Half-dose depot triptorelin in pituitary suppression for multiple ovarian stimulation in assisted reproduction technology: a randomized study

BACKGROUND: Pituitary suppression by depot GnRH agonist may be excessive for ovarian stimulation in assisted reproduction technology. This study compares the efficacy of standard and half-dose depot triptorelin in a long protocol. METHODS: A total of 180 patients were randomized into two groups using sealed envelopes. Pituitary desensitization was obtained in group 1 (90 patients) with half-dose (1.87 mg) triptorelin depot in the mid-luteal phase of their menstrual cycle, and in group 2 (90 patients) with full-dose (3.75 mg) triptorelin. RESULTS: There was no premature LH surge, with LH levels being lower in the full-dose group (1.04+/-0.05 versus 0.7+/-0.06 IU/l on the day of hCG). The number of FSH ampoules used was lower in group 1 (42+/-2 versus 59+/-3). The numbers of mature oocytes (10.1+/-0.54 versus 7.4+/-0.55), of fertilized oocytes (8.24+/-0.35 versus 6.34+/-0.37) and of embryos (7.8+/-0.36 versus 5.9+/-0.37) were significantly higher in group 1. No significant differences were found in pregnancy (38.8 versus 25.3%), implantation (22.6 versus 13.8%) or abortion (6.1 versus 5.0%) rates. Cumulative pregnancy (fresh plus frozen embryo transfers: 56.8 versus 35.4%) rate was significantly higher in group 1. CONCLUSION: A half-dose of depot triptorelin can be successfully used in ovarian stimulation for IVF and produce a higher number of good quality embryos with a good chance of implantation.     

A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI

BACKGROUND: A prospective randomized study was carried out in two centres to compare the number of oocytes retrieved after two different starting doses of recombinant human FSH (rhFSH) (Gonal-F) in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) cycles using the multiple dose regimen of the gonadotrophin-releasing hormone (GnRH) antagonist cetrorelix (Cetrotide) to prevent induction of the premature LH surge. METHODS: Sixty women were randomized to receive rhFSH 150 IU ('low'), and 60 women to receive rhFSH 225 IU ('high') as the starting dose for the first 5 days of stimulation. From stimulation day 6 and onwards, including the day of human chorionic gonadotrophin (HCG) administration, the women received 0.25 mg of cetrorelix as a daily dose. The primary endpoint was the number of oocytes retrieved. RESULTS: The mean number (+/- SD) of oocytes was 9.1 +/- 4.4 and 11.0 +/- 4.6 in the 'low' and 'high' groups respectively (P = 0.024). The mean number of 75 IU ampoules of rhFSH was significantly lower in the 'low' group (23.0 +/- 6.3 versus 30.5 +/- 5.6, P < 0.0001). The ongoing pregnancy rate per started cycle and per embryo transfer were 25.9 and 28.8% versus 25.4 and 26.8% respectively in the 'low' and 'high' rhFSH groups (P = NS). CONCLUSIONS: When using a starting dose of 225 IU rhFSH combined with the multiple dose of 0.25 mg cetrorelix from stimulation day 6, significantly more oocytes were obtained than with a starting dose of 150 IU rhFSH.     

A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists

BACKGROUND: Eliciting an endogenous LH surge by GnRH-agonist for the induction of final oocyte maturation may be more physiological compared with the administration of HCG. However, the efficacy of this intervention in patients treated for IVF with GnRH antagonists remains to be assessed. METHODS: 106 patients were randomized to receive either 10 000 IU urinary HCG or 0.2 mg Triptorelin for triggering final oocyte maturation. Ovarian stimulation for IVF was performed with a fixed dose of 200 IU recombinant FSH and GnRH antagonist was started on stimulation day 6. Luteal phase was supported with micronized vaginal progesterone and oral estradiol. The study was monitored continuously for safety and stopping rules were established. RESULTS: No significant differences were present in the number of cumulus-oocyte complexes retrieved, in the proportion of metaphase II oocytes, in fertilization rates or in the number and quality of the embryos transferred between the two groups. However, a significantly lower probability of ongoing pregnancy in the GnRH agonist arm prompted discontinuation of the trial, according to the stopping rules established (odds ratio 0.11; 95% confidence interval 0.02-0.52). CONCLUSIONS: Lower probability of ongoing pregnancy can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing ovarian stimulation for IVF with GnRH antagonists.     

Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial

BACKGROUND: In approximately 12-14% of young normogonadotrophic women treated with a depot GnRH agonist long protocol, the initial ovarian response to recombinant human FSH (rFSH) can be suboptimal. We have tested the hypothesis that these women may benefit from recombinant human LH (rLH) supplementation in a multicentre, prospective, randomized trial compared with patients treated with an rFSH step-up protocol. METHODS: A total of 260 young normogonadotrophic women undergoing controlled ovarian stimulation with a GnRH agonist long protocol for IVF/ICSI were enrolled. The starting dose of rFSH was 225 IU. One hundred and thirty patients with serum estradiol levels <180 pg/ml and with at least six follicles with a mean diameter >5 mm but none >10 mm on both day 5 and day 8 of stimulation were randomly allocated to two groups. From the eighth day of stimulation, women in group A (n=65) received 150 IU of rLH in addition to rFSH, while those in group B (n=65) had an increase of 150 IU in the daily dose of rFSH (step-up protocol). One hundred and thirty normally responding women continued monotherapy with rFSH and served as a further control population (group C). RESULTS: The mean number of cumulus-oocyte complexes retrieved in group A (9.0+/-4.3) was significantly higher (P<0.01) compared with group B (rFSH 6.1+/-2.6) but significantly lower compared with group C (10.49+/-3.7, P<0.05). Implantation and pregnancy rates were significantly lower (P<0.05) in the rFSH step-up group (10.5 and 29.3% respectively) when compared with normal responders (18.1 and 47.3% respectively). CONCLUSIONS: rLH supplementation is more effective than increasing the dose of rFSH in terms of ovarian outcome in patients with an initial inadequate ovarian response to rFSH alone.     

Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol

BACKGROUND: Suppression of endogenous LH production by mid-follicular phase GnRH-antagonist administration in controlled ovarian hyperstimulation protocol using recombinant (rec) FSH preparations void of LH activity may potentially affect ovarian response and the outcome of IVF treatment. The present study prospectively assessed the effect of using a combination of recFSH and recLH on ovarian stimulation parameters and treatment outcome in a fixed GnRH-antagonist multiple dose protocol. METHODS: 127 infertile patients with an indication for IVF or ICSI were recruited and randomized (using sealed envelopes) to receive a starting dose of either 150 IU recFSH (follitropin alpha) or 150 IU recFSH plus 75 IU recLH (lutropin alpha) for ovarian hyperstimulation. GnRH-antagonist (Cetrorelix) 0.25 mg was administered daily from stimulation day 6 onwards up to and including the day of the administration of recombinant HCG (chorion gonadotropin alpha). Gonadotropin dose adjustments were allowed from stimulation day 6 onwards, HCG was administered as soon as three follicles > or =18 mm were present. The primary outcome parameter was treatment duration until administration of HCG. RESULTS: Exogenous LH did not shorten the time necessary to reach ovulation induction criteria. Serum estradiol (E(2)) and LH levels were significantly higher on the day of HCG administration in the recLH-supplemented group (1924.7 +/- 1256.4 vs 1488.3 +/- 824.0 pg/ml, P < 0.03), and 2.1 +/- 1.4 vs 1.4 +/- 1.5 IU/l, P < 0.01, respectively). CONCLUSIONS: Except for higher E(2) and LH levels on the day of HCG administration, no positive trend in favour of additional LH was found as defined by treatment outcome parameters.     

Depot versus daily administration of GnRH agonist protocols for pituitary desensitization in assisted reproduction cycles: a Cochrane Review

This paper is based on a Cochrane review published in The Cochrane Library, issue 4, 2002 (see www.CochraneLibrary.net for information) with permission from The Cochrane Collaboration. Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review. BACKGROUND: GnRH agonists have been widely used in cycles of IVF. There are two types of GnRH agonist administration that can be used to lead to hypophysis desensitization in IVF cycles in the long protocol: one consisting of daily low doses of GnRH agonist and the other the administration of analogues in higher, long-acting doses (depot). The objective of this study is to compare the use of a single long-acting depot dose with that of daily GnRH agonist doses in IVF cycles. METHODS: Relevant randomized controlled trials were identified by electronic search of the following databases: MEDLINE, EMBASE, LILACS (Latin American and Caribbean Center on Health Sciences Information) and the Cochrane Controlled Trials Register. Six studies, with a total of 552 women, were included and analysed. RESULTS: The studies do not indicate that there is a statistically significant difference between the use of depot GnRH agonist and of daily GnRH agonist in the primary outcome, clinical pregnancy rates per woman [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.65-1.37]. However, there was sufficient evidence showing that the use of depot GnRH agonist for pituitary desensitization in IVF cycles increased the number of gonadotrophin ampoules [weighted mean difference (WMD) 3.30, 95% CI 1.27-5.34] and the duration of the ovarian stimulation (WMD 0.56, 95% CI 0.31-0.81), as compared with the use of daily GnRH agonist. CONCLUSIONS: Although we recognize that the clinical pregnancy rates per woman are not the ideal primary outcome, we found no evidence of differences between the long protocols using depot or daily GnRH agonist for IVF cycles. However, the use of depot GnRH agonist is associated with increased requirements for gonadotrophins and a longer time needed for ovarian stimulation. If these differences could be shown to translate into economic benefit, depot GnRH agonist would increase the overall costs of IVF treatment.     

A comparison of three gonadotrophin-releasing hormone analogues in an in-vitro fertilization programme: a prospective randomized study

The use of gonadotrophin-releasing hormone analogues (GnRHa) has resulted in improved pregnancy rates in in-vitro fertilization (IVF) treatment cycles. Traditionally, short-acting analogues have been employed because of concerns over long-acting depot preparations causing profound suppression and luteal phase defects adversely affecting pregnancy and miscarriage rates. We randomized 60 IVF patients to receive a short-acting GnRHa, nafarelin or buserelin, or to receive a depot formulation, leuprorelin, all commenced in the early follicular phase and compared their effects on hormonal suppression and clinical outcome. We found that on day 15 of administration there was a significant difference in the suppression of oestradiol from initial concentrations, when patients on buserelin were compared with patients on nafarelin or leuprorelin (54 versus 72 and 65%; P < 0.05) and also in the number of patients satisfactorily suppressed, (80 versus 90 and 90%; P < 0.05), though there were no differences between the analogues by day 21. Similarly there was no difference in hormonal suppression during the stimulation phase or in implantation, pregnancy or miscarriage rates in comparing the three agonists. We conclude that with nafarelin and leuprorelin, stimulation with gonadotrophins may begin after 2 weeks of suppression and that long-acting GnRHa are as effective as short-acting analogues with no detrimental effects on the luteal phase.     

Simultaneous evaluation of basal FSH and oestradiol response to GnRH analogue (F-G-test) allows effective drug regimen selection for IVF

To determine whether preliminary assessment of ovarian reserve by simultaneous evaluation of basal follicle-stimulating hormone (FSH) and oestradiol response to gonadotrophin releasing hormone (GnRH) analogue (F-G-test) can be used to tailor individually the drug regimen for ovarian stimulation, the in-vitro fertilization (IVF) results of 238 patients were retrospectively analysed. Sixty-two women with abnormal response to the test (DeltaE2 <180 pmol/l and/or FSH >9.5 mIU/ml) had commenced buserelin nasal spray in the mid-luteal phase and discontinued it on cycle day 1. Ovarian stimulation was started on cycle day 3 with 375 IU/day of gonadotrophin. Fifty-three patients completed the treatment cycle (group A). A total of 176 women with normal response to the test (DeltaE2 >180 pmol/l and FSH <9.5 mIU/ml) had continued the GnRH analogue throughout the stimulation cycle and a starting dose of 225 IU/day of gonadotrophin was used from cycle day 3. A total of 158 patients completed the treatment cycle (group B). Group A had significantly higher age (34.9 +/- 4.2 versus 33.2 +/- 4.2) (P < 0.05) and basal FSH (9.2 +/- 3.8 versus 7.0 +/- 2.2) (P < 0.05) and required a higher total dose of gonadotrophin. The numbers of oocytes retrieved and embryos transferred were significantly lower. However, fertilization, clinical pregnancies, and implantation rates were similar in both groups. It was concluded that simultaneous evaluation of basal FSH and oestradiol response to GnRH analogue can be useful in identifying subcategories of women with reduced ovarian reserve who may benefit from reduced GnRH analogue administration and a higher starting dose of gonadotrophin.     

Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study

BACKGROUND: When administered in the late follicular phase to prevent an LH surge, GnRH antagonists induce a sharp decrease in serum LH levels that may be detrimental for assisted reproductive technology cycle outcome. Therefore, a prospective study was designed to assess the effects of recombinant human (r)LH supplementation during GnRH antagonist (cetrorelix) administration. METHODS: The protocol consisted of cycle programming with oral contraceptive pill, ovarian stimulation with rFSH and flexible administration of a single dose of cetrorelix (3 mg). A total of 218 patients from three IVF centres were randomized (by sealed envelopes or according to woman's birth date) to receive (n = 114) or not (n = 104) a daily injection of rLH 75 IU from GnRH antagonist initiation to hCG injection. RESULTS: The only significant difference was a higher serum peak E2 level in patients treated with rLH (1476 +/- 787 versus 1012 +/- 659 pg/ml, P < 0.001) whereas the numbers of oocytes and embryos as well as the delivery rate (25.2 versus 24%) and the implantation rate per embryo (19.1 versus 17.4%) were similar in both groups. CONCLUSIONS: These results show that in an unselected group of patients, there is no evident benefit to supplement GnRH antagonist-treated cycles with rLH.     

Ovarian cyst formation following GnRH agonist administration in IVF cycles: incidence and impact

BACKGROUND: The formation of functional ovarian cysts has been recognized as one of the side effects of GnRH agonist administration. The formation of cysts during IVF treatment may be of no clinical significance or may negatively influence its outcome. The objective of this study was to determine the incidence of ovarian cyst formation following GnRH agonist administration and to examine their effect on IVF outcome. METHODS: A prospective study of 1317 IVF patients who developed one or more functional ovarian cysts of >or=15 mm following GnRH agonist treatment was performed. Transvaginal ultrasonographic-guided cyst aspiration was carried out in 76 randomly allocated patients out of 122 patients who were found to have functional ovarian cysts before starting ovarian stimulation with gonadotropins. RESULTS: The incidence of follicular cyst formation was 9.3%. Cyst cycles in comparison with non-cyst cycles had significantly elevated day 3 basal FSH (mean+/-SD of 8.3+/-3.2 versus 5.3+/-2.6 mIU/ml, P<0.05) and required more ampoules of gonadotropins (46.3+/-16.5 versus 35+/-14.6, P<0.01). Furthermore, they showed a statistically significant decrease in the quality and number of oocytes retrieved, fertilization rate, number and quality of embryos, implantation and pregnancy rates, with a significant increase in cancellation and abortion rates. Patients with bilateral cysts had a significantly lower number of oocytes and embryos retrieved, with a lower proportion of metaphase II oocytes. They also had a higher proportion of poor quality embryos. Cyst aspiration was not associated with a significant difference in the above parameters. CONCLUSIONS: The incidence of cyst formation during GnRH agonist treatment is lower than previously reported. In such cases, the quality of oocytes and embryos were significantly compromised, with a significant increase in the cycle cancellation rate and a decrease in the implantation and pregnancy rates. Neither conservative management nor cyst aspiration improved the IVF outcome.     

Use of cetrorelix in combination with clomiphene citrate and gonadotrophins: a suitable approach to 'friendly IVF'?

BACKGROUND: With the recently introduced GnRH antagonists, soft stimulation protocols on the basis of clomiphene pretreatment should be possible as the pituitary remains fully sensitive at the beginning of the cycle. METHODS: A prospective trial was carried out on 107 patients undergoing IVF treatment using the multiple dose GnRH antagonist protocol (cetrorelix), clomiphene citrate, and either HMG (n = 54) or recombinant FSH (rFSH) (n = 53). Different stimulation protocols were used to find the most appropriate one for clinical application. RESULTS: Both treatment groups, HMG and rFSH, yielded comparable results concerning gonadotrophin dose, stimulation days and pregnancy rate. A mean number of 6.34 +/- 4.4 metaphase II oocytes was retrieved and a mean number of 2.45 +/- 0.65 embryos was transferred. However, the overall rate of premature LH surges was 21.5% (defined as measurement of LH >10 IU/l and progesterone >1 ng/ml) which is unacceptable for clinical practice. CONCLUSIONS: Increasing the daily cetrorelix dose from 0.25 to 0.5 mg might decrease the number of premature LH surges. Soft stimulation protocols with clomiphene should be used cautiously.     

GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial

BACKGROUND. This is the first published report of a prospective, randomized, controlled trial comparing a fixed, multi-dose GnRH antagonist protocol with a long GnRH agonist protocol in poor responders undergoing IVF. METHODS. Sixty-six poor responders were randomized into two groups: the study group received 0.25 mg of cetrorelix daily starting on day 6 of stimulation; the control group received 600 microg of buserelin acetate daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a fixed dose of recombinant FSH (300 IU daily) for stimulation. RESULTS. There were no significant differences in the cycle cancellation rates, duration of stimulation, consumption of gonadotrophins, and mean numbers of mature follicles, oocytes and embryos obtained. The implantation rates were similar, but the number of embryos transferred was significantly higher for the antagonist group (2.32 +/- 0.58 versus 1.50 +/- 0.83; P = 0.01). The pregnancy rates were also higher in the antagonist group, but the difference was not statistically significant. CONCLUSION. A fixed multi-dose GnRH antagonist protocol is feasible for patients who are poor responders on a long agonist protocol; however, our study failed to demonstrate an overall improvement in ovarian responsiveness. Clinical outcomes may be improved by developing more flexible antagonist regimens, an approach that requires further evaluation.     

Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication

A new treatment option for patients undergoing ovarian stimulation is the gonadotrophin-releasing hormone (GnRH) antagonist protocol, with the possibility to trigger a mid-cycle LH surge using a single bolus of GnRH agonist, reducing the risk of developing ovarian hyperstimulation syndrome (OHSS) in high responders and the chance of cycle cancellation. This report describes the use of 0.2 mg triptorelin (Decapeptyl) to trigger ovulation in eight patients who underwent controlled ovarian hyperstimulation with recombinant FSH (rFSH, Puregon) and concomitant treatment with the GnRH antagonist ganirelix (Orgalutran) for the prevention of premature LH surges. All patients were considered to have an increased risk for developing OHSS (at least 20 follicles > or =11 mm and/or serum oestradiol at least 3000 pg/ml). On the day of triggering the LH surge, the mean number of follicles > or =11 mm was 25.1 +/- 4.5 and the median serum oestradiol concentration was 3675 (range 2980-7670) pg/ml. After GnRH agonist injection, endogenous serum LH and FSH surges were observed with median peak values of 219 and 19 IU/l respectively, measured 4 h after injection. The mean number of oocytes obtained was 23.4 +/- 15.4, of which 83% were mature (metaphase II). None of the patients developed any signs or symptoms of OHSS. So far, four clinical pregnancies have been achieved from the embryos obtained during these cycles, including the first birth following this approach. It is concluded that GnRH agonist effectively triggers an endogenous LH surge for final oocyte maturation after ganirelix treatment in stimulated cycles. Our preliminary results suggest that this regimen may prove effective in triggering ovulation and could be said to prevent OHSS in high responders. The efficacy and safety of such new treatment regimen needs to be established in comparative randomized studies.     

A relative reduction in mid-follicular LH concentrations during GnRH agonist IVF/ICSI cycles leads to lower live birth rates

BACKGROUND: The effect of early- and mid-follicular LH concentrations on the ovarian response and pregnancy outcomes was evaluated in women receiving pituitary down-regulation with a GnRH agonist and ovarian stimulation with recombinant FSH (rFSH) during IVF/ICSI treatment. METHODS: Blood samples were collected prospectively from 701 cycles (560 patients) of assisted reproduction and analysed retrospectively. On the basis of LH concentrations on stimulation day 7/8, the patients were divided into two groups: LH<1.2 IU/l (n=179) and LH>or=1.2 IU/l (n=522). Cycle outcomes were also compared on the basis of a ratio of mid- to early-follicular LH concentrations (0.5, n=491). RESULTS: Patients with low LH concentrations were found to have a significant reduction in the late-follicular estradiol concentrations (P<0.001), the number of oocytes retrieved (P<0.01) and the number of usable embryos (P<0.01), and they required significantly more rFSH (430 IU difference, P<0.01). These differences did not translate into a significant change in live birth rates. Conversely, a ratio of or=50%) was associated with a significant reduction in live birth rates per embryo transfer and per cycle started (27.3 versus 19.0%, P<0.05 and 22.2 versus 15.8%, P<0.05, respectively). CONCLUSIONS: Low mid-follicular levels of LH have a significant impact on ovarian response but not on live birth rates. A fall in LH level of >or=50% from the early- to mid-follicular phase resulted in a lower live birth rate.     

Will GnRH antagonists provide new hope for patients considered 'difficult responders' to GnRH agonist protocols?

We have assessed the use of cetrorelix, a gonadotrophin releasing hormone (GnRH) antagonist, in conjunction with clomiphene citrate and gonadotrophin in 31 in-vitro fertilization (IVF)/gamete intra-Fallopian transfer (GIFT) cycles for 25 difficult responders. Group I included 18 poor responders (24 cycles) with no live birth in 23 previous IVF cycles with GnRH agonists. Group II included seven patients (seven cycles) with polycystic ovaries. Thirteen previous IVF/GIFT cycles with GnRH agonists had resulted in one live birth and three of these patients had developed ovarian hyperstimulation syndrome (OHSS). The treatment protocol involved a daily dose of clomiphene citrate 100 mg for 5 days and gonadotrophin injections from cycle day 2. Cetrorelix 0.25 mg/day was started when the leading follicle reached 14 mm. The outcome in both groups was favourable compared to previous treatment with GnRH agonists. In group I the abandoned cycle rate was 29 versus 57% (P = 0.06). More oocytes were produced (6.4 versus 4.7 oocytes/cycle) at a lower dose of follicle-stimulating hormone (FSH) (709 versus 1163 IU/oocyte; P = 0.08) and two live births resulted (11.8%). In group II fewer oocytes were produced (10.2 versus 14.5 oocytes/cycle), using a lower dose of gonadotrophin (170 versus 189 IU/oocyte) and resulted in one ongoing pregnancy. No patients experienced OHSS. This report is preliminary and a further controlled randomized study is required.     

Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF

BACKGROUND: The significance of suppressed LH levels in GnRH antagonist cycles for IVF outcome is currently unknown. The purpose of this study was to evaluate prospectively the association between LH levels and ongoing pregnancy achievement after GnRH antagonist initiation in IVF cycles. METHODS: Ovarian stimulation with a fixed dose of 200 IU recombinant FSH and daily GnRH antagonist (ganirelix) 0.25 mg from day 6 of stimulation was initiated in 116 women. Patients were not pretreated with an oral contraceptive. Induction of final oocyte maturation was performed with HCG 10,000 IU as soon as three follicles of > or =17 mm were present in ultrasound, and was followed by oocyte pick-up, conventional IVF or ICSI, and embryo transfer. The luteal phase was supplemented with vaginal progesterone. RESULTS: A significant decrease of both ongoing pregnancy rate and implantation rate was present across groups of patients with increasing LH levels. The highest implantation rate and ongoing pregnancy rate was present in those patients with LH levels on day 8 of stimulation < or =0.5 IU/l. CONCLUSIONS: Profound suppression of LH on day 8 of stimulation is associated with a significantly higher chance of achieving an ongoing pregnancy. More studies are necessary to evaluate this phenomenon further.     

A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report

BACKGROUND: Use of letrozole, a selective inhibitor of aromatase, reduces the gonadotrophin dose required to induce follicular maturation. We evaluated whether incorporation of letrozole could be an effective low-cost IVF protocol for poor responders. METHODS: A randomized, controlled, single-blind trial was conducted in the Assisted Reproduction Unit, Institute of Reproductive Medicine, Kolkata, India. Thirty-eight women with a history of poor ovarian response to gonadotrophins were recruited. Thirteen women (Let-FSH group) received letrozole 2.5 mg daily from day 3-7, and recombinant FSH (rFSH) 75 IU/day on days 3 and 8; and 25 women (GnRH-ag-FSH group) underwent long GnRH agonist protocol and stimulated with rFSH (300-450 IU/day). Ovulation was triggered by 10,000 IU of HCG followed by IVF-embryo transfer. The main outcome measures were total dose of rFSH (IU/cycle), terminal estradiol (E2) (pg/ml), numbers of follicles, oocytes retrieved and transferable embryo, endometrial thickness (mm), and pregnancy rate. RESULTS: Compared with the GnRH-ag-FSH group (2865 +/- 228 IU), the Let-FSH group (150 +/- 0 IU) received a significantly (P < 0.001) lower total dose of FSH. Except for terminal E2, which was significantly higher (P < 0.001) in the GnRH-ag-FSH group (380 +/- 46 pg/ml) than the Let-FSH group (227 +/- 45 pg/ml), the treatment outcomes in all other respects, including pregnancy rate, were statistically comparable. CONCLUSIONS: Adjunctive use of letrozole may form an effective means of low-cost IVF protocol in poorly responding women.     

Initiation of GnRH antagonist on Day 1 of stimulation as compared to the long agonist protocol in PCOS patients. A randomized controlled trial: effect on hormonal levels and follicular development

BACKGROUND The optimal time for GnRH antagonist initiation is still debatable. The purpose of the current randomized controlled trial is to provide endocrine and follicular data during ovarian stimulation for IVF in patients with polycystic ovarian syndrome (PCOS) treated either with a long GnRH agonist scheme or a fixed day-1 GnRH antagonist protocol. METHODS Randomized patients in both groups (antagonist: n = 26; long agonist: n = 52) received oral contraceptive pill treatment for three weeks and a starting dose of 150 IU of follitropin beta. The primary outcome was E(2) level on Day 5 of stimulation, while secondary outcomes were follicular development, LH during ovarian stimulation and progesterone levels. RESULTS Significantly more follicles on days 5, 7 and 8 of stimulation, significantly higher estradiol (E(2)) levels on days 1, 3, 5, 7 and 8 and significantly higher progesterone levels on days 1, 5 and 8 of stimulation were observed in the antagonist when compared with the agonist group. E(2) was approximately twice as high in the antagonist when compared with the agonist group on day 5 of stimulation (432 versus 204 pg ml(-1), P lt; 0.001). These differences were accompanied by significantly lower LH levels on days 3 and 5 and significantly higher LH levels on days 1, 7 and 8 of stimulation in the antagonist when compared with the agonist group. CONCLUSIONS In PCOS patients undergoing IVF, initiation of GnRH antagonist concomitantly with recombinant FSH is associated with an earlier follicular growth and a different hormonal environment during the follicular phase when compared with the long agonist protocol.     

Effect of reduced dose of triptorelin at the start of ovarian stimulation on the outcome of IVF: a randomized study.

BACKGROUND: Partial pituitary desensitization using gonadotrophin-releasing hormone (GnRH) agonists may be sufficient in women undergoing controlled ovarian hyperstimulation for assisted reproduction. However, the minimal effective agonist dose remains to be determined. The aim of the study was to investigate the effect of a reduced daily dose of triptorelin, administered at the start of ovarian stimulation, on the results of IVF and intracytoplasmic sperm injection. METHODS: A total of 132 patients was randomized in two groups. Pituitary desensitization was obtained in group 1 (66 patients) with a single 3.75 mg injection (i.m.) of triptorelin. In group 2, 66 patients received 100 microg triptorelin daily, which was then reduced to 50 microg at the start of follicle-stimulating hormone (FSH) stimulation. RESULTS: No significant differences were found in terms of pregnancy rate per transfer (38% in group 1 versus 34.9% in group 2), implantation rate (20.2 versus 18%) and abortion rate (8.3 versus 9.1%). The number of FSH ampoules used, as well as the number of days stimulation required, was significantly reduced in group 2 (41 +/- 26 versus 46.6 +/- 25.3, P < 0.03 and 11 +/- 1.3 versus 11.8 +/- 1.5, P < 0.002 respectively). No significant differences were seen in oestradiol concentrations and in follicle number, in the quantity of oocytes collected and fertilized, or in the number of embryos obtained or transferred. CONCLUSION: A reduced dose of triptorelin is enough for pituitary suppression during ovarian stimulation but provides no significant improvement in IVF cycle outcome when compared with depot formulation. The possibility of a shorter treatment protocol requiring lower amounts of gonadotrophins should be considered in view of its economic advantage.     

Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix

Luteinizing hormone (LH) is mandatory for the maintenance of the corpus luteum. Ovarian stimulation for IVF has been associated with a defective luteal phase. The luteal phases of two groups of patients with normal menstrual cycles and no endocrinological cause of infertility were retrospectively analysed in IVF cycles. Thirty-one infertile patients stimulated with human menopausal gonadotrophins (HMG) for IVF to whom the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix 0.25 mg was also administered to prevent the LH surge (group I) were compared with 31 infertile patients stimulated with HMG alone (group II). Despite differences in the stimulation outcome, luteal LH serum concentrations were similar in the two groups. LH values dropped from 2.3 +/- 1 IU/l on the day of human chorionic gonadotrophin (HCG) administration to 1.1 +/- 0.7 IU/l on day HCG +2 in group I (P < 0.0001) and from 5.1 +/- 3 to 1.2 +/- 1.7 IU/l (P < 0.0001) in group II. In the mid-luteal phase, LH concentrations were low in both groups. Our results suggest that suppressed LH concentrations in the early and mid-luteal phase may not be attributed solely to the GnRH-antagonist administration. Pituitary LH secretion may be inhibited by supraphysiological steroid serum concentrations via long-loop feedback and/or by the central action of the exogenously administered HCG via a short-loop mechanism.