Is an Elevation in Basal Follicle-Stimulating Hormone Levels in Unexplained Infertility Predictive of Fecundity Regardless of Age?

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1 Endocrine Journal 2001, 48 (6), NOTE Is an Elevation in Basal Follicle-Stimulating Hormone Levels in Unexplained Infertility Predictive of Fecundity Regardless of Age? Koji KUGU*, MIKIo MOMOEDA*, SIYA S. SHARMA*,**, YUTAKA OSUGA*, TosHIHIRO FUJIWARA*, RYUGo OKAGAKI*, HIROKO FUKUSHIMA*, TETSU YANO*, OSAMU TSUTSUMI* AND YUJI TAKETANI* *Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo , Japan **Present address: Department of Gynaecology & Obstetrics, Kasturba Medical College, Man ipal , India Abstract. An elevation in follicle-stimulating hormone (FSH) levels is considered to reflect lowered ovarian function, resulting in poor fecundity in infertile women. However, it remains to be clarified whether or not the significance of FSH levels applies equally to all women irrespective of age. The objective of the present study is to compare basal FSH levels in infertile women who conceived or not after stratification by age. A total of 144 infertile women between ages 25 and 45 who underwent infertility treatment due to unexplained infertility in the University of Tokyo Hospital were included in the retrospective study. Subjects were divided by age into two groups, <38 (n=98) vs?38 (n=46) years, with ages ranging from 25 to 37, and from 38 to 45, respectively. Blood samples were collected in early follicular phase (day 4-6) for assessment of basal levels of LH, FSH, and PRL. In the older group, pregnant cases had significantly lower FSH levels (6.07±2.83 miu/ml) than nonpregnant cases (9.60±3.67 miu/ml), whereas no difference in basal FSH levels was observed between pregnant and nonpregnant cases in the younger group. Basal FSH levels of pregnant cases in the older group were significantly lower than those of pregnant cases in the younger group (8.26±2.95 miu/ml). Basal LH and PRL levels were not related to fecundity in either group. Thus, an increase in basal FSH levels as a predictor of fecundity should be considered in the context of age. Key Words: Basal FSH level, Unexplained infertility, Age (Endocrine Journal 48: , 2001) Received: February 5, 2001 Accepted: August 15, 2001 Correspondence to: Koji KUGU, M.D., Ph.D., Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo , Japan REPRODUCTIVE aging is characterized by a decline in fertility, which begins in the thirties [1, 2]. It is well accepted that the hallmark of changes with aging is an isolated increase of circulating FSH levels in the follicular phase [3, 4]. Thus, elevated basal FSH levels can be taken to suggest diminished ovarian reserve such that fertility potential is lowered in older infertile women with elevated basal FSH levels when treated by ovulation induction or in vitro fertilization. Although a decline in fecundity with aging parallels an increase in basal FSH level, many other (patho)physiological factors modulate FSH levels [5]. Thus, it remains uncertain whether basal FSH levels can serve as a determinant of future fecundity even in relatively younger women. The store of ovarian oocytes in human females, as in most other mammals, declines exponentially until 35 years of age. According to some reports [6-8], the exponential line of oocyte decline accelerates at some age between 35 and 40. We investigated this idea by comparing basal FSH levels in infertile women who conceived or not after stratification by age.

2 712 KUGU et al. Materials and Methods Table 1. Pregnancy outcome by age All women with unexplained infertility, who visited the infertility division, outpatient clinic of the University of Tokyo Hospital from January 1997 through December 1998, were studied. Those patients with endocrine disorders such as polycystic ovary syndrome, luteal insufficiency and hyperprolactinemia, blocked fallopian tubes, manifest endometriosis or male-related infertility, were excluded. We also excluded the cases who proceeded to assisted reproductive technologies. The remaining 144 cases, who ranged in age between 25 and 45 years, were put into the following retrospective study. The percentage of cases who underwent laparoscopy to rule out endometriosis was 13.8%. Subjects were divided by age into two groups, < 38 or >_ 38 years, and were followed up every 1 or 2 months at least for 12 months with or without infertility treatment. Follow-up ranged between 12 months and 35 months. Treatment modalities included ovulation induction and intrauterine insemination, the choice of treatment being based on a decision by the physician and the patient. Blood samples were collected from each subject on day 4-6 of menstrual cycle without medication. Serum samples were kept frozen until assayed for LH, FSH and PRL. Serum concentrations of LH, FSH and PRL were determined with the SPAC-S LH kit for LH (Daiichi Radioisotope Laboratories Ltd., Tokyo, Japan), SPAC-S FSH kit for FSH (Daiichi Radioisotope Laboratories Ltd.), and SPAC-S PRL kit for PRL (Daiichi Radioisotope Laboratories Ltd.). Intra-assay and inter-assay coefficients of variation for these assays were less then 10%. Percentile values were used to express the pregnancy rates in each group. Basal LH, FSH and PRL levels were expressed as means ± SD. Student's t test was used for statistical analysis of basal LH, FSH and PRL levels, with p <0.05 considered to be significantly different. We divided the patients Results into two groups: younger (<38 years; n=98), and older (>38 years; n=46). The mean age of each group was 33.4 years and 40.1 years, respectively. In the younger group, 31 pregnancies were confirmed (pregnancy rate: 31.6%), while 15 women became pregnant in the older group, giving a pregnancy rate of 32.6%, which is essentially the same as that in the younger group (Table 1). In the younger group, 4 pregnancies were achieved without ovulation induction whereas 2 and 25 conceived by the administration of clomiphene and gonadotropin, respectively. In the older group, only one conceived without medication, with the remaining 14 pregnancies having been achieved by gonadotropin administration. Basal LH, FSH and PRL levels were not different between the two groups (Table 2). LH levels did not differ between pregnant and nonpregnant cases in either group. No significant differences in PRL levels were found between pregnant and nonpregnant cases in either group. Interestingly, FSH levels of pregnant cases were significantly lower than those of nonpregnant cases in the older group, but not in the younger group. FSH levels of pregnant cases in the older group were significantly lower when compared with those of pregnant cases in the younger group. Discussion It is well known that maternal age strongly affects the outcome of infertility treatment. This seems to be due to lowered oocyte quality rather than deteriorated endometrial function, since older women over 40 years receiving donor oocytes do as well in in vitro fertilization as those under the age of 40 despite very poor results when using their own oocytes. As

3 FSH LEVEL AND FECUNDITY 713 Table 2. Serum hormone levels according to the pregnancy outcome anticipated by the positive correlation between the basal FSH level and age in premenopausal women, an increase in basal FSH levels during early follicular phase has been increasingly recognized to reflect waning ovarian function and, therefore, to predict the probability of achieving pregnancy. Hitherto reported studies point to the importance of basal FSH levels as predictors of fecundity in women at advanced reproductive age [9-11]. However, it remains to be determined whether basal FSH level retains its predictive value in relatively younger women. Here we demonstrated that basal FSH levels were different between pregnant and nonpregnant cases in women at age 38 and older but not in women less than 38 years old, suggesting that an elevation in basal FSH levels may have a predictive value for fecundity only in women at advanced age. This is in line with a report by van Montfrans et al. [12] documenting that there was no statistically significant difference in cumulative pregnancy rates between women with elevated basal FSH concentrations and controls in women whose mean age was 34 years. It is of interest to note that the mean FSH levels did not differ between the younger and older study group despite a well-known age related increase in circulating FSH levels. In this context, a recent study demonstrated higher basal FSH levels in unexplained infertility compared with fertility-proven women, a finding suggesting a subtle diminution of ovarian reserve as one of the etiologic factors in unexplained infertility [13]. A more recent study shows that higher basal FSH levels in women with imminent ovarian failure are associated with larger amplitudes of FSH pulses and greater responses of FSH to GnRH [14]. Given these findings, the present data that the average FSH level in the younger group matched that in the older group make it attractive to speculate that the younger group includes a considerable portion of women with a latently increased FSH level, which may constitute an etiologic factor for unexplained infertility. On the other hand, a slight elevation in FSH levels in the older group may reflect the aging process of reproductive system, which, per se, have an implication for reduced fecundity. The question arises as to why an elevation of basal FSH level is associated with poor fecundity only in older women despite their basal FSH levels being similar to those in younger infertile women as was observed in this study. It is widely accepted that an increase in FSH level at advanced age, which results from a decline in peripheral concentrations of inhibin, is coupled with reduced oocyte quality and, therefore, diminished fertility despite gonadotropin treatment [15-19]. On the other hand, subtle increases in serum FSH levels were observed in a considerable portion of relatively younger women (30 years on average) diagnosed with unexplained infertility [20]. Interestingly, these women had reduced estradiol levels in the follicular phase and subnormal progesterone levels in the late luteal phase, which is a different endocrine profile from that seen in their older counterparts [21]. The condition of elevated FSH in younger women was interpreted to be a consequence of disturbances in ovarian metabolism. One might expect that, unlike older women with elevated FSH, younger women with elevated FSH could conceive in response to clomiphene citrate or gonadotropins. Unfortunately, at present, it remains unresolved as to how to manage older women with elevated FSH. The possibility is raised that ooplasmic transfer, a recently developed technique to restore normal growth in developmentally compromised oocytes, might be a strategy to address this issue, although, needless to say, ethical aspects need to be taken into account.

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