Human Reproduction, Vol. 16, No. 9, 1875-1879,
September 2001
© 2001 European Society of Human Reproduction and Embryology
Rescue of IVF cycles by HMG in pituitary down-regulated normogonadotrophic young women characterized by a poor initial response to recombinant FSH
1 Dipartimento Clinico di Emergenza Ostetrica, Ginecologica e Medicina della Riproduzione, Area Funzionale di Medicina della Riproduzione ed Endoscopia Ginecologica, Università degli Studi di Napoli `Federico II', Naples, 2 Istituto di Clinica Ginecologia, II Università di Napoli, Largo Madonna delle Grazie, 80128 Naples and 3 Centre for Reproductive Biology Clinica Villa del Sole,Via Manzoni, 15, 80126 Naples, Italy
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Abstract |
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BACKGROUND: The aim of this study was to investigate the effects of adding human menopausal gonadotrophin (HMG) during controlled ovarian stimulation in normoovulatory normogonadotrophic patients showing an initial suboptimal response to a standardized long protocol therapy with recombinant FSH (rFSH) (300 IU/day). METHODS: A total of 43 such patients were randomized in two groups. In Group A, 150 IU rFSH was substituted by 150 IU HMG after day 8 of stimulation. The stimulation protocol of Group B involved a simple increase of the daily rFSH dose to 375 IU after day 8. A total of 40 BMI and age matched patients with an optimal ovarian response formed the control group (Group C). RESULTS: The mean Group A serum concentration of oestradiol on the day of HCG administration and average number of oocytes retrieved were significantly higher than Group B (P < 0.001) and equivalent to Group C. A total of 10 pregnancies (50%) in Group A, 8 (34.8%) in Group B and 19 (47.5%) in the control group were achieved. CONCLUSIONS: The data suggest that LH supplementation improves the ovarian outcome in patients characterized by an inadequate initial response to rFSH therapy in a long protocol.
Key words: gonadoptrophin/human oocyte/luteinizing hormone/pituitary/poor responders
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Introduction |
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Theories of human folliculogenesis classically follow the two cell, two gonadotrophin theory which suggests that both FSH and LH are required for folliculogenesis in humans (Fevold, 1941
; Short, 1962; Filicori, 1999; Lèvy et al., 2000). FSH is necessary throughout the gonadotrophin-regulated phase of follicular development. Because of the FSH stimulus, LH receptors and aromatase activity are acquired by granulosa cells (Erickson and Hsueh, 1978). LH is needed for the biosynthesis of androgens, which are the substrate for aromatase activity, mainly during the middle–late follicular phase (Schoot et al., 1992). Apart from the classically established role for LH during this phase, hypotheses that are more controversial suggest that a small amount of LH activity is required throughout folliculogenesis (Lèvy et al., 2000).
The evidence for the role of LH during the early phases of folliculogenesis is difficult to establish unequivocally (Lèvy et al., 2000). However, several lines of evidence point to the hypothesis. The use of high concentrations of gonadotrophin-releasing hormone (GnRH) antagonist in combination with recombinant FSH (rFSH) produces a dose-dependent decline in serum oestradiol during stimulation, oocyte retrieval and pregnancies, together with an increase in abortions, suggesting that FSH alone is not sufficient for folliculogenesis (The Ganirelix dose-finding study group, 1998). Furthermore, the ovarian response to controlled ovarian stimulation (COH) with rFSH is often reduced in women who required prolonged GnRH agonist treatment to achieve down-regulation, with a subsequently profound suppression of endogenous gonadotrophins (Fleming et al., 1998; Ravhon et al., 2000), although normal folliculogenesis has also been reported in some patients (Couzinet et al., 1988; Ben-Chetrit et al., 1998). In addition, a less profound pituitary down-regulation was achieved with the GnRH-agonist short protocol (Tasdemir et al., 1996), and low dose GnRH-agonist protocols seem to improve the outcome in patients stimulated by rFSH with a known poor response to the `long protocol' (Feldberg et al., 1994; Olivennes et al., 1996; Surrey and Schoolcraft, 2000), again suggesting that FSH alone is not sufficient for efficient folliculogenesis and oogenesis.
Pituitary down-regulation with GnRH agonist prior to COH with exogenous gonadotrophins [GnRH agonist `long protocol' (Hughes et al., 1992)] is a well established protocol for the treatment of many patient groups undergoing cycles of IVF. In young, normogonadotrophic women this protocol is the most commonly adopted COH protocol for IVF stimulation cycles worldwide (Tan et al., 1992; Filicori, 1996). According to the two cell, two gonadotrophin theory, the low concentrations of serum LH are sufficient to support follicular and oocyte development when the `long protocol' is used with urine-derived highly purified FSH or rFSH (Loumaye et al., 1997; Sills et al., 1999). However, in a subset of patients, the ovarian response to this protocol is suboptimal. This may be due to low LH activity caused either by low serum concentrations of LH (Noci et al., 1998; Ludwig et al., 1999) or low LH bioactivity (Schroor et al., 1999). Patients characterized by a poor response to the classical `long protocol' may benefit from the use of LH-containing gonadotrophin preparations (The European Recombinant Human LH Study Group, 1998; Laml et al., 1999; Fleming et al., 2000; Lèvy et al., 2000; Westergaard et al., 2000). However, excessive concentrations of LH during folliculogenesis can also be detrimental (Chappel and Howles, 1991; Yamashita et al., 1996; Liu et al., 2000), suggesting that the use of LH should be carefully controlled. In this study, we tested whether the addition of HMG during mono-therapy with rFSH improved the IVF outcome of normo-ovulatory normogonadotrophic, pituitary down-regulated patients characterized by a poor ovarian response to rFSH. We established criteria for the use of LH-containing preparations during COH protocols for IVF and show that these protocols, when applied to patients at risk of cycle cancellation during the `long protocol', increase the outcome significantly more than a simple increase of the FSH dose. The data establish the need for LH supplementation in specific patient groups, despite the lack of a priori indications.
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Materials and methods |
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Patient selection
All patients undergoing their first intracytoplasmic sperm injection (ICSI) attempt between November 1999 and July 2000 were considered for the present study. All of them underwent clinical and biochemical assessments for metabolic, autoimmune, infectious and genetic disorders. Only subjects with menstrual cycles in the range of 24–35 days (intra-individual variability ± 3 days), and with hysteroscopic evidence of a normal uterine cavity were enrolled. Exclusion criteria were: elevated basal FSH concentrations (bFSH>10 IU/l); age
37 years; body mass index [BMI = weight (kg)/height (m2)] >29; biochemical and/or ultrasound evidence of polycystic ovarian syndrome; stage III–IV endometriosis; autoimmune, thyroid, and chromosomal abnormalities; presence of only one ovary. A total of 92 subjects were enrolled. The study protocol was approved by the Department's Ethics Committee and a consent form was signed by all the patients before entering the study.
Ovarian stimulation protocols
Pituitary desensitisation was induced with triptorelin (Decapeptyl 3.75 depot; Ipsen SpA, Milan, Italy) on the first day of the menstrual cycle. After 15 days, pituitary suppression was assessed by measuring serum oestradiol and LH concentrations; endometrial and ovarian status was also assessed by trans-vaginal ultrasound. If the concentration of serum oestradiol was 
0.15 pmol/ml, serum LH was 1.5 IU/l, the thickness of the endometrium was 5 mm, and follicular development appeared to be arrested, then gonadotrophin administration was started. Patients with delayed suppression were excluded from the study. A fixed dose of 150 IU of rFSH (Gonal-F; Serono Pharma, Rome, Italy) was administered s.c. twice daily (at 8:00 am, and between 6:00 and 8:00 pm), as per our clinic routine. Serum oestradiol concentrations were measured and follicular growth was monitored with ultrasound on the fifth and the eighth day of the stimulation and thereafter on alternate days until HCG was administered. On the fifth day of stimulation, serum oestradiol was measured at 8:00 am and the evening rFSH dose was reduced to 75 IU in patients whose concentrations were >0.6 pmol/ml. On the eighth day of stimulation, patients with serum oestradiol concentrations 0.6 pmol/ml and ultrasound evidence of no follicles with a mean diameter >10 mm were randomized into two groups using random number tables (Figure 1). In Group A (n = 20; mean age ± SD = 31.6 years ± 3.8), the evening rFSH dose was substituted by 150 IU of HMG (Menogon; Ferring S.p.A., Milan, Italy, see Figure 1). The stimulation regime of Group B (n = 23; mean age = 30.4 ± 3.8) involved the increase of the evening rFSH dose to 225 IU (total rFSH daily dose 375 IU, Figure 1). Patients characterized by a tripling of serum oestradiol concentrations between days 5 and 8 and >4 follicles >10 mm in diameter on day 8 constituted Group C (control group; n = 40; mean age = 30.1 ± 3.5, see Figure 1). Nine patients with 1–4 follicles of diameter >10mm on day 8 were outside the criteria for inclusion in Groups A, B, or C and were therefore excluded from the present study. COH cycles were cancelled when <5 follicles of 12 mm in diameter were observed on day 12 of stimulation. When 3 follicles measured at least 17 mm in diameter, HCG (Profasi; Serono Pharma) was administered. Oocytes were retrieved by trans-vaginal ultrasound-guided aspiration 35 h after the HCG injection. Patients began 50 mg/day i.m. progesterone supplementation (Prontogest; AMSA S.r.l., Rome, Italy) on the day of oocyte retrieval.
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Hormone measurement
Serum concentrations of oestradiol and LH were measured using an enzyme-linked fluorescent assay (ELFA) technique (Vidas oestradiol II and Vidas LH respectively; BioMérieux sa, Lyon, France). The detection limits, defined as the lowest concentration which is significantly different from zero with a probability of 95%, were 0.03 pmol/ml for oestradiol and
0.1 mUI/ml for LH. The intra- and interassay coefficients of variation (CV) were <8%. Serum FSH was determined by an immunometric assay based on enhanced luminescence (Amerlite FSH assay; Amersham International plc, Amersham Pharmacia Biotech, Little Chalfont, Buckinghamshire, UK). The detection limit was 0.5 IU/l. The intra- and interassay CVs were <7.5%.
Statistical analysis
The results are reported as the mean ± SD. Data were analysed with the Statistica `98 version 5.1 statistics package (Stat. Soft. Inc., Tulsa, USA). One way analysis of variance (ANOVA) was used to determine the effect of the stimulation protocol on continuous variables. The post hoc Fisher least-significant-difference (PLSD) method was used to assess differences between groups. 
2 statistics were used to compare discontinuous data. P < 0.05 was considered significant. The Mann–Whitney U-test was applied to test the significance of non-parametric distributions.
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Results |
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In the present study, 83 IVF cycles were analysed. The two study groups and the control population were comparable for age, BMI, basal serum FSH and LH concentrations, and serum LH after pituitary suppression. Mean duration of infertility and indication for IVF were also similar in the two groups (Table I
). No statistically significant differences were observed in the mean stimulation length (in days) between the two study groups (14.85 ± 1.60 Group A versus 15.17 ± 1.11 Group B, Table II). However, a significantly lower mean stimulation length (11.65 ± 1.29) was observed in the control population when compared with both Groups A and B (P < 0.001, Table II). In Group A, the mean number of ampoules of HMG utilized was 12.85 ± 3.15 (Table II) and the total number of ampoules was 56.20 ± 6.96; the latter did not statistically differ from the total number of ampoules administered to patients in Group B (Table II). The number of ampoules used in the control group (Group C) was significantly inferior to both Groups A and B (Table II).
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The group of patients receiving HMG (Group A) had significantly higher mean serum oestradiol concentrations than Group B on the day of HCG administration (7.83 ± 2.79 versus 4.29 ± 1.66 pmol/ml, P < 0.001, Table II
). Furthermore, the average number of oocytes retrieved (11.30 ± 6.91 versus 5.87 ± 2.32) was also significantly higher in Group A (P < 0.001, Table II). Interestingly, the results in Group A were similar to those observed in the control group (Group C, Table II). We achieved 10 pregnancies (50%) in Group A, 8 (34.78%) in Group B and 19 (47.5%) in Group C. Furthermore, we noted a trend towards a higher abortion rate in Group B (Table II), although we could not test for significance because of the small number of patients involved. |
Discussion |
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The introduction of rFSH has brought about an improvement in the number of oocytes retrieved during COH, greater overall success rates and a lowering of reported cases of OHSS during cycles of IVF (Hedon et al., 1995
; Aboulghar et al., 1998; Out et al., 1998). However, the advantages of rFSH have not yet improved the outcome in a subset of patients that remain difficult to treat for IVF. Urinary gonadotrophin preparations, traditionally used in COH protocols for IVF, unavoidably contain an inherent bioactivity of LH. This bioactivity has previously been thought to be disadvantageous during COH because of the reported negative effects of LH on oocyte quality (Chappel and Howles, 1991; Liu et al., 2000). With the introduction of rFSH, the bioactivity of LH has been eliminated from FSH preparations. The present data suggests that the lack of LH becomes a critical factor for the outcome in some patients. The protocol outlined in the present data furthermore provides a test for the use of LH during COH.
We have tested whether LH supplementation during COH, as opposed to increasing the daily rFSH dose, can improve the outcome in normo-ovulatory normogonadotrophic patients characterized by a poor initial response after rFSH treatment. We showed that the use of LH-containing preparations caused an increase in success rates that matched the control group, i.e. normoresponders. A simple augmentation of the FSH daily dose, although rescuing the COH cycle, did not result in success rates equivalent to normoresponders, strongly suggesting that LH supplementation was necessary in these cases. Two hypotheses may explain these data. Firstly, LH concentrations after pituitary suppression in these patients may be unable to sustain multiple follicular growth. Secondly, the bioactivity of LH in some groups of patients could be subnormal. Examples of reduced LH bioactivity caused by the presence of different isoforms or altered subunits of this hormone have been reported in the literature (Huhtaniemi et al., 1999; Jiang et al., 1999; Ropelato et al., 1999). Whether reduced LH bioactivity is an indication for infertility in patients with normal serum LH concentrations has not yet been tested.
We examined whether a cut-off value of serum LH able to sustain multiple follicular growth existed by measuring serum LH on day 1 of stimulation (after pituitary suppression). However, we did not find any statistically significant differences between the three groups (see Table I). Our results suggest a small trend to lower LH suppression concentrations in the two study groups. If the first hypothesis proposed above is correct, LH concentrations may decrease to the critical value during COH, showing significant differences only on the eighth day of stimulation. In the present work, this hypothesis does not appear to be supported by the data. In the patients where serum LH concentrations were tested on day 8 of stimulation, no significant differences were found (see Table I). If the immunoreactive concentrations of LH are not correlated with the requirement for LH during folliculogenesis suggested by the present data, the bioactivity of LH may play a role. Although immunoreactive LH and bioactive LH concentrations are correlated, differences are often observed (Schroor et al., 1999). We suggest that the combination of low serum LH and low LH bioactivity in certain patient groups may be the cause of the inadequate response to COH where rFSH is used alone.
In conclusion, our data demonstrates that LH supplementation in a subset of patients with an initial poor response to rFSH therapy can rescue COH cycles, increase the number of oocytes retrieved and increase peak oestradiol concentrations significantly more than a simple increase of the daily rFSH dose. The availability of recombinant LH will enable a greater degree of control over the LH dosage during COH without modifying the dosage of rFSH. It is not currently possible to establish an a priori indication for this protocol, however the protocol described in the present report is highly efficient in the rescue of COH cycles where day 8 indications otherwise suggest a poor outcome.
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4 To whom correspondence should be addressed. E-mail: calviggi{at}hotmail.com
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References |
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Submitted on December 29, 2000; accepted on June 14, 2001.
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