In vitro fertilization and embryo transfer for the treatment of infertility associated with polycystic ovary syndrome

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1 Assisted reproductive techno.logy FERTILITY AND STERILITY Vol. 60, No.5, November 1993 Copyright 199a The American Fertility Society Printed on acid-free paper in U. S. A. In vitro fertilization and embryo transfer for the treatment of infertility associated with polycystic ovary syndrome Roy Homburg, M,B., B.S.* Drorit Berkowitz, M.D. Tally Levy, M.D, Dov Feldberg, M,D. Jacob Ashkenazi, M.D. Zion Ben-Rafael, M.D. Infertility Unit, Department of Obstetrics and Gynecology, Golda Medical Center, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Objective: To examine the outcome of treatment with IVF -ET of women with polycystic ovarian syndrome (PCOS) who failed to conceive on conventional treatment. Design: Retrospective analysis with an age-matched control group, Setting: University hospital infertility clinic and IVF unit. Patients, Interventions: Sixty-eight women with PCOS who had failed to conceive on treatment with clomiphene citrate and during six ovulatory cycles on gonadotropins underwent 208 cycles of IVF-ET. An age-matched group of 68 women with a tubal mechanical factor who received 143 treatment cycles during the same period served as controls. Main Outcome Measures: Cumulative conception rates, the cumulative livebirth rates, and IVF-ET data were compared between the two groups. Results oftreatment with and without GnRH agonist (GnRH-a) within the groups were also compared. Results: A comparison of PCOS and mechanical factor (control) groups showed almost identical results at 6 months for cumulative conception rate (82% versus 85%) and cumulative livebirth rate (69% versus 65%). Significantly more oocytes were retrieved but a smaller percentage fertilized in PCOS, and the pregnancy rate per ET did not differ between the two groups (23% versus 26%). Treatment with GnRH-a and gonadotropins as opposed to gonadotropins alone improved the cumulative conception rate, miscarriage rate, and cumulative livebirth rate in the PCOS but not in the control group and improved fertilization rates in both groups. Conclusions: For patients with PCOS who fail to conceive with gonadotropin treatment, IVF ET is a successful treatment alternative, producing results equal to those for women with a mechanical tubal factor. Better results were achieved with GnRH -a in women with PCOS but made no difference to those with a mechanical tubal factor compared with treatment with gonadotropins alone, Fertil Steril 1993;60: Key Words: Polycystic ovarian syndrome, in vitro fertilization, cumulative conception rate, cumulative livebirth rate, gonadotropin-releasing hormone agonist. For women with anovulatory infertility associated with polycystic ovarian syndrome (PCOS), failure to conceive on treatment with clomiphene citrate (CC) is usually followed by treatment with gonadotropins. Whether given as hmg, "pure" Received December 29, 1992; revised and accepted July 22, * Reprint requests: Roy Homburg, M.B., B.S., Golda Medical Center, Petah Tikva 49372, Israel. FSH in conventional or low-dose regimens, or in combination with GnRH-agonist (GnRH-a), a hard core of patients with PCOS fails to conceive. In vitro fertilization and embryo transfer provide an additionalline of treatment for this refractory group. Previous reports of the treatment of women with PCOS by IVF-ET (1-5) have suffered from a lack of conformity in patient selection and are relatively small series, making comparisons difficult. No comparison has been made ofthe choice of superovula- 858 Homburg et al. IVF for the treatment of PCOS Fertility and Sterility

tion induction protocol best suited to this group of patients. Cumulative live birth rates have not been stated, and this important information for both the infertile couple and physician are lacking.

2 tion induction protocol best suited to this group of patients. Cumulative live birth rates have not been stated, and this important information for both the infertile couple and physician are lacking. In this present series, a retrospective analysis of the results of a large number of IVF -ET treatment cycles of women with PCOS who failed to conceive after six ovulatory cycles with gonadotropin therapy (1) has been made and compared with an agematched control group of patients with a tubal factor. In addition, we have examined the results of treatment with and without GnRH-a in both groups. Definitions MATERIALS AND METHODS The diagnosis of PCOS was based on the typical ultrasound criteria (a hyperechogenic central stroma and at least 10 follicles of <9 mm diameter) (6). It was accompanied by anovulation and infertility for at least 1 year and either oligomenorrhea/ amenorrhea and/or hirsutism. Treatment Protocol All women in the IVF program received a standard stimulation protocol consisting of three ampules per day of FSH (Metrodin; Teva, Petah Tikva, Israel) for 3 days followed by three ampules per day of hmg (Pergonal; Teva). Adjustments of the dose of hmg were based on the individual dose response scheme whereby the dose was raised by one ampule per day every 5 days until a follicular growth response and an increase in 17{3-E2 levels were noted, whereupon this daily effective dose was continued. Human chorionic gonadotropin (Chorigon; Teva), 10,000 IU 1M, was administered when serum E2 concentrations reached a mean of 150 to 200 pg/ml (530 to 700 pmol/l) per preovulatory follicle of 15 to 16 mm or above and there were at least two follicles> 15 mm. Ovum pick-up was performed 32 to 36 hours after hcg administration by vaginal US and ET 48 hours later. Hydrogenized P vaginal suppositories, 50 mg, two times per day (privately manufactured by separation of the chemical compound into small micrometer-size particles providing optimal absorption and maximal levels of biologically active P) were given throughout the luteal phase and were continued until a pregnancy test was negative or up to the 7th week of pregnancy. The GnRH -a employed was Decapeptyl (D-Trp6; Ferring, Malmo, Sweden) in the form of microcapsules in a single injection of 3.75 mg 1M. The women with PCOS given GnRH-a were injected 3 weeks after a progestin-induced withdrawal bleed or spontaneous menstruation and those in the control group on days 20 to 21 of the cycle. Two weeks after this injection the serum concentration of E2 was measured and US examination of the ovaries performed. If the E2 concentration was <20 pg/ml ( <70 pmol/l) and there were no follicles or cysts> 10 mm diameter, gonadotropin treatment was started. If this ovarian quiescence had not been achieved, a further examination was performed 1 week later. Patients and Study Design This retrospective study analyzes the results of IVF -ET of 68 women with PCOS through 208 cycles yielding 46 pregnancies. All of them had failed to conceive in 6 ovulatory cycles after ovulation induction with gonadotropins. They had all been thoroughly investigated by hysterosalpingography, partner semen analyses, and postcoital tests, and most of them also by laparoscopy and hysteroscopy, but no cause for their infertility was discovered over and above the anovulation associated with PCOS. The mean age was 32.4 ± 4.5 years and mean body mass index (BMI) was 27.9 ± 5.8 kg/m2. Endocrine evaluation revealed mean serum concentrations of LH 17.8 ± 8.8 IU/L, FSH 6.6 ± 2.7 IU/L, and T 0.77 ± 0.3 ng/ml (2.67 ± 1.0 nmol/l). The control group consisted of 68 women with a pure tubal mechanical factor as the cause of infertility. They were age-matched with women in the PCOS group and underwent 143 treatment cycles of IVF -ET yielding 38 pregnancies. Women in the PCOS group received 124 cycles with GnRH-a and 84 cycles with FSH/hMG alone and in the control group, 67 cycles with GnRH-a, and 76 with FSH/hMG alone. There were no preselection criteria for the allocation of patients to treatment with or without GnRH -a, and both treatment alternatives were used concurrently throughout the study. Within the treatment groups, the distribution of patients according to mean age, BMI, and mean serum concentrations of LH, FSH, and T did not differ between those receiving GnRH -a and those who did not. Both PCOS and Vol. 60, No.5, November 1993 Homburg et al. IVF for the treatment of peas 859

3 control groups were treated during the same time period by the same team. Statistical analyses of the results were computed using unpaired Student's t-tests or X 2 analysis when appropriate. All data were expressed as means ± SD. Cumulative conception rates were analyzed by life-table analysis (7) as were cumulative livebirth rates. Cumulative livebirth rates are analyzed on all treatment cycles leading to the first livebirth; thus, a cycle that resulted in a conception that terminated in a miscarriage was recorded as a failed treatment cycle. RESULTS The clinical pregnancy rate (PR) per ET did not differ between the PC OS and mechanical tubal factor control group (22.6% versus 26.5%) nor did the spontaneous miscarriage rate (23.4% versus 36.8%) or the multiple PR (19.1 % versus 15.8%) (Table 1). The cumulative conception rates of the two groups were almost identical: after six cycles, 82% for PCOS and 85% for controls. Similarly, the cumulative livebirth rates of the two groups followed an almost exact pattern: 69% for PCOS and 65% for controls after six cycles. A comparison of the IVF -ET cycle characteristics of the two groups is made in Table 1. A significantly greater number of oocytes were retrieved but a smaller percentage fertilized in the PCOS group compared with controls. A differential analysis of the impact of cotreatment with GnRH -a within the two groups on the cumulative conception rate is illustrated in Figure 1. Although GnRH -a produces a better cumulative conception rate than treatment with FSH/hMG alone throughout the 6 cycles in the PCOS group, this difference is not seen in the controls. When examining cumulative livebirth rates in a similar fashion, this difference is even more pronounced (Fig. 2). In other words, GnRH-a is capable of mildly improving cumulative conception rate and greatly improves cumulative livebirth rates in PC OS compared with treatment with FSH and hmg alone, but its addition to the treatment of mechanical factor patients has no significant effect. The improvement in the cumulative livebirth rate with GnRH -a in PCOS may be attributed to the fact that the miscarriage rate with GnRH -a was 6 of 34, 17.6% compared with treatment with FSH/ hmg alone, 5 of 13, 38.1 % (Table 2). In contrast, GnRH -a had no such impact on the miscarriage rate in the control group. Table 2 also shows the IVF characteristics in the two groups broken down into treatment with and without GnRH -a. In the PC OS group, the number of oocytes retrieved was not different, but the proportion of oocytes fertilized was significantly greater when GnRH -a was used. In contrast, treatment with GnRH -a in the control group produced a larger harvest of oocytes in addition to an increase in the fertilization rate. Treatment with GnRH-a produced an equally high multiple PR in PCOS and control groups (23%) compared with treatment with gonadotropins alone (7.7% and 5.9%, respectively) (Table 2). DISCUSSION Women with PCOS who were selected for this study group of treatment by IVF -ET had all failed to conceive on treatment with CC and during six ovulatory cycles of gonadotropin therapy. In agreement with Urman et al. (1), we consider this a fair trial of in vivo treatment. Although it may be ar- Table 1 In Vitro Fertilization Cycle Characteristics and Outcome of Treatment in PCOS Versus Mechanical Factor Groups PCOS Mechanical factor Significance Patients Cycles Age (y)* Oocytes retrieved per cycle* Fertilization (%) Embryos transferred* Clinical pregnancies per ET Miscarriages Multiple pregnancies * Values are means ± SD. t, not significant ± ± ± (22.6)* 11/47 (23.4) 9/47 (19.1) ± ± ± (26.5) 14/38 (36.8) 6/38 (15.8) * Values in parentheses are percents. t p = P < Homburg et ai. IVF for the treatment of peas Fertility and Sterility

4 CCR S 100 CCR S 70 pcos MECHANICAL FACTOR 5 6 the physician a true appreciation of the chances of conception and a livebirth. The relative success of IVF-ET in this group of women with peos who had all failed to conceive during six ovulatory cycles of gonadotropin therapy has two possible explanations. First, induction of ovulation for IVF is much more aggressive and allows greater license to achieve higher levels of E2 with a reduced risk of ovarian hyperstimulation syndrome if the majority of the follicles are punctured at ovum pick-up, compared with in vivo ovulation induction. In our experience of in vivo induction of ovulation for peos (8), the chance of conception is directly proportional to the degree of ovarian stimulation. Second, treatment by IVF -ET may overcome the problem of a subtle tubal factor CLBRI 100 peas TREATMENT CYCLE 6 I-GnRHa+FSHIhMG x FSHlhMGI Figure 1 Cumulative conception rates (CCR) for PCOS and mechanical factor according to treatment with or without GnRH-a. gued that a small number of these may have conceived by persisting with this line of therapy, the satisfactory results by switching to the more aggressive approach of IVF-ET seem to justify the decision and the timing of the switch rather than a more conservative approach. In fact, as found by other investigators (1-5), the results obtained by IVF-ET for peos were equal to those obtained for women with pure mechanical tubal factor, the group who have the best prognosis for this form of therapy. Although previously published series (1-5) have not used standard criteria for admission to the IVF program and have often been too small to allow a true statistical analysis, this study consolidates their findings. In addition, we have adopted the concept of the use of cumulative conception and livebirth rates to give both the infertile couple and o CLBRI s 6 MECHANICAL FACTOR TREATMENT CYCLE GnRHa+FSHIhMG x FSHlhMO I 4 s 6 Figure 2 Cumulative livebirth rates for PCOS and mechanical factor according to treatment with or without GnRH-a. Vol. 60, No.5, November 1993 Homburg et al. IVF for the treatment of peas 861

5 Table 2 Comparison of Treatment With and Without GnRH-a in PCOS and Mechanical Factor Groups PCOS Mechanical factor GnRH-A No GnRH-a GnRH-a No GnRH-a Cycles Oocytes retrieved* Fertilization (%) Clinical pregnancies per ET Miscarriages Multiple pregnancies ± 7.8t (27.4)11 6/34 (17.6) 8/34 (23.5) ± 7.1 t (15.5) 5/13 (38.5) 1/13 (7.7) ± 5.2:1: (31.3) 8/21 (38.1) 5/21 (23.8) ± 3.2:1: (22.4) 6/17 (35.3) 1/17 (5.9) * Values are means ± SD. t Not significant. :I: P = p = II P < Values in parentheses are percents. undetected by the relatively crude methods available. It is fascinating to note the differential effect of treatment with GnRH-a within the peas and control groups. In the mechanical tubal factor group, cotreatment with GnRH-a and FSHjhMG increased the oocyte harvest and fertilization rate compared with treatment with gonadotropins alone but had no advantageous influence on the clinical results. In the peas group, the addition of GnRHa to the treatment protocol improved overall results regarding cumulative conception rate and cumulative livebirth rates compared with treatment with FSH and hmg alone. Notably, GnRH-a reduced the spontaneous miscarriage rate by half in the peas group but had no influence on the high number of miscarriages in the controls. As we have previously suggested (9), the improved results achieved by cotreatment with GnRH -a for women with peas may well be due to its ability to block endogenous gonadotropin secretion and reduce high tonic levels of LH in the follicular phase, which are thought to have a deleterious effect on conception and miscarriage rates (10-15). This hypothesis is strengthened by the results of the present study in which GnRH-a was capable of improving results of women in the peas group who had high mean serum concentrations of LH but had no similar effect on controls who were normally ovulating women with a pure mechanical factor and normal LH levels. This study may also help to clarify the possible mechanism of the detrimental effect of high LH levels. Although, as expected, more oocytes were retrieved from the peas group, a significantly smaller proportion of these were fertilized compared with those retrieved from the controls. Within the peas group, those receiving GnRH-a had a significantly larger proportion of oocytes fertilized and a much reduced miscarriage rate than those receiving gonadotropins alone. These facts suggest that high LH levels have a detrimental effect on oocyte quality. An additional effect on the endometrium is also possible. In conclusion, IVF -ET is a very viable alternative treatment for women with peas who failed to conceive during six ovulatory cycles of gonadotropin therapy, producing results equal to those of women with a mechanical tubal factor. Hyperstimulation protocols employing GnRH-a produce improved cumulative conception rate, cumulative livebirth and miscarriage rates compared with treatment with gonadotropins alone in women with peas. REFERENCES 1. Urman B, Fluker MR, Ho Yuen B, Fleige-Zahradka BG, Zouves CG, Moon YS. The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins. Fertil SteriI1992;57: Salat-Baroux J, Alvarez S, Antoine JM, Cornet D, Tibi C, Plachot M, et al. Results of IVF in the treatment ofpolycystic ovary disease. Hum Reprod 1988;3: Dor J, Shulman A, Levran D, Ben-Rafael Z, Rudak E, Mashiach S. The treatment of polycystic ovarian syndrome patients by in vitro fertilization and embryo transfer: a comparison of results with those of tubal infertility patients. Hum Reprod 1990;5: Dale PO, Tanbo T, Abyholm T. In vitro fertilization in infertile women with the polycystic ovarian syndrome. Hum Reprod 1991;6: Ashkenazi J, Feldberg D, Dicker D, Yeshaya A, Ayalon D, Goldman J. IVF-ET in women with refractory polycystic ovarian disease. Eur J Obstet GynecoI1989;30: Adams J, Polson DW, Abdulwahid N, Morris DV, Franks S, Mason HD, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin-releasing hormone. Lancet 1985;2: Cooke ID, Sulaimen RA, Lenton EA, Parsons J. Fertility 862 Homburg et a1. IVF for the treatment of peas Fertility and Sterility

6 and infertility statistics: their importance and application. Clin Obstet GynecoI1981;8: Farhi J, Homburg R, Lerner A, Ben-Rafael Z. The choice of treatment for anovulation associated with polycystic ovary syndrome following failure to conceive with clomiphene. Hum Reprod. In press. 9. Homburg R, Levy T, Berkovitz D, Farchi J, Feldberg D, Ashkenazi J, et al. Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnancies achieved in women with polycystic ovary syndrome. Fertil Steril 1993;59: Jacobs HS, Porter RN, Eshel.A, Craft 1. Profertility uses of LHRH analogues. In: Vickery BH, Nestor JJ Jr, editors. LHRH and its analogues: contraceptive and therapeutic applications. Part 2. Lancaster, United Kingdom: MTP Press, 1987: Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS. Influ- ence of serum lutein ising hormone concentrations on ovulation, conception and early pregnancy loss. Br Med J 1988;297: Stanger JD, Yovich JL. Reduced in vitro fertilization of human oocytes from patients with raised basalluteinising hormone levels during the follicular phase. Br J Obstet Gynaecol 1985;92: Howles CM, MacNamee MC, Edwards RG, Goswamy R, Steptoe PC. Effect of high tonic levels of luteinising hormone on outcome of in vitro fertilisation. Lancet 1986;2: Regan L, Owen EJ, Jacobs HS. Hypersecretion of luteinising hormone, infertility and miscarriage. Lancet 1990;336: Johnson P, Pearce MJ. Recurrent spontaneous abortion and polycystic ovarian disease: comparison of two regimens to induce ovulation. Br Med J 1990;300: Vol. 60, No.5, November 1993 Homburg et al. IVF for the treatment of pcas 863

Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnancies achieved in women with polycystic ovarian syndrome

FERTILITY AND STERILITY Copyright e 1993 The American Fertility Society Vol. 59, No.3, March 1993 Printed on acid-free paper in U.S.A. Gonadotropin-releasing hormone agonist reduces the miscarriage rate