1 Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, Adelaide University, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA 5011, Australia
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Abstract |
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Key words: age/BMI/controlled ovarian stimulation/FSH/ovulation induction
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Introduction |
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Materials and methods |
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The key elements of the protocol for OI were as follows: day 2 or 3 (either a natural or artificial menstrual cycle): baseline serum FSH; day 5: 75 IU HMG given daily i.m.; after 5 days treatment: serum estradiol (E2) measurement and vaginal ovarian ultrasound scan to assess the response in order to decide whether to vary the dosage or to cancel the treatment cycle; day 10 onwards: if no more than three large follicles (defined as >16 mm in diameter) were present, then 5000 IU HCG was administered i.m. and natural intercourse 3640 h later advised or insemination carried out. If more than three large follicles were present, HCG was withheld and the couples were advised against intercourse or not inseminated. The clinical management, for example the starting dose of HMG or the adjustment of dose, was subject to some minor variation based on clinical judgement in individual subjects although overall the treatment programmes were performed within tight guidelines of the above protocol. The protocols for COS associated with IVF have been previously described (Sathanandan et al., 1989). Briefly, all patients included in the analysis utilized a gonadotrophin agonist (Leuprolide Acetate®; Abbott Pharmaceuticals, Sydney, Australia) either as a pituitary luteal phase desensitizing protocol or occasionally a flare protocol. Gonadotrophins were introduced on day 2 of the induced menstrual bleed in the luteal desensitizing protocol. The ovarian response was monitored in a similar fashion to OI but the criteria for the administration of HCG was determined by the presence of at least two follicles >17 mm in diameter. The cancellation criterion was less than two follicles being present on ultrasound scan on day 9 of the treatment cycle. HCG administration was only withheld if there was a serious clinical potential for ovarian hyperstimulation syndrome (OHSS) as indicated by a >50 nmol/l serum E2 level at day of HCG.
Five groups of women who had undertaken ovulation induction were identified based on the following features from the database: (i) those subjects with moderately elevated basal FSH levels (1020 IU/l); (ii) those subjects with grossly elevated FSH levels (>20 IU/l); (iii) those with a BMI <20 kg/m2 (thin); (iv) those with a BMI > 30 kg/m2 (obese) and (v) those of 40 years of age (aged group). Each subject was selected with only one feature outside the range generally considered normal. For example, women aged 40 years or more would have a FSH level <10 IU/l and BMI between 2030 kg/m2. Similar groups were extracted from the IVF population though there was no patient with FSH >20 IU/l owing to its rarity. This enabled the influence of the selected factors, age, BMI or basal FSH level, to be studied independently. Subjects who had undergone OI or COS during the same period but did not exhibit any of the specified features were used for comparison and designated the 'normal' group.
The main outcome variables analysed included: the starting dose of HMG, the total HMG dose administered and the duration (days), the response to HMG in terms of the maximum serum E2 reached, the number of oocytes recovered and the outcome of the cycles including cancellation due to an inadequate or excessive response, and the occurrence of clinical pregnancy, as defined by the detection of fetal heart by an ultrasound scan on week 67 of gestation.
Statistical analysis was performed by analysis of variance (ANOVA) or 2-test to test the differences between the groups. Intra-group comparisons were made using Tukey's test. Where the data were not normally distributed, KruskalWallis ANOVA on ranks was carried out. All statistical analysis was done with SPSS (SPSS Inc., Chicago, MI, USA).
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Results |
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Response to HMG: serum E2, follicle numbers and cycle cancellation
The women with high FSH had only 0.5 large follicle on average, which was significantly fewer than the normal group. This group also had a much lower E2 concentration (0.5 nmol/l, P = 0.001) compared with that (1.6 nmol/l) in the normal group. Lower E2 concentrations were also observed in three other groups (ranging from 0.91.0 nmol/l). Cancellation due to excess stimulation, i.e. more than three large follicles, occurred in 19% of the normal group. Thin women also displayed a similar propensity (11%) while hyperstimulation was rare in other groups. Conversely obese women had a significantly higher risk of hypostimulation (14%, P < 0.05), compared with the normal group.
Clinical pregnancy
Pregnancy rate was 11% in the normal group and 30% in thin subjects but this difference was not significant due to the small sample size. Obese and aged groups also had similar pregnancy rates to the normal group while women with elevated FSH had very poor pregnancy rates (0% for high and 5% for moderately high FSH).
Controlled ovarian stimulation (Table II)
There were 354 cycles (79 in the normal group) derived from 175 subjects. The BMI of the thin subjects was 18.7 kg/m2 and the obese group 33.6 kg/m2, significantly different from the normal group. The moderately high FSH group had a mean FSH of 13.9 IU/l, which was statistically higher (P < 0.01) than the normal group. The mean age of the older women was 42.1 years, again significantly greater than the normal group.
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Response to HMG: serum E2, number of oocytes and embryos and cancellation rate
The normal group had a maximum serum E2 of 6.7 nmol/l. The only group that failed to respond well was the older group, which had a mean E2 of just 4.6 nmol/l, lower than the normal group (P < 0.001). All other groups reached similar levels as the normal group (5.66.9 nmol/l). The mean number of oocytes recovered in the normal group was 10.9, significantly more than the older group (8.5, P < 0.05) but similar to the other groups (range 9.110.6). The number of embryos formed from the IVF procedures was also significantly lower in older (5.0) and obese women (5.1) compared with the normal group (6.6, P < 0.05), while thin women also appeared to have fewer embryos (5.2), but not statistically significantly so. Interestingly, women with a moderately high FSH had similar numbers of embryos (6.7) formed as the normal group. Cancellation due to possible hyperstimulation was very low (1%) in all groups. By contrast cancellation due to poor response was common, 1516% in women with moderately high FSH, the thin and the older groups, significantly higher than the 10% cancellation rate in the normal group (P < 0.05). Only 9% of the cycles among the obese subjects were cancelled.
Clinical pregnancy
The pregnancy rate per completed cycle was 26% in the normal group, similar to the moderately high FSH group (23%, 13 pregnancy cycles) and the obese patients (23%, 15 pregnancy cycles). However the pregnancy rate was significantly lower in the older (11%, six pregnancy cycles, P < 0.01) and the thin groups (9%, five pregnancy cycles, P < 0.01) compared with the normal group.
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Discussion |
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In the present study of non-PCOS women, those with a high basal FSH level also had a poor response to stimulation and no pregnancy even after an extended stimulation with high dose of HMG (mean 1650 IU). By contrast those women with only moderately raised FSH levels generally responded satisfactorily to an average dosage regime though their pregnancy rate was low (5%). This may suggest that the remaining complement of oocytes have poor pregnancy potential even though the subjects were 'young'. Studies of PCOS women have found little influence of BMI on the response to ovulation induction (McClure et al., 1992). Dale et al. concluded that increased BMI in PCOS women was the only factor that they investigated that was associated with a decreased response to clomiphene administration (Dale et al., 1998
). In the present study about one quarter of the obese women and half of the thin women required an increase in HMG dosage to effect a satisfactory response. Clearly the extremes of BMI make the choice of the optimal dosage regime more difficult than in patients with a normal BMI. Normal BMI increases the success rate in OI while weight disturbances, especially overweight, have a deleterious effect (Chong et al., 1986
; Kably-Ambe et al., 1999
). Both thin and obese women utilized more HMG than others and required a longer duration of treatment but the eventual response was reasonable and the expectation of pregnancy was also satisfactory. The older women in this study with normal FSH levels and BMI responded well to gonadotrophin stimulation and the pregnancy rate was also as good as the normal group. Age per se (within the range in this study) did not seem to have an obvious adverse effect. This is in some contrast to COS where age was an important factor with excessive gonadotrophin dosage only resulting in a poor ovarian response and a reduced pregnancy potential (see below). The cancellation rate was 19% in the normal group, essentially to avoid multiple pregnancy rather than to avoid OHSS, which did not occur in the study population and has been rare in our OI programme. Cancellation for an excessive response was less likely in thin or obese women (11 and 3% respectively).
Controlled ovarian stimulation
The objective of gonadotrophin stimulation for COS has been to achieve an optimal ovarian response which is crucial to the efficiency of IVF procedures. The clinical features commonly associated with a poor or hyper response to stimulation, including age, BMI and moderately high FSH level, were studied in non-PCOS patients. Non-PCOS women constituted more than half the patients receiving COS in our programme. The older women with mean age of 42 years and the women with moderately high FSH (up to twice normal in the present study) were not considered post-menopausal in the clinical sense so both groups were not in extreme clinical situations. High FSH lead to a poor response to gonadotrophins in COS (Ebrahim et al., 1993) as reflected by the high cancellation rate due to hypostimulation. This rate was also influenced by a government policy of enforcing a 'stop or go' decision at day 9 for financial reimbursement purposes, nevertheless the clinical decision-making was similar for all the groups investigated. However, due to the large amount of HMG used, there was the potential for a hyper response as the high risk of OHSS suggested. Excessive stimulation in COS can lead to life-threatening clinical situations and therefore monitoring of the ovarian response is essential.
Increasing age is an important adverse factor and our policy of limiting access to IVF for women >43 years of age meant that there were fewer cycles in this group and limited statistical power to draw conclusions. Nonetheless, this group started with a higher gonadotrophin dose and used a greater total amount of HMG. Even so, this group still had 15% of the cycles cancelled due to poor response and among those responding, the response was poor in terms of maximum E2 and number of oocytes recovered. Since the mean FSH levels were higher in this group (6.7 nmol/l) than other groups except the moderately high FSH group, it could be that some form of mild incipient ovarian failure is present with no obvious clinical manifestation (Cahill et al., 1994). Roest et al. also found an increased rate of poor ovarian response in women >40 years of age but a proportion with a good response and with a satisfactory outlook for conception (Roest et al., 1996
). Overall there was no particularly consistent effect of BMI on the response to COS, a finding similar to that reported by Lewis et al. (Lewis et al., 1990
) and Lashen et al. (Lashen et al., 1999
). This result was contrary to that reported by Crosignani et al. (Crosignani et al., 1994
). Somewhat surprisingly, thin patients required more gonadotrophin (2628 IU) than obese women (2187 IU). The starting dose of gonadotrophin was similar for them. It should be noted that the response of thin patients was a little in excess of the obese women in terms of E2 levels (6.2 versus 5.6 nmol/l) and number of oocytes recovered (10.6 versus 9.1). The explanation for the need for more total gonadotrophin in thin women is not clear, since the best indicator of the need for gonadotrophin, namely the basal FSH level, was similar in both obese and thin women. Weight loss, even limited, has been shown to be effective in causing the recovery of ovulation or increasing response to gonadotrophin stimulation (Clark et al., 1995
).
Comparing the responses of the various groups with both OI and COS, some differences were apparent. In ovulation induction, patients with moderately high basal FSH responded well to gonadotrophin stimulation but with a poor chance of conception. Similar subjects under COS had a satisfactory (23%) pregnancy rate; perhaps this group would benefit from a slightly more aggressive gonadotrophin regime. For the thin group under COS, the amount of gonadotrophin used was not excessive and the response was also normal with adequate serum E2 levels, numbers of oocytes and embryos created although 15% of cycles were cancelled because of an excessive response. This was in contrast to thin women undertaking ovulation induction where no cycle was cancelled for a poor ovarian response. The obese subjects undertaking OI tended to respond poorly while similar patients under COS responded, by and large, normally and had a similar expectation of pregnancy as non-obese women. Generally BMI was not a significant factor in the response to either OI or COS but clinical management during the treatment cycle was clearly more demanding in both thin and obese subjects. The influence of age was also interesting. Older normogonadotrophic women of normal BMI undertaking OI appeared to present no particular special issue and responded normally. However similar women undertaking COS required excessive gonadotrophin (3128 IU) to reach an acceptable, albeit lower, response level. Since there was no overlapping of these two groups of patients this may indicate that the older ovary has less reserve to respond to the call for multiple follicles even though basal FSH levels are normal.
Although miscarriage rate and multiple pregnancy rate are important parameters in infertility treatment, due to the small sample size, they were not assessed here. This limitation in statistical power also meant that the interaction between these important clinical factors could not be properly studied.
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Conclusions |
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Non-PCOS patients undergoing COS with moderately high basal FSH responded normally with a normal pregnancy rate. Thin or obese patients generally responded normally and had a normal chance of conception. Older women who were normogonadotrophic and of normal BMI required a larger amount of gonadotrophin and achieved a less optimal ovarian response with a low expectation of conception.
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Acknowledgements |
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Notes |
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3 To whom correspondence should be addressed. E-mail: jim.wang{at}adelaide.edu.au
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References |
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Submitted on June 8, 2001; resubmitted on October 12, 2001; accepted on December 3, 2001.