Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age*

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1 FERTILITY AND STERILITY Vol. 58, No.4, October 1992 Copyright It! 1992 The American Fertility Society Printed on acid-free paper in U. S.A. Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age* Anthony C. Pearlstone, M.D. Nicole Fournet, M.D. Joseph C. Gambone, D.O. Samuel C. Pang, M.D.t Richard P. Buyalos, M.D.:j: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California, School of Medicine, Los Angeles (UCLA), Los Angeles, California Objectives: To determine pregnancy and livebirth rates for women age 40 and older undergoing ovulation induction and to assess the impact of basal follicle-stimulating hormone (FSH) on outcome in these patients. Design: Prospective, observational. Setting: Fertility service of university medical center. Patients: Infertile couples in whom the female partner was age 40 or older referred for ovulation induction therapy. Intervention: Assessment of basal hormonal status; ovulation induction. Main Outcome Measures: Clinical pregnancy rate (PR), livebirth rate. Results: Analysis of 402 cycles in 85 women age 40 and older demonstrated a clinical PR of 3.5% per cycle (95% confidence interval [Clj1.7% to 5.3%). The livebirth rate was 1.2% per cycle (95% CI 0.1% to 2.3%). Women with a basal FSH < 25 lull and age < 44 years had a clinical PR of 5.2% per cycle (95% CI 2.5% to 7.9%) compared with 0.0% per cycle (95% CI 0.0% to 2.1 %) in cases in which either basal FSH was 25 lull or age was 44 (P < 0.005). The prognostic importance of basal FSH and chronological age was confirmed by multivariate logistic regression analysis. The predictive value of the resulting regression equation was high (R 2 = 0.94; P < 0.01). Conclusions: Pregnancy and livebirth rates are generally low during ovulation induction in women age 40 and older. In combination, basal FSH and chronological age are accurate predictors of PR, in these couples and can define a subset of patients with a more favorable prognosis. The spontaneous abortion rate in women who do conceive is high, substantially lowering the livebirth rate. Fertil Steril 1992;58:674-9 Key Words: Pregnancy rates, age 40, ovulation induction, follicle-stimulating hormone Women age 40 and older are seeking infertility care in increasing numbers (1). This has prompted recent interest in the efficiency of various modalities Received February 21, 1992; revised and accepted June 17, * Presented in part at the 47th Annual Meeting of The American Fertility Society, Orlando, Florida, October 21 to 24, t Present address: Department of Gynecology and Obstetrics, Lorna Linda University School of Medicine, Lorna Linda, California. :j: Reprint requests: Richard P. Buyalos, M.D., Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, UCLA School of Medicine, Le Conte Avenue, CRS , Los Angeles, California for the treatment of such patients. To date, investigations have focused on the outcome of assisted reproductive techniques (ART) in these women, including in vitro fertilization (IVF) (2), gamete intrafallopian transfer (3), and oocyte donation (4). However, ART is often not the initial treatment of choice for most couples. In general, first line therapy for a substantial proportion of infertile patients has evolved toward empiric ovulation induction (1, 5). Yet, there are only limited data that specifically address the efficacy of this therapeutic option in women age 40 and older. The available information suggests a poor prognosis for this approach in these 674 Pearlstone et ai. Basal FSH and ovulation induction in women 40 Fertility and Sterility

2 patients with clinical pregnancy rates (PRs) of 2.1 % to 5.3% per cycle, as well as high spontaneous abortion rates (83% to 100%) ([6]; Arcaini L et ai., unpublished observations, 1990). Accumulating evidence indicates that chronological age may not be the best predictor of fertility potential. Data obtained from IVF patients suggest that functional ovarian status, as assessed by basal follicle-stimulating hormone (FSH) levels, is a more important determinant of therapeutic outcome (7). The current investigation was undertaken with two objectives. First, to determine pregnancy and livebirth rates for women age 40 and older during ovulation induction and second, to quantitatively define the impact of basal FSH on prognosis in these patients. MATERIALS AND METHODS Subjects and Study Design The study population consisted of women age 40 or older undergoing ovulation induction at the University of California, Los Angeles Fertility Center from January 1989 through August Basal FSH measurements were prospectively obtained on cycle days 2 or 3 in these women as part of an institutional review board approved protocol. All couples were diagnosed as infertile based on the inability to conceive after a minimum of 1 year of unprotected coitus. The women in this series had regular menstrual cycles (24 to 35 days), with the exception of those who were diagnosed with ovulatory dysfunction. Diagnostic evaluation included assessment of ovulation, a semen analysis, evaluation ofthe luteal phase, exclusion of a cervical factor, and confirmation of tubal patency (hysterosalpingography and/or laparoscopy). Laparoscopy was performed in a selective manner consistent with published protocols (8, 9). Patients were classified into one of six diagnostic categories based on their principal diagnosis, including ovulatory dysfunction, donor insemination, male factor, endometriosis, tubal factor, and unexplained infertility. Ovulatory dysfunction included patients with oligo-ovulation secondary to either hyperprolactinemia or polycystic ovarian disease as diagnosed by standard criteria. These women did not manifest elevated basal FSH levels, suggestive of a perimenopausal state. Donor insemination referred to those patients undergoing such therapy with no known female factors. Male factor subfertility was diagnosed based on results of at least two semen analyses separated by 3 months that confirmed any of the following abnormalities: sperm density < 20 X 10 6 /ml, motility < 50%, or morphology < 50% normal forms (10). Therapy in these couples used sperm from the male partner. Endometriosis was diagnosed at laparoscopy and classified according to the revised American Fertility Society classification system (11). Patients with tubal factor had evidence of tubal obstruction or of distorted adnexal anatomy but with at least one patent fallopian tube. Couples without evidence of abnormalities throughout their evaluation were classified as unexplained infertility. Ovulation Induction Protocols Stimulated cycles employed clomiphene citrate (CC) and human menopausal gonadotropins (hmg). Clomiphene citrate was administered in doses ranging from 50 to 150 mg/d for 5 days, with therapy initiated on cycle day 3, 4, or 5. Transvaginal ultrasound (US) examinations were performed to assess follicular development. Human menopausal gonadotropins therapy was started on cycle day 2 at an individualized dose ranging from one to four ampules per day, with a usual starting dose of two ampules. Each ampule contained 75 IU of FSH and 75 IU of luteinizing hormone (LH). Adjustments in dosage were made on the basis of serial US examinations and estradiol (E 2) levels. Other medication regimens, including sequential CC/hMG, bromocriptine, and pulsatile gonadotropin-releasing hormone were occasionally used in selected cases. Inseminations were timed by either home urinary LH assay, rapid serum LH testing, or the administration of human chorionic gonadotropin (hcg). Human chorionic gonadotropin was administered (10,000 IU) intramuscularly when the lead follicle(s) attained a mean diameter of 16 mm in hmg cycles and 18 mm in CC cycles. Single inseminations were performed the morning after a home urinary LH surge, the morning after a rapid serum LH surge, and 36 to 40 hours after the injection of hcg. The modes of insemination were intrauterine insemination, timed intercourse, and in selected donor cycles, cup insemination. For purposes of analysis, cup insemination was classified as timed intercourse for mode of insemination. All donor cycles used cryopreserved semen for insemination. Outcomes Clinical pregnancies were defined by a positive serum hcg with sonographic confirmation of a gestational sac or pathologic confirmation of villous Vol. 58, No.4, October 1992 Pearlstone et al. Basal FSH and ovulation induction in women

3 Table 1 Characteristics of 85 Patients in a Total of 402 Cycles Age (y) Duration of infertility (y) Gravidity Parity Cycles Patient characteristics 42.7 ± 2.0 (42.3 ± 0.2)' 2.7 ± 2.4 (2.0 ± 0.3) 1.6 ± 1.7 (1.0 ± 0.2) 0.4 ± 0.8 (0.0 ± 0.1) 4.7 ± 3.2 (4.0 ± 0.3), Values are means ± SD with median and SE in parentheses. tissue. Livebirths referred to pregnancies ending in the delivery of a viable infant. Alllivebirths in this study were at term. Assays Hormone assays were performed by a single laboratory using commercially available radioimmunoassay (RIA) kits. The FSH assay (Amerlex; Amersham Corporation, Arlington Heights, IL) had a sensitivity of 2 IU/L, an intra-assay coefficient of variation (CV) ranging from 1.9% to 7.0%, and an interassay CV of 4.7% to 9.1 %. The E2 RIA (Pantex, Santa Monica, CA) had a sensitivity of 10 pg/ml, an intra-assay CV of 3.0% to 4.3%, and an interassay CV of 7.5% to 11.1 %. Statistical Analysis Statistical analysis used Student's t-test for the comparisons of means, Wilcoxon's rank sum test for comparisons of medians, and X2 and Fisher's exact tests for comparing proportions. One-sided hypothesis testing was prospectively used in the cases of chronological age and basal FSH because the alternative considerations were not biologically plausible (12). Otherwise, two-tailed analyses were employed. Statistical significance was defined as P < Multivariate analyses for the probability of clinical pregnancy were performed via logistic regression methods, including testing for possible interactions among prognostic variables. Goodnessof-fit was assessed via the likelihood ratio G 2 statistic and a calculated R2 statistic. Parameters were estimated via the maximum likelihood method (iteratively weighted least squares). RESULTS During the study interval, there were a total of 93 infertile couples in which the female partner was age 40 or older and who were referred for ovulation induction. Of these, 85 of93 (91.4%) had basal FSH levels obtained. Basal FSH was not measured in 8 (8.6 %) of these women secondary to either logistics or noncompliance. Thus, there were 85 patients and a total of 402 cycles available for analysis. The patient characteristics are summarized in Table 1. There were 14 clinical pregnancies out of 402 cycles, yielding an overall PR of 3.5% per cycle (95% confidence interval [CI] 1.7% to 5.3%). Ofthese, 9 (64%; 95% CI 39% to 84%) resulted in spontaneous abortion. There were five livebirths for a livebirth rate of 1.2% per cycle (95% CI 0.1% to 2.3%). In Table 2, these data are compared with age specific pregnancy /livebirth rates calculated from a contemporaneous data base at our center. Pregnancies were plotted separately as a function of FSH and age. Graphic analysis suggested cutoff values of 25 IU/L and 44 years, respectively. Statistical analysis confirmed the significance of these observations. Specifically, the cycle PR was 14/326 (4.3%) for those with basal FSH values < 25 IU/L, compared with 0/76 (0.0%) for values 25 IU/L (P < 0.05). Likewise, the cycle PR was 14/325 (4.3%) for those <44 years, versus 0/77 (0.0%) for those 44 years (P < 0.05). However, there was no detectable relationship between age and FSH based on regression analysis (r = 0.09; P = 0.39). Patients were also simultaneously stratified on the basis of both basal FSH and chronological age. Women with both a basal FSH < 25 IU /L and age < 44 years old had a clinical PR of 5.2% (14/267) per cycle (95% Table 2 Pregnancy and Livebirth Rates During Ovulation Induction as a Function of Female Age Age <30 (n = 273 cycles/ 73 women) 30 to 34 (n = 512 cycles/ 136 women) 35 to 39 (n = 560 cycles/ 134 women) 40 (n = 402 cycles/ 85 women) PR (95% CIl' Livebirth rate (95% CIl' 13.6 (9.5 to 17.7) 11.4 (7.6 to 15.2) 9.6 (7.0 to 12.2) 8.2 (5.8 to 10.6) 7.7 (5.5 to 9.9) 5.9 (3.9 to 7.9) 3.5 (1.7 to 5.3lt 1.2 (0.1 to 2.3lt Percent per cycle. t p < compared with all other age groups. 676 Pearlstone et al. Basal FSH and ovulation induction in women 40 Fertility and Sterility

4 CI 2.5% to 7.9%) compared with 0.0% (0/135) per cycle (95% CI 0.0% to 2.1 %) in cases in which either basal FSH was 25 IV /L or age was 44 (P < 0.005). The corresponding livebirthrates were 1.9% (95% CI 0.3% to 3.5%) versus 0.0% (95% CI 0.0% to 2.1 %) per cycle, respectively (P = 0.09). Potential covariates were then tested for their relationship to pregnancy and livebirth rates. By diagnosis, there were 5 patients (5.9%) classified as having ovulatory dysfunction, 6 (7.1%) as donor, 9 (10.6%) as endometriosis, 12 (14.1 %) with male factor, 13 (15.3%) as tubal factor, and 40 (47.1%) as unexplained infertility. Of the patients with endometriosis,7 (77.8%) had stage 1 disease, 1 (11.1%) had stage 2, and 1 (11.1 %) had stage 3 disease. The PR/cycle for ovulatory dysfunction was 1/12 (8.3%), for donor 2/29 (6.9%), for endometriosis 2/55 (3.6%), for male 0/39 (0.0%), for tubal1/62 (1.6%), and for unexplained 8/205 (3.9%). These differences were not statistically significant (P = 0.55). A similar analysis of cycle livebirth rate versus diagnosis demonstrated no significant differences. Analysis of the effect of medication regimen revealed a PRJ cycle of 5/228 (2.2%) in CC cycles, 3/86 (3.5%) in hmg cycles, 5/79 (6.3%) in unstimulated cycles, and 1/9 (11.1 %) in cycles using other medications. These differences were not significant (P = 0.20). Similar findings were observed for livebirth rates. These analyses were also performed for both the method of timing and the mode of insemination. No statistically significant effects were detected for either of these variables (P values = 0.78 and 0.49, respectively). Laparoscopy was performed in 44 of 85 (54.1 %) patients. The PR in women with normal findings at laparoscopy was 3 of 96 (3.1 %), compared with 3 of 111 (2.7%) for those with documented abnormalities, and 8 of 195 (4.1 %) in women who did not undergo laparoscopy (P = 0.80). Analysis of livebirth versus laparoscopic status also did not reveal a significant association (P = 0.33). Multivariate analysis was performed for the probability of clinical pregnancy, using the above cited parameters as well as basal E2 values and the number of mature ovarian follicles. The only two prognostic variables that achieved statistical significance were the basal FSH level (P < 0.05) and chronological age (expressed to the nearest month, P < 0.05). Interaction terms were not significant for any of the tested models. The equation quantifying this relationship is p = 1/(1 + e- 1ogit score), where p = probability of pregnancy and the logit score = (FSH) (age). This relationship is graphically depicted in Figure 1. The calculated R2 value was 0.94 (P < 0.01), indicating a very close fit between the data and the multivariate model. DISCUSSION There were two hypotheses underlying this investigation. First, that pregnancy and livebirth rates during ovulation induction in women age 40 and older would be definable but generally low. Second, it was postulated that as basal FSH levels increased, pregnancy and live birth rates would decline. The rationale for assessing the modality of ovulation induction was twofold. First, it has evolved into a primary therapy for a substantial subset of infertile couples (5). Additionally, to our knowledge, the impact of basal FSH levels on the PRs/cycle of women undergoing ovulation induction has yet to be defined. We chose to specifically study couples in whom the female partner was age 40 or older because the number of such couples seeking infertility care is rapidly increasing (1). Furthermore, the available data suggest that these patients have a poor prognosis while undergoing ovulation induction (6). Our findings are consistent with the limited information previously reported on this topic. Overall, clinical PRs were low (3.5% per cycle) and spontaneous abortion rates high (64%). Basal FSH level exerted a measurable impact on PRs, although it was not the only prognostic variable of importance. Stratified and multivariate logistic regression analyses indicated that chronological age was also an independent determinant of outcome. Our results are also compatible with the data reported from IVF cycles (7, 13). Toner et al. (7) demonstrated that basal FSH and chronological age were both determinants of IVF outcome. However, they concluded that basal FSH was a better predictor of IVF performance than age. In contrast, our data suggest that the relative importance of each variable is dependent on the values of both. It is hypothesized that basal FSH measurement functions as a marker for ovarian age or reserve (7). The mechanisms by which chronological age could diminish PRs independent of FSH are unknown but might include adverse influences on oocyte quality and or endometrial receptivity (14, 15). The patients in this study were classified on the basis of a single basal FSH measurement. Data from IVF patients suggest that once a woman demonstrates an elevated basal FSH, her response is diminished even in cycles in which the basal FSH is Vol. 58, No.4, October 1992 Pearlstone et at. Basal FSH and ovulation induction in women ;;0,;

5 0.10 iii 0.09 U >- u 0.08., >- u 0.01 c co c <II 0.06 GI.t "ii 0.05 u : :a...a _ _ Basal FSH (lull) Figure 1 Clinical PR/cycie as a function of both basal FSH and chronological age for women age 40 and older undergoing ovulation induction (based on multivariate logistic regression analysis). normal (16). Our observations are consistent with this finding because no patient with an FSH 25 lull achieved a pregnancy. However, it is possible and even probable that some of the patients with lower FSH values actually had higher levels in subsequent cycles. Thus, our analysis might slightly understate the prognosis for patients with a persistently favorable FSH. In addition, recent IVF data suggest an intermediate prognosis for patients with intercycle variation compared with consistently low or high values (Stein DE et ai., unpublished observations, 1991). The role for serial basal FSH measurements remains to be determined. It should be noted that the data in Table 2 for women < 40 years of age are intended to provide a framework for interpreting our pregnancy and livebirth rates in women age 40 and older. This information was obtained from women < 40 years of age who were referred for ovulation induction at our center during the study interval. These results indicate an age-dependent decline in pregnancy and livebirth rates, consistent with published data (5). Our findings also suggest a particularly marked decline in success rates for the 40-year-old patients. However, a more detailed comparison of these groups (including distribution of diagnoses and basal FSH levels) would be necessary to formally exclude confounding variables as an alternative explanation for these results. Finally, we would caution against directly generalizing these observations to populations beyond the bounds of the study group (i.e., <40 or using other therapeutic modalities). However, it does seem that in the women studied to date, basal FSH levels of 25 lull do portend a poor prognosis for both IVF and ovulation induction patients. In summary, pregnancy and livebirth rates are generally low during ovulation induction in women age 40 and older. However, basal FSH level and chronological age are both important determinants of PRs in these women and can define a subset of patients with a more favorable prognosis. Alone, neither is sufficient to adequately counsel a couple regarding chances for success. Together, these factors are accurate predictors of PRs in such women. It is, however, important to remember that these patients experience a high rate of spontaneous abortion, which substantially impacts the ultimate livebirth rate. Ackrwwledgments. Special thanks to Ms. Peggy Ketting Olivier for her help in the preparation of this manuscript, Sally Pitzer, R.N.P., for coordinating patient care, and to Jeffrey Gornbein, Ph.D., of the Biomathematics Department at the University of California, Los Angeles, Los Angeles, California, for his assistance with the statistical analyses. REFERENCES 1. Gindoff PR, Jewelewicz R. Reproductive potential in the older woman. Fertil SteriI1986;46: Romeu A, Muasher SJ, Acosta AA, Veeck LL, Diaz J, Jones GS, et al. Results of in vitro fertilization attempts in women 678 Pearlstone et al. Basal FSH and ovulation induction in women 40 Fertility and Sterility

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