Linda M. Chafi'kin, M.D. John C. Nulsen, M.D. Anthony A. Luciano, M.D. Deborah A. Metzger, Ph.D., M.D.t

Transcription

1 FRTILITY AND STRILITY Copyright <> 1991 The American Fertility Society Vol. 55, No.2, February 1991 Printed on acid-free paper in U.S.A. A comparative analysis of the cycle fecundity rates associated with combined human menopausal gonadotropin (hmg) and intrauterine insemination (lui) versus either hmg or lui alone* Linda M. Chafi'kin, M.D. John C. Nulsen, M.D. Anthony A. Luciano, M.D. Deborah A. Metzger, Ph.D., M.D.t Division of Reproductive ndocrinology and Infertility, Depart';ent of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut Human menopausal gonadotropin (hmg) superovulation combined with washed intrauterine insemination (lui) has been advocated for the treatment of various forms of infertility when more traditional therapy has failed. To assess the relative efficacy of combined treatment with hmg and lui compared with either hmg or lui alone, pregnancy outcomes of the three treatment groups were compared in couples having infertility because of male factor, cervical factor, endometriosis, or unexplained. A total of 751 cycles were analyzed from 322 couples. The mean cycle fecundity rate associated with hmg/iui therapy was significantly higher than either hmg or lui therapy alone for all patients (hmg/iui = 19.6%, hmg = 6.3%, lui = 3.4%). The improvement in cycle fecundity rates with hmg/iui therapy was also observed when the couples were separated by infertility diagnostic groups: male factor (hmg/iui = 15.3%, hmg = 4.4%, lui = 3.%), cervical factor (hmg/iui = 26.3%, hmg = 7.9%, lui = 5.1%), endometriosis (hmg/iui = 12.85%, hmg = 6.6%), and unexplained infertility (hmg/iui = 32.6%, hmg = 5.5%, lui = %). Moreover, in patients who had failed to conceive with hmg or lui alone, the cycle fecundity rate when they were switched to hmg/iui therapy equaled that of patients who received combined therapy from the onset. We conclude that cycle fecundity rates and cumulative pregnancy rates are significantly greater using a combination ofhmg and lui compared with either modality alone in the treatment of male factor, cervical factor, endometriosis, or unexplained infertility. Indeed, in couples with nontubal related infertility, cycle fecundity rates with hmg/iui approach the rates seen with in vitro fertilization and gamete intrafallopian tube transfer. Fertil Steril55:252, 1991 The combined therapy of controlled superovulation with human menopausal gonadotropins (hmg) and intrauterine insemination (lui) has recently been introduced as an effective method of treating infertile couples with patent fallopian tubes when more traditional therapy has failed. 1,2 Received April 24, 199; revised and accepted October 4, 199. * Presented in part at the 45th Annual Meeting of The American Fertility Society, San Francisco, California, November 13 to 16, t Reprint requests: Deborah A. Metzger, M.D., Ph.D., Department of Reproductive ndocrinology, University of Connecticut Health Center, Farmington, Connecticut 63. Although the efficacy of the combined treatment has been demonstrated to be superior to hmg or lui alone in unexplained infertility,3 the relative efficacy of hmg, lui, and hmgjlui has not been adequately defined for other causes of infertility. A comparison of the cycle fecundity rate for hmgj lui versus that associated with the use of hmg or lui alone would provide the basis for assessment of whether the relative chances of pregnancy justify the increased cost and may help us define the best treatment for each of the various infertility diagnoses. Thus, we performed this retrospective study to evaluate the hypothesis that the cycle fecundity rate is improved with controlled hmg superovulation combined with lui. In addition, we 252 Chaff'kin et al. Combined hmgjiui versus hmg or lui alone Fertility and Sterility

2 also evaluated the efficacy of superovulation in conjunction with lui in patients who had previously failed either hmg or lui alone. MATRIALS AND MTHODS The records of 322 patients who had been treated with lui, controlled hmg superovulation, or hmg combined with lui (hmg/iui) during 1986 to 1989 at the University of Connecticut Health Center were reviewed retrospectively. Before treatment, all couples underwent a complete infertility evaluation that included ovulation assessment by basal body temperature (BBT) recording and endometrial biopsy, postcoital test (PCT), hysterosalpingogram (HSG), semen analysis, and, in the majority of cases, diagnostic laparoscopy. We excluded couples in whom anovulation was the sole documented cause of infertility. Patients were grouped according to infertility diagnosis. When multiple factors were present, each factor was separately tabulated. Infertility subgroups were defined as follows: (1) male factor in which two or more semen analyses obtained at least 1 month apart revealed a sperm density < 2 X 1 6 sperm/ml and/or <4% motile sperm and/or <4% normal morphology. Most of these men underwent a urologic assessment consisting of luteinizing hormone (LH), follicle-stimulating hormone, testosterone, prolactin, and physical exam, and had no demonstrable etiology for the semen analysis abnormalities; (2) cervical factor in which poor PCT with poor cervical mucus «1 by modified Insler score), or <5 sperm noted per high power field, or <3% progressively motile sperm in the absence of documented infection; (3) endometriosis in which implants were documented by laparoscopic visualization with or without biopsy. All of these patients underwent laparoscopic laser ablation or excision of implants with lysis of adhesions as indicated. Patients who were included in this study had failed to conceive 6 to 24 months after surgery; and (4) unexplained in which infertility of > 18 months' duration was documented with ovulatory cycles, normal semen analysis, endometrial biopsy, HSG, PCT, and diagnostic laparoscopy. Cycle fecundity rates were examined in three therapeutic groups: 56 patients (19 cycles) underwent lui alone timed by urine-lh (lui group), 131 patients (244 cycles) underwent hmg superovulation without insemination (hmg group), and 135 patients (317 cycles) were treated with hmg superovulation combined with lui (hmg/iui group). Twenty-two patients from the lui group and 29 patients from the hmg group who failed therapy were subsequently treated with the combined hmg/iui regimen. Human menopausal gonadotropin was administered as two or three ampules per day from cycle days 2 to 4. Human chorionic gonadotropin (hcg, 5, units) was administered when two or more follicles reached an average diameter of 16 mm. Follicle size was monitored by ultrasound beginning on day 5 or 6, with changes in hmg (Pergonal; Serono, Randolph, MA) dosage made according to ovarian response. Intrauterine insemination was performed 36 hours after the hcg injection or according to urine-lh changes and BBT charts in spontaneous cycles. In the hmg group, in which lui was not performed, couples were instructed to have coitus 24 to 36 hours after the administration ofhcg. Semen was collected by masturbation into a sterile jar after 48 hours of ejaculatory abstinence. After an initial analysis, 1 cc aliquots of semen were layered onto prewarmed Percoll gradients (4%, 6%,9%) containing Ham's F-I medium (Gibco, Grand Island, NY). Centrifugation was performed for 2 minutes at 3 X g (5.5 setting on GLC-Z; Sorvall, Wilmington, D). All but the lower 1 ml (9% of gradient) was discarded. The lower 1 ml was washed three times with 1 ml Ham's F-I. The final pellet was diluted in.5 ml of medium and used for lui. Intrauterine insemination was performed using a Tomcat catheter (no Fr.; Sherwood Medical, St. Louis, MO) connected to a tuberculin syringe. The catheter was passed transcervically into the uterine fundus and.5 cc of washed sperm was placed. After removal of the catheter, the patient remained supine for approximately 2 to 5 minutes and was given no subsequent activity restrictions. Cumulative pregnancy rates (PRs) were calculated using the life table analysis method of Cramer et a1. 4 Curves were fitted using a computer-generated curve. Statistical analysis was performed using x 2 test. RSULTS There were 56 couples who underwent treatment with lui alone, 131 couples who received only hmg therapy and 135 couples who were treated with combined hmg superovulation with lui. The mean age of the patients in the various diagnostic Vol. 55, No.2, February 1991 Chaffkin et al. Combined hmg/iui versus hmg or lui alone 253

3 L,_ Lkggg;gg: Table 1 Diagnosis Male factor Cervical factor ndometriosis Unexplained Total Summary of Cycle Fecunditya lui 3. (3/15)b 5.1 (3/58) b. (/11)' 3.4 (6/174)d HMG 4.4 (3/68)' 7.9 (6/76) b 6.6 (5/76) 5.5 (1/18)' 6.3 (15/238) d a Values are percents. b p <.5., P <.5 by x 2 compared with hmg/iui group. d P <.1. HMG/IUI 15.3 (17/111) 26.3 (24/91) 12.8 (14/19) 32.6 (15/46) 19.6 (7/357) groups ranged from 32. to 33.1 years and was not statistically different. The lui group had a significantly higher proportion of couples with male factor infertility (55.3% lui, 26.7% hmg, 37.8% hmg/iui; P <.5) and a lower percentage of couples with endometriosis (16% IUI,38.2% hmg, 37.% hmg/iui; P <.5), which is consistent with the generally accepted indications for lui therapy. The percent of couples whose diagnosis included cervical factor (35.7% lui, 29.% hmg, 25.9% hmg/iui), or unexplained infertility (5.4% lui, 11.5% hmg, 8.9% hmg/iui) did not differ statistically between the treatment subgroups. The cycle fecundity rates associated with each therapeutic regimen for the various infertility factors are summarized in Table 1. As expected, lui was of therapeutic value only in cervical or male factor infertility. No pregnancies were noted when both male and cervical factors were present or in the presence of documented pelvic adhesions. The cumulative proportion of patients pregnant after five cycles of lui alone was 18.% (Fig. 1), varying from 15.4% to 24.%, according to the specific infertility factor(s) (Fig. 2). Human menopausal gonadotropin therapy alone was associated with an average cycle fecundity rate of 6.3% (15/238), ranging from 4.4% to 7.9% depending on the infertility factors present (Table 1). After four cycles oftherapy, 25.5% of patients were pregnant (Fig. 1), ranging from 9% to 36.3% for the different infertility factors (Fig. 2). The mean estradiol ( 2 ) at the time of hcg administration in successful cycles was 3,114 pmoljml, and the mean number of follicles> 15 mm was 2.8. Hyperstimulation was encountered in 21 % of pregnancy cycles, half were mild and half were of moderate degree. None of the patients required hospitalization for hyperstimulation. One patient had a successful twin gestation for a multiple PR of 5.3%. For patients receiving hmg/iui therapy, the average cycle fecundity rate was 19.6% (7/357), ranging from 12.8% to 32.6% (Table 1). The cumulative proportion of patients achieving pregnancy was 56.8% after four treatment cycles (Fig. 1), varying from 42% to 8% depending on the infertility diagnosis. The mean 2 level at the time of hcg administration in successful cycles was 3,272 pmoljml, and the mean number of follicles> 15 mm was 3.2. Hyperstimulation was noted in 19% of successful cycles, with 8% of the cases reported as mild, 15% moderate, and 5% severe. There was a 6.5% rate of multiple gestation in hmg/iui associated pregnancies, 84 % of these were twin, and 16% triplet gestations. As demonstrated in Table 2, the cycle fecundity rate when determined by cycle is relatively constant for lui and hmg but for hmg/iui shows a significant decrease after three cycles. By the fourth cycle, the cycle fecundity rates for hmg and hmg/iui treatments are no different. Thus, the differences in cumulative pregnancy between hmg and hmg/iui are reflected in the much higher cycle fecundity rates in the hmg/iui treatment group during the first three cycles. To assess the effect of treatment alteration on cycle fecundity, we evaluated 22 patients who failed therapy with lui alone and subsequently underwent hmg superovulation combined with lui. Within this group, 7 pregnancies occurred in 4 cycles (cycle fecundity 17.5%). Similarly, of 29 patients who had previously undergone a total of 63 cycles of hmg alone and failed to conceive, 9 achieved a pregnancy during a total of 64 cycles when switched to the combined hmg/iui regimen C IG c 1 til ~ lui c. 8 HMG.t. c.g ~ c. f! c. GI.~ ::I ::I Cycle Figure 1 Overall cumulative proportion of pregnant patients comparing hmg, lui, and combined hmg/iui therapies. Life table analysis was calculated by the method of Cramer et al.! and the curves were fitted by computer analysis of the individual data points. 254 Chaffkin et a1. Combined hmg/iui versus hmg or lui alone Fertility and Sterility

4 -c c ~ A C o t: o A!! A I i ::a ::a U I U I Cervlc81 ndometrloale HMG 6... factor & Unexplained HMG/IUI Cycle Figure 2 Cumulative PRs by therapeutic groups (lui, hmg, or hmg/iui) with each infertility factor examined separately. (cycle fecundity 14%). The cumulative PR after the initiation of hmgjiui therapy in these treatment failure groups (58% after 4 cycles oftherapy) Table 2 Cycle number Cycle Fecundity Rates by Cycle Number" " Values are percents. lui HMG HMG/1U c c 1 a I!! Do 8 c ~ Do.. Do > ;: -; 2 ::I 8 4 lui o HUG Cycle number Figure 3 Cumulative PRs with combined hmg/iui therapy in patients who previously failed either lui or hmg therapy. was similar to that of patients who received hmg in combination with lui from the onset (Fig. 3). DISCUSSION Intrauterine insemination has been employed for many years in the treatment of the infertile couple. Success rates with male factor and unexplained infertility have generally been discouraging,3,5-14 although patients with cervical factor infertility appear to fare somewhat betterp-21 A literature review by Allen et al.19 noted an overall PR of 25% for lui-treated male factor infertility (range 7%12 to 66%13) and 6% for cervical factor infertility (range 52%16 to 7%13). The mean overall PR reported was 28% (range 3.4%2 to 62.%13), similar to our results in the lui alone group. Although hmg has been recently advocated21 for the treatment of ovulatory women with longstanding idiopathic infertility, improvement in cycle fecundity in ovulatory women with male factor infertility, cervical factor infertility, or endometriosis has not been demonstrated when hmg is used alone. Our results suggest that hmg alone is of minimal therapeutic benefit when compared with the cycle fecundity and cumulative PRs associated with combined hmgjiui therapy. Considering the expense and risks involved with controlled hmg superovulation therapy, it is logical to maximize the benefits to the patient by the addition of lui. The results of our experience with hmg combined with lui are very encouraging and similar to those reported by other investigators, although a direct comparison of cycle fecundity with hmg, lui, and hmgjiui has not been previously reported. Recently, Dodson and colleagues1 reported a cycle fecundity with hmg JIUI therapy of 29% for Vol. 55, No.2, February 1991 Chaffkin et al. Combined hmg/iui versus hmg or lui alone 255

5 cervical factor, 17% for endometriosis, and 19% for idiopathic infertility. Couples with abnormalities in semen analysis were excluded from this study. Serhal et a1. 3 reported a cycle fecundity rate of 26.4% with hmg/iui in the treatment of unexplained infertility and noted this to represent a 1- fold increase when compared with patients who received lui alone. Corson et a1.2 reported a statistically significant increase in cycle fecundity rate (from 5% to 11%) with hmg/iui treatment as compared with lui alone in patients who had cervical factor abnormalities. Our results confirm the therapeutic efficacy of the combined hmg/iui therapy as reported in these studies and suggest that the combined therapy is much more effective than either lui or hmg alone for all infertility factors studied. Attempts at improving PRs with infertility associated with endometriosis have been somewhat discouraging. Recent controlled studies demonstrate no enhancement of fertility after medical therapy with both treated and expectantly managed groups having cycle fecundity rates between 2% and 6%.22 Although women with mild and moderate endometriosis fare as well with in vitro fertilization (IVF) as women with tubal factor infertility,2 there are no less invasive procedures with demonstrated efficacy in enhancing fertility in endometriosis. The results of this study are significant for two reasons: (1) all of the women in the study had undergone laparoscopic laser surgery as initial treatment for their endometriosis and failed to conceive 6 to 24 months after treatment. Thus, these patients represent a group of treatment failures, and (2) the cycle fecundity rates observed with combined hmg/iui are two to six times higher than reported with expectant management or hormonal therapy and two times that observed with hmg alone. Thus, these results suggest that combined hmg/ lui therapy may be an effective alternative to IVF for the treatment of infertility associated with endometriosis. Several factors can account for the dramatic improvement in cycle fecundity with hmg/iui therapy, regardless of the apparent etiology of infertility. The number and concentration of sperm in the upper genital tract are increased, while simultaneously, a greater number of target oocytes are made available. This may improve chances of fertilization where a gametotoxic effect may be present, as has been suggested for endometriosis-associated infertility.24 Occult ovulatory disturbances may be corrected and barriers to sperm that may be present in the cervical mucus are bypassed. The procedure also offers the technical benefit of improving the timing of insemination relative to ovulation. The advantages of hmg/iui are similar in theory to those offered by gamete intrafallopian transfer (GIFT). Both techniques increase the number of male and female gametes present at the site of fertilization. The cycle fecundity rate in our experience is equivalent to that reported for IVF but not quite as good as GIFT.25 However, hmg/iui therapy avoids the need for general anesthesia, invasive oocyte retrieval, and provides a significant savings in cost. Intensive monitoring, however, is still required to minimize the risks of ovarian hyperstimulation and multiple pregnancy, which must be considered when evaluating this mode of therapy. In conclusion, we found the cycle fecundity rates and cumulative PRs to be significantly greater using a combination ofhmg and lui when compared with either modality used alone in the treatment of male factor, cervical factor, or unexplained infertility. The increase in cycle fecundity rate in patients with laparoscopic evidence of endometriosis approached, but did not meet, the criteria for statistical significance when comparing hmg/iui therapy with hmg alone. Human menopausal gonadotropin/lui appears to be a viable treatment option in patients with infertility refractory to other treatments, or before the institution of IVF /GIFT therapy in patients with patent fallopian tubes. RFRNCS 1. Dodson WC, Whitesides DB, Hughes CL, Jr, asley HA III, Haney AF: Superovulation with intrauterine insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization. Fertil SteriI48:441, Corson SL, Batzer FR, Gocial B, Maislin G: Intrauterine insemination and ovulation stimulation as treatment of infertility. J Reprod Med 34:397, Serhal PF, Katz M, Little V, Woronowski H: Unexplained infertility-the value Pergonal superovulation combined with intrauterine insemination. 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