Human Reproduction, Vol. 17, No. 8, 2016-2021,
August 2002
© 2002 European Society of Human Reproduction and Embryology
Ovarian response and pregnancy outcome related to mid-follicular LH levels in women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH stimulation
1 The Fertility Clinic, Skive Sygehus, DK-7800, Skive and 2 Laboratory of Reproductive Biology, Section 5712, University Hospital of Copenhagen, Copenhagen, Denmark
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Abstract |
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BACKGROUND: The effect of LH levels on stimulation day 8 on ovarian response and pregnancy outcome were evaluated in women receiving pituitary down-regulation with GnRH agonists (0.8 mg Suprefact® s.c. daily until pituitary down-regulation and 0.4 mg/day during ovarian stimulation) and ovarian stimulation with recombinant FSH. METHODS: Blood samples were prospectively collected from a total of 207 normal women undergoing assisted reproduction and analysed retrospectively. Based on LH levels on stimulation day 8 patients were divided into four groups: <0.5, 0.51–1.0, 1.01–1.5, >1.51 IU/l. RESULTS: Estradiol levels on day 8 and estradiol per oocyte retrieved showed a highly significant correlation with LH concentrations on day 8. The total consumption of exogenous FSH and duration of gonadotrophin stimulation was inversely related to LH levels on day 8 (P < 0.002). The frequencies of fertilization and clinical pregnancies were superior in the two middle groups. Only 12% of the patients showed LH levels <0.5 IU/l, which, however, may be explained by the particular mode and doses of GnRH agonist used. CONCLUSIONS: Circulating levels of LH on day 8 have a significant impact on ovarian response and pregnancy outcome. LH should neither be too high nor too low. The mode of administration and the dose of the GnRH agonist used may determine the number of women who experience LH levels below 0.5 IU/l.
Key words: GnRH agonist/IVF/luteinizing hormone/ovarian response/pituitary suppression
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Introduction |
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Normal follicular growth is controlled by pituitary secretion of FSH and LH. Both these hormones are essential for normal follicular estradiol biosynthesis as described by the two-cell two-gonadotrophin model (Falck, 1959
; Sasano et al., 1989). Luteinizing hormone stimulates androgen production in the theca cells, which the granulosa cells aromatize to estradiol under the action of FSH. During the mid-follicular phase granulosa cells acquire LH receptors in addition to the FSH receptors and both are of importance for the pre-ovulatory estradiol production and possibly for the production of competent oocytes (Hillier, 2001). It is well known that too high or too low levels of LH during the follicular phase may exert adverse effects on normal follicular maturation and the possibility of achieving pregnancy as observed in women with polycystic ovary syndrome (Homburg et al., 1988) and in women with hypogonadotrophic hypogonadism (Shoham et al., 1991; Balasch et al., 1995) respectively. Women with hypogonadotrophic hypogonadism can be stimulated to follicular development with FSH-alone preparations, but the estradiol depleted environment affects fertilization rates of retrieved oocytes (Balasch et al., 1995), and although one hypogonadotrophic hypogonadal woman obtained a pregnancy receiving stimulation with FSH alone, the pregnancy resulted in a miscarriage in the 8th week, and no births have been reported (Battaglia et al., 2000). As a consequence, a lower limit of LH activity which allows the establishment of a pregnancy does exist, but a precise limit has not yet been determined. In accordance with this, recent studies have indicated that a group of normogonadotrophic women undergoing ovarian stimulation with GnRH agonist and recombinant FSH (rFSH) or pure FSH may experience such profound suppression of levels of LH that a negative effect on treatment outcome becomes manifest (Fleming et al., 1996, 1998; Westergaard et al., 2000; Esposito et al., 2001). On the other hand, a number of studies do suggest that so-called resting levels of LH, as seen in women undergoing ovarian down-regulation with the use of GnRH agonists and stimulation with pure FSH preparations, are sufficient to support development and maturation of follicles and oocytes in normogonadotrophic women (Chappel and Howles, 1991; Daya et al., 1995; Loumaye et al., 1997), and one recent study showed no significant differences in either performance or clinical outcome among groups of patients with varying degrees of LH suppression (Balasch et al., 2001). The aim of this prospective study was to evaluate further ovarian response and pregnancy outcome in relation to mid-follicular LH levels after down-regulation with GnRH agonist and ovarian stimulation with rFSH and at the same time to approach the mechanisms, determining the residual LH activity in these women.
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Materials and methods |
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Patients and hormonal treatment
A total of 207 women undergoing IVF or ICSI treatment from September 2000 until June 2001 was included in this study. Patients fulfilling the following inclusion criteria were prospectively enrolled in a consecutive manner: (i) female age <40 years; (ii) baseline FSH <10 IU/l; (iii) standard hormonal treatment as follows: pituitary down-regulation with GnRH agonist (Suprefact®; Hoechst, Hørsholm, Denmark) 0.8 mg s.c. daily from the mid-luteal phase for between 12 and 20 days. After pituitary down-regulation, the dose of GnRH agonist was reduced to 0.4 mg s.c.daily and ovarian stimulation was initiated with rFSH (Gonal F®; Serono Nordic, Copenhagen, Denmark or Puregon®; Organon, Skovlunde, Denmark) using an individualized dose of between 100 IU and 375 IU s.c. per day according to age, ovarian volume, baseline FSH and body mass index (BMI). The ovarian response was monitored by ultrasound examination starting on day 8 of stimulation and the dose of FSH administered was adjusted if necessary. When at least three follicles had reached a diameter of
17 mm, 10000 IU of HCG (Profasi®; Serono Nordic) was administered to induce final follicular maturation. Oocyte retrieval was performed 35 h later by vaginal ultrasound-guided follicle aspiration. A maximum of two embryos was transferred on day 2, 3 or 5 after retrieval according to the number of good available embryos. Luteal phase support was given by daily vaginal administration of micronized progesterone, either 400 mg twice a day (Cyklogest®; Hoechst, Copenhagen, Denmark) or 90 mg once a day (Crinone® 8%; Serono Nordic) starting the day following oocyte retrieval and continuing until the day of pregnancy test (i.e. day 12 after embryo transfer). A positive pregnancy test was defined by a plasma ß-HCG concentration >10 IU/l. A clinical pregnancy was defined as an intrauterine gestational sac with a heartbeat 3 weeks after a positive HCG test. Implantation rate was calculated as the ratio of gestational sacs determined by ultrasound after 7 weeks in relation to the total number of embryos transferred. The Ethics Committee of Viborg County approved the study, and each patient gave written consent.
Blood samples and hormone assays
Blood samples were taken on stimulation days 1 and 8. Sera were immediately analysed for estradiol and aliquots frozen at –20°C for subsequent analysis of LH. LH was measured by time-resolved immunofluorometric assay, the AutoDelfia® hLH spec. kit (Wallac Oy, Turku, Finland). The assay was performed at the Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark in order to compare data with those of Westergaard, who used the same department and the same assay (Westergaard et al., 2000). The detection limit of the LH assay as given by the manufacturer is 0.05 IU/l and Department of Clinical Biochemistry, Odense found the intra- and interassay variation of samples containing 0.1–0.2 IU/l LH to be <3% (Westergaard et al., 2000). Estradiol was monitored in our laboratory using a Vidas® kit (bioMerieux, France) showing a detection limit of 33 pmol/l.
Statistical methods
Statistical differences were evaluated using analysis of variance (ANOVA), 
2 test or linear regression analysis as appropriate.
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Results |
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Based on LH measurements on cycle day 8, women were allocated to one of four groups, <0.5, 0.51–1.0, 1.01–1.5 and >1.51 LH IU/l respectively. The number of women in each group was 24, 108, 38 and 37 respectively, and the overall median value of LH was 0.86 IU/l. Thus, the frequency of women with LH levels <0.5 IU/l on day 8 was 12%, and 64% had <1.0 IU/l.
Patient characteristics for all patients as a whole, and divided into the four groups according to the LH levels of day 8, are shown in Table I. There were no differences among the groups regarding infertility diagnosis and number of previous IVF/ICSI attempts, and pre-treatment levels of FSH did not differ significantly (ANOVA, P > 0.10, not significant). Age and BMI did not differ among the groups (Table II).
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In contrast, consumption of FSH showed a significant inverse correlation with LH levels on day 8 (P < 0.002, r = 0.22). When the <0.5 IU/l group was compared with the >1.51 IU/l group, the mean consumption of FSH was reduced by 28%. The duration of gonadotrophin stimulation also showed a significant correlation with LH levels on day 8 (P < 0.001, r = 0.28). Levels of estradiol were significantly correlated to the level of LH on day 8 (ANOVA, P < 0.001). In addition, linear regression analysis of levels of LH on day 8 and levels of estradiol on day 8 from each patient showed a highly significant correlation (r = 0.55, P < 0.001). The estradiol level of day 8 per oocyte aspirated showed a similar significant correlation to levels of LH on day 8 (P < 0.001, r = 0.42).
The number of retrieved oocytes gradually increased from 8.7 ± 1.0 in the group with LH levels <0.5 IU/l to 10.4 ± 0.9 in the group with LH levels >1.51 IU/l, however, this difference did not reach statistical significance (Table III). The number of fertilized oocytes and the frequency of fertilization were significantly higher in the two middle groups as compared with the two flanking groups. The number of positive pregnancy tests was similar in the <0.5, 0.51–1.0 and in the 1.01–1.5 IU/l group, whereas the number was significantly reduced in the >1.51 IU/l group compared with the two middle groups. The number of clinical pregnancies was significantly lower in the >1.5 IU/l group compared with the 0.51–1.0 IU/l group, whereas the 1.01–1.5 IU/l group reached a level of significance between 0.05 and 0.1. The implantation rate of embryos from the <0.5 IU/l group was significantly increased compared with the >1.51 IU/l group (P < 0.05), whereas the implantation rate of embryos from the two middle groups did not differ significantly from the two flanking groups. Similar pregnancy rates were observed when the median LH level on day 8 (i.e. 0.86 IU/l) was used to create a low and a high LH group (data not shown).
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When median levels of estradiol on day 1 (i.e. 0.08 nmol/l) and day 8 (i.e. 1.92 nmol/l) were used to create two groups with high and low estradiol levels, pregnancy rates were similar on both days of estradiol measurement. When the low and high estradiol groups were further divided according to the median LH level (i.e. 1.14 IU/l on day 1 and 0.86 on day 8), thus creating a total of four groups (e.g. day 8, group 1: estradiol <1.92 nmol/l plus LH <0.86 IU/l; group 2: estradiol <1.92 nmol/l plus LH >0.86 IU/l; group 3: estradiol >1.92 nmol/l plus LH <0.86 IU/l; group 4: estradiol >1.92 nmol/l plus LH >0.86 IU/l), no differences in pregnancy rates were observed.
When the median number of oocytes retrieved (i.e. 9.0 oocytes) was used to create two groups with a high and low number of oocytes, pregnancy rates in these two groups were similar (45.3 versus 52.0%).
The pregnancy outcome correlated to the level of LH on day 8 is shown in Table IV. No statistical difference was observed in relation to early pregnancy loss and the level of LH on day 8.
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Discussion |
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In the present study <12% of the women experienced LH levels <0.5 IU/l on day 8 of stimulation. This figure is substantially lower than the one obtained in a previous study in which 48% of the women reached LH levels <0.5 IU/l on stimulation day 8 (Westergaard et al., 2000
). This difference was observed despite a number of similarities between the two studies: (i) both used the long GnRH agonist protocol employing s.c. injections of GnRH agonist (i.e. buserelin) and rFSH; (ii) the assay used to monitor LH was identical between the two studies; (iii) the LH assay was performed by the same independent laboratory; (iv) patient characteristics and time of blood collection were similar. Despite these similarities, especially concerning LH monitoring, the median level of LH increased from 0.52 IU/l in the study of Westergaard et al. (2000) to 0.86 IU/l in the present study. The different numbers of women experiencing profound LH suppression highlights one of the important questions of the current debate on the impact of LH during ovarian stimulation; how large a fraction of normogonadotrophic women will actually experience LH levels so low that the outcome is affected? In fact, the present study suggests one new aspect. In the study of Westergaard et al. (2000) administration of GnRH agonist (i.e. buserelin) was performed with 0.5 mg s.c. per day until pituitary desensitization was achieved and then reduced to 0.2 mg s.c. per day during ovarian stimulation. In the present study 0.8 mg per day was used until pituitary desensitization was achieved and after this the dose was reduced to 0.4 mg per day. Therefore, during the course of ovarian stimulation the amount of buserelin administered was twice as high in our study compared with Westergaard et al. (2000). GnRH agonists are characterized by their pituitary desensitization effect, but they also cause receptor activation leading to a stimulatory effect. At these low levels of LH, the stimulatory effect may actually be of importance and may account for the substantial difference in median LH levels observed in the two studies. Earlier studies give support to this hypothesis, since a profound fall in LH levels was observed when the GnRH agonist leuprolide acetate was discontinued after 5 days of administration compared with a continued administration (Sungurtekin and Jansen, 1995). In addition to the amount of GnRH agonist used, a recent study showed that ovarian response and pregnancy rates correlated to the mode of GnRH agonist administration (Westergaard et al., 2001). Intranasal administration of buserelin resulted in significantly less depressed levels of mid-follicular LH levels and higher pregnancy rates as compared with s.c. administration. Taken together, the precise administration of GnRH agonist has to a large extent been neglected previously which might explain the variation in treatment outcome by apparently similar regimes. In addition, it may explain the difference in residual LH levels as reported in a number of previous studies (Westergaard et al., 1996, 2001; Loumaye et al., 1997; Filicori et al., 1999). The present study emphasizes the importance of the amount and the mode of GnRH agonist administration for the mid-follicular LH levels.
Residual levels of LH on stimulation on day 8 were found to have a significant impact on the ovarian response in GnRH agonist treated women receiving rFSH. Estradiol production on day 8 and levels of estradiol on day 8 per oocyte retrieved correlated positively to LH levels on day 8 suggesting that follicles exposed to the highest levels of LH were the most steroidogenically active on day 8. This supports other findings (Phelps et al., 1999; Filicori et al., 1999); in the latter study GnRH agonist down-regulated women receiving exogenous HCG in combination with rFSH developed a stronger estradiol response compared with those who did not receive HCG, suggesting that availability of androgen substrate was a major determinant for estradiol output in follicles approaching ovulation. The present data are also in accordance with a recent preliminary report (Fanchin et al., 2001), which defined two groups based on LH measurements on days 6 and 9 (LH levels being consistently higher or lower than 2 IU/l). Higher peak estradiol concentrations were found in the high LH group compared with the low LH group. Other studies have shown that exogenous administered LH activity, either in the form of LH or HCG, has a positive effect on the estradiol output (The European Recombinant Human LH Study Group, 1998; Westergaard et al., 2001).
Consumption of FSH also showed a significant inverse relationship with LH levels on day 8 resulting in a reduction of 28% when comparing the low LH group (i.e. <0.5 IU/l) with the high LH group (i.e. >1.51 IU/l). The circulating LH in the present study was derived from endogenous stores, but in combination with the results of others (Filicori et al., 1999, 2001), who used exogenous gonadotrophins, this suggests that LH plays a significant role in the development of pre-ovulatory follicles. We also found a significant shortening of the duration of ovarian stimulation and an acceleration of follicle development, in accordance with other observations (Filicori et al., 1999, 2001; Fanchin et al., 2001). This is in contrast to Westergaard, who found that the duration of ovarian stimulation was unrelated to the administration of exogenous LH and HCG (Westergaard et al., 2001).
Although the actual number of oocytes retrieved did not differ significantly among the four groups, the quality of the retrieved oocytes seemed to be affected by the LH levels on day 8. The number and the frequency by which they underwent fertilization was significantly correlated to LH levels; the two middle groups (i.e. LH levels between 0.51–1.0 and 1.01–1.5 IU/l) perform significantly better than the two flanking groups. This contrasts with the findings of Fanchin et al. (2001), who found significantly higher numbers of oocytes, and significantly higher numbers of embryos plus a significantly higher pregnancy rate in the group of women with LH measurements >2 IU/l on both days 6 and 9 compared with the group of women in which both LH measurements were <2 IU/l. The study by Fleming also found a significantly increased number of fertilized oocytes and supernumerary embryos per case in the group of women with mid-follicular LH above 0.5 IU/l compared with those below (Fleming et al., 1998). This difference is not readily explainable, but may relate to the different mode of pituitary down-regulation or to the definitions of more groups in the present study.
Taken together, there are now substantial data to suggest that LH activity, derived from either endogenous stores or administered exogenously, in GnRH agonist treated women has a significant impact on the ovarian response during ovarian stimulation.
The present study was unable to demonstrate differences in pregnancy outcome when median LH levels on day 8 was used to create two groups. However, dividing data into four groups, we found that LH levels between 0.51 and 1.5 IU/l (i.e. the two middle groups) exhibit the best chances of a pregnancy, whereas LH levels >1.5 IU/l and <0.5 IU/l show a reduced frequency (i.e. the two flanking groups). This suggests that the two middle groups experience sufficient LH to sustain pregnancy. The low LH group tended to show a reduced pregnancy rate, but this group represented too few cases to draw any conclusions regarding pregnancy outcome and early pregnancy loss. However, the frequency of early pregnancy loss did not seem to correlate to the LH levels on day 8. It is remarkable that pregnancy outcome is significantly reduced in the group of women with LH day 8 >1.5 IU/l compared with the 0.51–1.0 group. This is in contrast to other studies which found superior pregnancy rates in the high LH group when the median LH level is used to create two groups (Phelps et al., 1999; Fanchin et al., 2001; Westergaard et al., 2001). In addition, this group is relatively small and other studies are needed to confirm the findings. However, the results may suggest that a relatively low `ceiling level' of LH actually does exist; or perhaps more likely, that this group of women experiences other endocrinologically related fertility problems.
The present study uses a single measurement of LH on day 8 to correlate ovarian response and pregnancy outcome. A more detailed LH monitoring during the day and over time could provide more detailed information, since it cannot be excluded that short-term, intra-patient variations of LH secretion occur and that LH levels may vary during FSH treatment. However, the significant correlation between estradiol and LH levels day 8 suggests that a single measurement in fact provides a good measure for the residual LH activity present during the follicular phase. Further, it should be emphasized that the present study is unable to show whether LH is the mediator of outcome or a marker. An important question for future studies to address should therefore be the exact role of LH in affecting outcome.
In conclusion, the present study suggests for the first time that the regime and the dose of GnRH agonist in connection with ovarian stimulation have an important effect on the residual LH activity in circulation. In addition, the concentrations of LH during the course of ovarian stimulation should remain in the middle range and neither become too low nor too high in order to secure the best chance for a successful treatment.
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The assistance of study nurse Alice Mikkelsen, laboratory technicians and other nurses is gratefully acknowledged.
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3 To whom correspondence should be addressed. E-mail: peter.humaidan{at}vibamt.dk
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References |
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Submitted on October 15, 2001; resubmitted on February 20, 2002; accepted on May 2, 2002.
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E.M. Kolibianakis, K. Zikopoulos, J. Schiettecatte, J. Smitz, H. Tournaye, M. Camus, A.C. Van Steirteghem, and P. Devroey Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF Hum. Reprod., November 1, 2004; 19(11): 2490 - 2496. [Abstract] [Full Text] [PDF]
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J. Penarrubia, F. Fabregues, M. Creus, D. Manau, R. Casamitjana, M. Guimera, F. Carmona, J. A. Vanrell, and J. Balasch LH serum levels during ovarian stimulation as predictors of ovarian response and assisted reproduction outcome in down-regulated women stimulated with recombinant FSH Hum. Reprod., December 1, 2003; 18(12): 2689 - 2697. [Abstract] [Full Text] [PDF]
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