle fecundity rates were determined and statistically examined using life table analysis as described by Cramer et al. (5). Wilcoxon's rank sum test was used to compare patient characteristics. RESULTS
There were no differences in the age, E2 level on the day of hCG, number of preovulatory follicles ~ 14 mm on the day of hCG, and number of days on hMG for patients with and without a baseline cyst. In 37.4% of all cycles, an echolucent cyst> 10 mm in mean diameter was seen on the baseline sonogram. If a cyst was present, the mean (±SD) diameter was 26.5 ± 8.9 mm with a range from 11 to 50 mm. The presence of a cyst was more common in subsequent treatment cycles than on the first (41.5% versus 15.8%, P < 0.01). Cyst formation did not appear to be repetitive in these patients, which agrees with findings by Tummon et al. (1). A X2 test of homogeneity revealed no difference in the patient diagnosis between those with and without a baseline ovarian cyst. The cycle fecundity if a baseline cyst> 10 mm in mean diameter was present at the time of the menstrual cycle day 3 vaginal sonogram was 0.06 versus 0.25 if no cyst was present (P < 0.01). A cyst was found in only one of four cycles where a baseline serum E2 > 312 pmol/mL was present. Also, no pregnancies were noted if the baseline E2 was >312 pmol/mL. In this study population, cycle fecundity did not differ whether or not an lUI was performed. DISCUSSION
The present study demonstrates that an ovarian cyst> 10 mm in mean diameter on the baseline 454
Akin and Shepard Communications-in-brief
vaginal sonogram of a COH cycle not in conjunction with IVF or GIFT is associated with a significantly lower chance for conception. The mechanism of the lowered fecundity, however, is not as clear. Recent studies (2-4) have evaluated the effects of baseline cysts during COH associated with IVF and GIFT. These studies have shown no adverse effects on peak E2 levels, number of follicles present at retrieval, number of oocytes retrieved, fertilization rates, or pregnancy rates. The main difference between the above data and that presented by this paper is the mechanism of sperm-oocyte interaction. With either IVF or GIFT, the oocytes are collected via needle aspiration and then placed in proximity to the sperm. However, COH patients undergoing either lUI or timed intercourse have to rely on the fallopian tube to pick up the oocyte once ovulation has occurred. Residual cysts that remain during the time of ovulation may thus represent a physical obstacle to the fallopian tube attempting to retrieve an oocyte, particularly because Tummon et al. (1) demonstrated that residual cysts may persist throughout one or more menstrual cycles before completely regressing. The question of whether hMG superovulation should be performed every other month or in consecutive cycles has been addressed by Diamond et al. (6). They report that hMG administration in multiple repetitive cycles for ovulation induction has no significant effect on ovarian response based on peak E2 levels and the day of hCG administration. The results of the present study indicate that consecutive cycles have no adverse effects if no baseline cyst> 10 mm in mean diameter is found. Delay in infertility treatment can be frustrating to the anxious infertile couple, but if the delay is beneficial it is warranted. We feel that our data suggest that baseline ovarian cysts do decrease the chances for pregnancy in COH not associated with IVF or GIFT, and hMG stimulation should be delayed until these cysts are resolved. SUMMARY
Patients undergoing COH were prospectively studied in 174 cycles for the presence of baseline ovarian cysts. In 37.4% of all cycles, a baseline cyst > 10 mm mean diameter was found, but a cyst was more common in subsequent cycles than on the first (41.5% versus 15.8%). Cycle fecundity as determined by life table analysis was significantly higher if no baseline cyst were present (0.25 versus 0.06, P < 0.01). These findings suggest that baseline ovarian Fertility and Sterility
cysts may adversely affect the chances for pregnancy in COH not associated with IVF or GIFT.
3.
Key Words: Ovarian cyst, controlled ovarian hyperstimulation, cycle fecundity. 4.
REFERENCES 1. Tummon IS, Henig I, Radwanska E, Binor Z, Rawlins R, Dmowski WP. Persistent ovarian cysts following administration of human menopausal and chorionic gonadotrop"ins: an attenuated form of ovarian hyperstimulation. Fertil Steril 1988;49:244-8. 2. Penzias AS, Jones EE, Seifer DB, Grifo JA, Thatcher SS, DeCherney AH. Baseline ovarian cysts do not affect clinical
Vol. 59, No.2, February 1993
5.
6.
response to controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 1992;57:1017-21. Goldberg JM, Miller FA, Friedman CI, Dodds WG, Kim MH. Effect of baseline ovarian cysts on in vitro fertilization and gamete intrafallopian transfer cycles. Fertil Steril 1991;55: 319-23. Hornstein MD, Barbieri RL, Ravnikar VA, McShane PM. The effects of baseline ovarian cysts on the clinical response to controlled ovarian hyperstimulation in an in vitro fertilization program. Fertil Steril 1989;52:437-40. Cramer DW, Walker AM, Schiff 1. Statistical methods in evaluating the outcome of infertility therapy. Fertil Steril 1979;32:80-6. Diamond MP, DeCherney AH, Baretto P, Lunenfeld B. Multiple consecutive cycles of ovulation induction with human menopausal gonadotropins. Gynecol EndocrinolI989;3: 237-40.
Akin and Shepard
Communications-in-brief
455
FERTILITY AND STERILITY Copyright
Printed on acid-free paper in U.S.A.
1993 The American Fertility Society
The effects of baseline ovarian cysts on cycle fecundity in controlled ovarian hyperstimulation*
James W. Akin, M.D·t Marguerite K. Shepard, M.D. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
Protocols for controlled ovarian hyperstimulation (COH) tend to vary among institutions. Some physicians routinely perform baseline so no grams and serum estradiol (E 2) levels before starting human menopausal gonadotropins (hMG) injections on all patients, whereas others delay sonograms until the E2 has reached a predetermined level. An argument for baseline sonographic screening is determination of any ovarian cysts that might be present. The baseline serum E2 may help identify whether any cysts present are hormonally active. Commonly, physicians performing baseline sonograms cancel the COH cycle if cysts are present. Weare aware of only one prior study to date that addresses the effects of baseline ovarian cysts on COH not associated with in vitro fertilization (IVF) or gamete intrafallopian tube transfer (GIFT). Tummon et al. (1) reported that in 56% of the cycles of patients undergoing superovulation with hMG, residual cysts;::: 14 mm were noted at the start of the next cycle if pregnancy was not achieved. Pregnancy occurred in 4 of 13 (30.8%) women with either anovulation or dysfunctional ovulation who had baseline cysts from a previous COH at the start of hMG stimulation (IVF patients excluded). However, no comparison of cycle fecundity was made to cycles
Received August 21, 1992; revised and accepted October 20, 1992. * Presented at the 48th Annual Meeting of The American Fertility Society Meeting, New Orleans, Louisiana, November 2 to 5,1992. t Reprint requests: James W. Akin, M.D., Department of Obstetrics and Gynecology, Indiana University Hospital, Room 2440, 550 North University Boulevard, Indianapolis, Indiana 462025274. Vol. 59, No.2, February 1993
that did not have a baseline cyst at time of hMG initiation. The purpose of the following study is to determine what effect baseline ovarian cysts have, if any, on the cycle fecundity in COH cycles not associated with either IVF or GIFT. MATERIALS AND METHODS
Over a 12-month period, 57 patients undergoing COH with various diagnoses (minimal or mild endometriosis = 18, unexplained infertility = 29, and polycystic ovarian disease [PCOD] = 29) were prospectively studied in 174 cycles. Diagnostic evaluation of patients included a normal postcoital test, a normal semen analysis (sperm count> 20 X 106 , motility and morphology> 50%), and a laparoscopy demonstrating bilateral patent tubes without adhesions. Patients with endometriosis were treated with the CO 2 laser at time of the laparoscopy and had been trying timed intercourse unsuccessfully for at least 12 months postoperatively. Patients with PCOD had either failed to achieve ovulation or pregnancy on clomiphene citrate before beginning the hMG. Each patient underwent a baseline vaginal sonogram and serum E2 level on menstrual cycle day 3. Previous IVF and GIFT studies (2-4) concerning the effects of baseline cysts on cycle fecundity defined baseline cysts as structures from> 10 mm to >14 mm in mean diameter. For purposes of the present study, a baseline ovarian cyst was defined as an echolucent structure> 10 mm in mean diameter. Patients received daily hMG injections until a follicle of 18 mm mean diameter was seen on vaginal sonogram in association with an appropriate E2 level Akin and Shepard
Communications-in-brief
453
at which time human chorionic gonadotropin (hCG) was given by injection to stimulate ovulation. The patients underwent either timed intercourse or intrauterine insemination (lUI) based on physician and patient preference. Pregnancy was defined as a delay in menses and a positive pregnancy test with subsequent sonographic evidence of a gestational sac. Patients not becoming pregnant underwent consecutive treatment cycles to a maximum of six. Serum E 2 levels were obtained in the early morning hours and assays run daily by the Indiana University Hospital Clinical Chemistry Laboratory. A radioimmunoassay by Diagnostics Products Corporation (Los Angeles, CA) was used. The interassay and intra-assay coefficients of variation were each <10%. Cycle fecundity rates were determined and statistically examined using life table analysis as described by Cramer et al. (5). Wilcoxon's rank sum test was used to compare patient characteristics. RESULTS
There were no differences in the age, E2 level on the day of hCG, number of preovulatory follicles ~ 14 mm on the day of hCG, and number of days on hMG for patients with and without a baseline cyst. In 37.4% of all cycles, an echolucent cyst> 10 mm in mean diameter was seen on the baseline sonogram. If a cyst was present, the mean (±SD) diameter was 26.5 ± 8.9 mm with a range from 11 to 50 mm. The presence of a cyst was more common in subsequent treatment cycles than on the first (41.5% versus 15.8%, P < 0.01). Cyst formation did not appear to be repetitive in these patients, which agrees with findings by Tummon et al. (1). A X2 test of homogeneity revealed no difference in the patient diagnosis between those with and without a baseline ovarian cyst. The cycle fecundity if a baseline cyst> 10 mm in mean diameter was present at the time of the menstrual cycle day 3 vaginal sonogram was 0.06 versus 0.25 if no cyst was present (P < 0.01). A cyst was found in only one of four cycles where a baseline serum E2 > 312 pmol/mL was present. Also, no pregnancies were noted if the baseline E2 was >312 pmol/mL. In this study population, cycle fecundity did not differ whether or not an lUI was performed. DISCUSSION
The present study demonstrates that an ovarian cyst> 10 mm in mean diameter on the baseline 454
Akin and Shepard Communications-in-brief
vaginal sonogram of a COH cycle not in conjunction with IVF or GIFT is associated with a significantly lower chance for conception. The mechanism of the lowered fecundity, however, is not as clear. Recent studies (2-4) have evaluated the effects of baseline cysts during COH associated with IVF and GIFT. These studies have shown no adverse effects on peak E2 levels, number of follicles present at retrieval, number of oocytes retrieved, fertilization rates, or pregnancy rates. The main difference between the above data and that presented by this paper is the mechanism of sperm-oocyte interaction. With either IVF or GIFT, the oocytes are collected via needle aspiration and then placed in proximity to the sperm. However, COH patients undergoing either lUI or timed intercourse have to rely on the fallopian tube to pick up the oocyte once ovulation has occurred. Residual cysts that remain during the time of ovulation may thus represent a physical obstacle to the fallopian tube attempting to retrieve an oocyte, particularly because Tummon et al. (1) demonstrated that residual cysts may persist throughout one or more menstrual cycles before completely regressing. The question of whether hMG superovulation should be performed every other month or in consecutive cycles has been addressed by Diamond et al. (6). They report that hMG administration in multiple repetitive cycles for ovulation induction has no significant effect on ovarian response based on peak E2 levels and the day of hCG administration. The results of the present study indicate that consecutive cycles have no adverse effects if no baseline cyst> 10 mm in mean diameter is found. Delay in infertility treatment can be frustrating to the anxious infertile couple, but if the delay is beneficial it is warranted. We feel that our data suggest that baseline ovarian cysts do decrease the chances for pregnancy in COH not associated with IVF or GIFT, and hMG stimulation should be delayed until these cysts are resolved. SUMMARY
Patients undergoing COH were prospectively studied in 174 cycles for the presence of baseline ovarian cysts. In 37.4% of all cycles, a baseline cyst > 10 mm mean diameter was found, but a cyst was more common in subsequent cycles than on the first (41.5% versus 15.8%). Cycle fecundity as determined by life table analysis was significantly higher if no baseline cyst were present (0.25 versus 0.06, P < 0.01). These findings suggest that baseline ovarian Fertility and Sterility
cysts may adversely affect the chances for pregnancy in COH not associated with IVF or GIFT.
3.
Key Words: Ovarian cyst, controlled ovarian hyperstimulation, cycle fecundity. 4.
REFERENCES 1. Tummon IS, Henig I, Radwanska E, Binor Z, Rawlins R, Dmowski WP. Persistent ovarian cysts following administration of human menopausal and chorionic gonadotrop"ins: an attenuated form of ovarian hyperstimulation. Fertil Steril 1988;49:244-8. 2. Penzias AS, Jones EE, Seifer DB, Grifo JA, Thatcher SS, DeCherney AH. Baseline ovarian cysts do not affect clinical
Vol. 59, No.2, February 1993
5.
6.
response to controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 1992;57:1017-21. Goldberg JM, Miller FA, Friedman CI, Dodds WG, Kim MH. Effect of baseline ovarian cysts on in vitro fertilization and gamete intrafallopian transfer cycles. Fertil Steril 1991;55: 319-23. Hornstein MD, Barbieri RL, Ravnikar VA, McShane PM. The effects of baseline ovarian cysts on the clinical response to controlled ovarian hyperstimulation in an in vitro fertilization program. Fertil Steril 1989;52:437-40. Cramer DW, Walker AM, Schiff 1. Statistical methods in evaluating the outcome of infertility therapy. Fertil Steril 1979;32:80-6. Diamond MP, DeCherney AH, Baretto P, Lunenfeld B. Multiple consecutive cycles of ovulation induction with human menopausal gonadotropins. Gynecol EndocrinolI989;3: 237-40.
Akin and Shepard
Communications-in-brief
455