Human Reproduction, Vol. 14, No. 2, 349-353,
February 1999
© 1999 European Society of Human Reproduction and Embryology
The clinical efficacy of low-dose step-up follicle stimulating hormone administration for treatment of unexplained infertility
Department of Obstetrics and Gynecology, Asahikawa Medical College, Asahikawa, Japan
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Abstract |
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The present study was designed to compare the clinical efficacy of low-dose step-up follicle stimulating hormone (FSH) administration with conventional FSH protocol (FSH was injected daily starting with a dose of 150 IU), both combined with intrauterine insemination (IUI), for the treatment of unexplained infertility. A total of 97 unexplained infertility couples was randomly assigned to one or other of the two treatment groups, either conventional FSH with IUI (48 patients) or low-dose step-up FSH with IUI (49 patients), and only the first treatment cycle was evaluated in each protocol. The difference in pregnancy rates per cycle was not statistically significant between the low-dose FSH group and the conventional group [seven of 49 (14.3%) and seven of 48 (14.6%) respectively]. A significant reduction in the incidence of ovarian hyperstimulation syndrome (OHSS) was observed in the low-dose group (8.3% versus 27.1%, P < 0.05). The incidence of moderate OHSS requiring hospitalization was reduced significantly in the low-dose group (low-dose 0% versus conventional 16.7%, P < 0.01). However, the low-dose protocol did not completely prevent multiple pregnancies. Our results suggest that the low-dose step-up FSH treatment appeared to be useful for the treatment of unexplained infertility because of the high pregnancy rates and the significant decrease in the incidence of OHSS.
Key words: follicle stimulating hormone/low-dose step-up/ovarian hyperstimulation syndrome/unexplained infertility
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Introduction |
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Several treatment protocols have been applied to couples with unexplained infertility. Treatment options range from an expected management to the various methods for assisted reproductive technology such as in-vitro fertilization (IVF) and gamete intra-Fallopian transfer. Ovulation induction with gonadotrophin has been used exclusively for the treatment of patients with ovulation disorders. Recently, the application of gonadotrophin treatment has been expanded to include infertility patients without ovulation disorders, and many reports have suggested its clinical efficacy for the treatment of unexplained infertility. It is now widely accepted that the efficacy of ovulation induction combined with intrauterine insemination (IUI) has been demonstrated to be superior to human menopausal gonadotrophin (HMG) treatment or IUI alone (Dodson et al., 1987
; Serhal et al., 1988; ESHRE Capri Workshop, 1996). Thus, gonadotrophin with IUI has been advocated as a treatment for unexplained infertility to produce more oocytes and improve pregnancy rates.
However, gonadotrophin treatment is highly associated with an increased risk of multiple gestation and ovarian hyperstimulation syndrome (OHSS). Several alternative regimens have been proposed to reduce these complications, including low-dose step-up, step-down administration of follicle stimulating hormone (FSH) and sequential FSH–pulsatile gonadotrophin-releasing hormone treatment (Mizunuma et al., 1991; Sagle et al., 1991; Kuwabara et al., 1995). Low-dose administration of FSH regimen is a safe and convenient treatment protocol, and many studies have confirmed the effectiveness and safety of this ovulation induction method in patients with polycystic ovarian syndrome (Buvat et al., 1989; Kuwabara et al., 1995). However, evaluation of the effectiveness of this therapeutic option for treatment of patients with non-ovulation disorders, including unexplained infertility, has been limited and remains unclear.
This study was designed to investigate whether low-dose step-up FSH administration reduces the risk of OHSS and multiple pregnancy and maintains high pregnancy rates compared with those of the conventional FSH protocol, both combined with IUI regimen, for the treatment of unexplained infertility.
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Materials and methods |
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Subjects
A total of 97 couples with long-standing unexplained infertility, who had previously been stimulated unsuccessfully with clomiphene citrate or a combination of clomiphene and FSH, was enrolled in the present study between April 1994 and June 1997. Informed consent was obtained from all participants and this study was approved by the local ethics committee. Unexplained infertility was defined as having a normal infertility evaluation, including biphasic basal body temperature recording, normal post-coital test, in-phase endometrial biopsy, luteal progesterone concentration
10 ng/ml, normal semen analyses (volume >1.5 ml, sperm count 20x106/ml, motility 50%, normal morphology 30%), normal hysterosalpingography and normal laparoscopic findings. All patients had normal basal luteinizing hormone (LH), FSH and prolactin concentrations. The couples were randomly assigned to two treatment groups and only the first treatment cycle was evaluated in each treatment protocol. Treatment assignments were based on random numbers and were concealed in sealed opaque envelopes. In the conventional FSH protocol, purified urinary FSH (Fertinorm P; Serono Japan, Tokyo, Japan) was administered daily starting with a dose of 150 IU from day 3 for 5 days and raised by 75 IU every 4 to 5 days until an adequate ovarian response was achieved. Low-dose step-up regimen consisted of administration of a starting dose of 75 IU per day of FSH from day 3. If there was no evidence of follicular development after 7 days of treatment (maximum follicular diameter <12 mm), the daily dose was increased by half an ampoule (37.5 IU) every 7 days. If the leading follicle reached 12 mm in diameter, the same dose of FSH was maintained until follicular maturation was achieved. For both protocols, follicular development was monitored by serum oestradiol assays and vaginal ultrasound scans. Serum LH was assayed daily from day 8 to rule out a LH surge. When the dominant follicle was at least 17 mm in diameter and serum oestradiol was >250 pg/ml, 5000 IU human chorionic gonadotrophin (HCG) was administered. None of the cycles in the present study was cancelled for any reason.
IUI with husband's spermatozoa was performed 24–28 h after HCG injection. In cycles where a LH surge was detected, insemination was performed the next day. Semen samples for IUI were washed twice by centrifugation for 5 min at 300 g after liquefaction and resuspended in human tubal fluid (HTF; Irvine Scientific, Santa Ana, CA, USA) medium supplemented with 0.3% human serum albumin (Sigma Chemical Co., St Louis, MO, USA). Sperm suspension (0.5 ml) was introduced into the intrauterine cavity using a Tomcat catheter (Sherwood Medical, St Louis, MO, USA). The luteal support consisted of HCG (3000 IU) on the third and sixth days after the initial dose of HCG. Premature LH surge was defined as a LH surge prior to formation of a mature follicle. OHSS was diagnosed by vaginal ultrasound at 3 and 10 days after HCG injection. Mild OHSS was defined by ovarian enlargement (6 to 10 cm), ascites evident by ultrasound and abdominal discomfort with or without abdominal pain. Moderate OHSS was diagnosed by ovarian enlargement (>10 cm), abdominal pain, haemoconcentration and remarkable accumulation of ascites (clinical evidence of ascites) requiring hospitalization, and the severe form was characterized by ascites, pleural effusion, coagulation and electrolyte disturbances. A clinical pregnancy was confirmed by detecting a gestational sac on an ultrasound scan.
Hormone assays
Serum oestradiol and progesterone were assayed using commercially available radioimmunoassay kits (Diagnostic Product Co., Los Angeles, CA, USA). LH was determined by immunoradiometric assays. The intra-assay and inter-assay coefficients of variation were <10% for all assays.
Statistical analysis
Statistical significance of the data was determined by the 
2 test, Fisher's exact test and unpaired t-test as appropriate. The differences were considered significant at a level of P < 0.05. All data are expressed as means ± SD. The number of cycles required per group was 45 cycles, based on 80% power and a 5% level of significance, accepting the null hypothesis of no difference between treatments.
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Results |
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Of the 97 couples enrolled in this study, 48 couples underwent conventional FSH with IUI treatment (group 1) and 49 underwent low-dose step-up with IUI treatment (group 2). In both groups, only the first treatment cycle was evaluated because some patients were unable to complete the consecutive cycles of therapy for a variety of reasons. Clinical characteristics of the patients in the two stimulation protocols are shown in Table I
. The mean age, duration of infertility, and clinical diagnoses were similar for both groups. The total number of motile spermatozoa and the proportion of morphologically normal spermatozoa in the original semen, and the total number of motile spermatozoa inseminated were similar between the two groups.
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Clinical results and the characteristics of ovarian response in both groups are summarized in Table II
. The total dose of FSH required for stimulation was significantly lower in couples treated with low-dose step-up protocol than in couples treated with the conventional protocol (932.8 ± 421 IU and 1381.2 ± 505 respectively, P < 0.01), although the duration of FSH treatment was significantly longer in group 2 than in group 1. The rate of monofollicular development (>15 mm) was more frequent with the step-up than with the conventional protocol (step-up 49.0% versus conventional 25.0%, P < 0.05). The mean number of large (>15 mm) and medium-sized (10–14 mm) follicles at the time of HCG administration were significantly lower in the step-up group. Plasma oestradiol concentration on the day of HCG was also significantly lower in group 2 (P < 0.01). The thickness of the endometrium on the day of HCG was not different between the two groups. There was also no difference in the incidence of premature LH surge.
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A total of 14 pregnancies was obtained during the trial: seven in the conventional group, and seven in the step-up group. The difference in pregnancy rates per cycle between the groups was not statistically significant (conventional 14.6% versus step-up 14.3%). There were six pregnancies in 36 cycles with monofollicular development (16.7%; two in group 1 and four in group 2) and eight in 61 cycles with multifollicular development (13.1%; five in group 1 and three in group 2). This difference was not significant. Similar pregnancy rates were also observed between the LH surge group and the non-LH surge group [two of 13 (15.4%) and 12 of 84 (14.3%) respectively]. There was no difference in the pregnancy rates between the primary infertility patients and the secondary infertility patients [nine of 68 (13.2%) and five of 29 (14.5%) respectively]. Similarly, female age did not affect pregnancy rates in each treatment groups [2/16 (12.5%)
30 years and 5/32 (15.6%) >30 years in group 1 and 2/14 (14.3%) 30 years and 5/35 (14.2%) >30 years in group 2 respectively]. With regard to outcome, there were two twin pregnancies and one miscarriage in group 1 and one twin pregnancy and one miscarriage in group 2. OHSS occurred in 13 cycles in the conventional group (27.1 %) and four cycles in the step-up group (8.3 %) and this difference was statistically significant (P < 0.05). In group 1, mild and moderate forms of OHSS were observed in 5 and 8 cycles respectively (10.4% and 16.7%, respectively). All OHSS showed mild form and no moderate OHSS was observed in group 2. The incidence of the moderate form of OHSS requiring hospitalization was significantly different between the two groups (P < 0.01). No severe OHSS was observed in both treatment groups.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Several treatment protocols have been empirically applied to patients with unexplained infertility. Recently, ovulation induction with gonadotrophin combined with IUI has been advocated as a treatment for unexplained infertility. A number of randomized clinical trials have addressed the use of IUI with or without HMG as augmentation therapy. These results indicated that the pregnancy rate per cycle was 3% in cycles of observation with timed intercourse, 6% in HMG cycles and 14% in cycles of HMG combined with IUI. From the logistic regression analysis, the effects of IUI and HMG treatment were similar: each treatment significantly increased the likelihood of conception twofold (ESHRE, 1996). Recent meta-analysis indicated that average fecundability is more than twofold higher in a cycle with either HMG and IUI treatment and fivefold higher when both treatments are used compared with that of untreated cycles (Hughes, 1997
).
This method is less invasive and more convenient than IVF. However, ovulation induction with gonadotrophin has been highly associated with OHSS and multiple pregnancy. The rate of multiple pregnancy was reported to be 20 to 30% with conventional gonadotrophin treatment. The incidence of moderate and severe OHSS has been reported to be 0.6 to 20% (Gelety et al., 1992; Rizk and Smitz, 1992).
A low-dose step-up gonadotrophin administration was used originally for the treatment of polycystic ovarian syndrome patients (PCOS) and was used successfully to reduce the risk of OHSS and multiple pregnancy (Polson et al., 1989). Reducing the risk for multiple pregnancy and OHSS but maintaining high pregnancy rates seem to be the main criteria for treatment of infertile patients. Therefore, we developed a randomized prospective study comparing results of conventional gonadotrophin cycles with low-dose step-up cycles for treatment of patients with unexplained infertility. Karlström et al. (1993) suggested that the first treatment cycle per couple is best used for evaluation of the results. Therefore, only the first treatment cycle's results were used to compare the two groups in this study.
In our study, we used a shorter interval (7 days) step-up protocol instead of that described in the 14 days chronic protocol (Polson et al., 1989; Sagle et al., 1991). From a clinical standpoint, this regimen is more convenient for the patients, since this protocol achieves the FSH threshold more promptly and may reduce the duration of gonadotrophin administration. Our results show that a low-dose step-up regimen could achieve ovulation induction by a smaller amount of FSH and results in a significant reduction in the number of large and medium-sized follicles compared with that of the conventional protocol (2.2 ± 1.0, 1.9 ± 2.7 for low-dose, 4.3 ± 3.2, 3.3 ± 3.0 for conventional respectively; P < 0.05). Although the longer duration of FSH treatment was required in the low-dose group, the incidence of a premature LH surge did not differ between the two groups. The incidence of single follicular maturation was significantly higher in the low-dose group compared with that of the conventional group. Significantly lower serum oestradiol concentrations observed on the day of HCG administration in the low-dose group may be related to the lower number of large and medium-sized follicles and the higher incidence of monofollicular development. Despite these facts, no difference was observed in pregnancy rates between the two groups. The same pregnancy rates were also observed between the cycles with monofollicular development and the cycles with multifollicular development. Our pregnancy rates per cycle were similar to those reported by several authors (Dodson et al., 1987; Welner et al., 1988; Dodson and Haney, 1991). In addition, our present studies indicate that premature LH surge did not affect the pregnancy outcome. This result is consistent with Dodson et al. (1991) and our previous reports (Sengoku et al., 1994). They showed that the prevention of premature LH surge or premature luteinization by using gonadotrophin-releasing hormone agonist did not necessarily enhance cycle fecundity.
Several reports show that, without treatment, 15–60% of the couples with unexplained infertility conceived by 1 year and 40–80% by 3 years (Templeton and Penney, 1982; Rousseau et al., 1983; Barnea et al., 1985). It is generally accepted that factors influencing the prognosis for pregnancy in unexplained infertility are duration of infertility, age of the female partner and pregnancy history (Collins and Rowe, 1989). In couples with persistent infertility (>3 years of infertility such as those included in the present study), untreated cycle fecundity rates range from 1 to 2% (Crosignani et al., 1993). The pregnancy rate with secondary infertility is nearly double the pregnancy rate with primary infertility, and advancing age over 30 years decreases the possibility of pregnancy (Collins and Rowe, 1989). In our study, female age and pregnancy history did not affect the pregnancy rates. These observations may be attributed to the relatively small number of patients and the evaluation based on only one treatment cycle in the present study.
No severe OHSS was observed in either treatment group, however, a significant reduction in the incidence of moderate form of OHSS requiring hospitalization was seen in the low-dose group. Of the seven pregnancies achieved, one twin pregnancy was observed in the low-dose group. This result is consistent with other reports (Mizunuma et al., 1991; White et al., 1996), which have suggested that the low-dose gonadotrophin regimens did not completely prevent multiple pregnancies in patients with PCOS. Thus, the low-dose step-up FSH treatment seems to be safer and more cost-effective than the conventional gonadotrophin treatment.
It has been suggested that the beneficial effects of ovulation induction with IUI may be related to the increased number of male and female gametes at the site of fertilization, correction of subtle and unknown ovulatory disorders, the accuracy of ovulation prediction or correction of subtle alterations in progesterone production during the luteal phase. The low-dose regimen may circumvent unpredictable ovulatory disturbance and subtle luteal-phase hormonal abnormalities, but is less effective with regard to increasing the number of gametes when compared with that of the conventional gonadotrophin treatment. It has been suggested that excessive serum oestradiol concentration has adverse effects on oocytes and the embryo (Dor et al., 1986). A high oestradiol milieu is also known to create a hostile endometrium and to have an adverse effect on implantation (Forman et al., 1988; Paulson et al., 1990). The lower level of oestradiol observed in the low-dose regimen may exert a beneficial effect on embryo development and the implantation process. Martin et al. (1995) suggested that pre-embryo developmental problems or implantation problems appear to be the major aetiology in unexplained infertility based on a retrospective analysis of IVF programme. Therefore, the beneficial effects of low-dose treatment on embryo development and implantation may overcome the decrease in the number of available oocytes. This concept is further supported by our finding indicating that there was no difference in pregnancy rates between multifollicular and monofollicular development cycles.
In conclusion, low-dose step-up FSH treatment appeared to be useful because of the same high pregnancy rates per cycle and the significant decrease in the incidence of moderate form of OHSS in comparison with that of the conventional gonadotrophin method. However, the low-dose regimen did not completely prevent multiple pregnancies. Further prospective studies are needed to confirm the efficacy of this protocol for reducing the multiple pregnancy rates.
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Acknowledgments |
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The authors thank Mr. Noel Whelan for his critique of the manuscript.
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Notes |
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1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Asahikawa Medical College, Nishikagura 4–5, Asahikawa, Japan 0788510
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Submitted on October 9, 1998; accepted on December 4, 1998.
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