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.     

Gonadotrophin-releasing hormone agonist dose-dependency of pituitary desensitization during controlled ovarian hyperstimulation in IVF

The aim of this study was to find the minimal effective daily s.c. dose of the gonadotrophin-releasing hormone (GnRH) agonist, triptorelin acetate, that suppresses the GnRH-induced release of luteinizing hormone (LH) at time of human chorionic gonadotrophin (HCG) injection and thereby prevents spontaneous LH surges during in-vitro fertilization (IVF) stimulation cycles. Therefore, a double-blind, prospective and randomized titration study was performed. A total of 48 IVF patients were divided into four groups of 12 patients. Each group received a different dose of triptorelin acetate, namely 5, 15, 50 or 100 microg s.c. daily. Standard ovarian stimulation was carried out using urinary follicle stimulating hormone (FSH) preparations. A 500 microg GnRH test was performed 90 min before the HCG injection in order to measure the degree of pituitary desensitization. Spontaneous LH surges were not detected in any of the groups, although three patients in the 5 microg group had ovulated at the time of ovum retrieval. The pituitary LH response to the GnRH test at time of HCG, expressed as area under the curve (AUC), appeared to be dose-dependent. Thus, a daily s.c. dose of 100 microg triptorelin acetate appears to be too high, since adequate desensitization of the pituitary (i.e. no spontaneous LH surge) can be achieved with doses as low as 15 and 50 microg.      

The effect of pituitary desensitization on ovarian volume measurements prior to in-vitro fertilization.

The measurement of ovarian volume has been recently shown to predict follicular response in in-vitro fertilization (IVF), specifically a lower number of retrieved oocytes with decreasing ovarian volume. This test appears to be better than basal follicle-stimulating hormone (FSH) as a prognostic measure of ovarian reserve. However, the effect of pituitary desensitization on ovarian volume has not been previously investigated. We prospectively evaluated 38 women undergoing IVF using a long luteal leuprolide acetate (LA) protocol. All women had their ovarian volume measurements performed on day 21, the day of LA start, and again on the day of gonadotrophin start. The mean age was 30.6 +/- 3.9 years (range 23-37). Basal FSH was 5.4 +/- 1.9 IU/l (range 1.2-10.2). The mean preLA ovarian volume was 7.0 +/- 3.6 cm3 (left ovary 6.8 +/- 3.9, right ovary 7.1 +/- 3.8), compared to 6.3 +/- 4.2 cm3 postLA (left ovary 6.0 +/- 4.9, right ovary 6.5 +/- 4.8) (not significant). The mean number of small antral follicles noted in both ovaries was also unchanged after pituitary desensitization. Pituitary desensitization using LA had no effect on overall ovarian volume measurements. The total number of retrieved oocytes decreased with increasing age and decreasing ovarian volume.     

Short term pituitary desensitization: effects of different doses of the gonadotrophin-releasing hormone agonist triptorelin

Gonadotrophin-releasing hormone agonists (GnRHa) are used toprevent inadequate luteinizing hormone (LH) surges during ovarianstimulation in in-vitro fertilization (IVF). Dose studies foroptimal dose assessment are lacking and unfavourable effectsof the agonist on granulosa function and oocyte quality havebeen suggested. This double-blind randomized study was undertakento assess the effect of four different doses of triptorelinon the degree of desensitization of the pituitary, and the recoverytime of pituitary function after withdrawal of the agonist.Sixty-six regularly cycling women were allocated to a treatmentgroup (n = 32) and a control group (n = 34). To assess the degreeof pituitary desensitization and restoration in the treatmentgroup, gonadotrophin releasing hormone (GnRH) challenges (100µg, i.v.) were performed during treatment (day 17), and2, 4 and 6 days after discontinuation of treatment At the sametime blood samples for oestradiol and triptorelin concentrationswere drawn. In the control group a GnRH test was performed onday 2 of the menstrual cycle. Both pituitary desensitizationduring and pituitary recovery after agonist treatment, expressedas the LH response to exogenous GnRH, appeared to be dose dependentAs the use of reduced dosages still offers a considerable degreeof pituitary suppression, studies on dose adjustments in theuse of triptorelin in ovarian stimulation in IVF are warranted.     

Endocrinology: Influence of serum follicle stimulating hormone to luteinizing hormone ratio during buserelin acetate-induced pituitary desensitizafion on ovarian response to exogenous gonadotrophins in an in-vitro fertilization and embryo transfer programme

We investigated the effect of endogenous gonadotrophins duringpituitary desensitization with gonadotrophin-releasing hormoneagonist (GnRHa) on ovarian responsiveness or the outcome ofin-vitro fertilization (IVF) and embryo transfer. The resultsof 67 women who participated in the IVF programme at NagasakiUniversity Hospital, Japan, were analysed retrospectively. Allwomen received GnRHa from the third day of the menstrual cycle,and ovarian stimulation with exogenous gonadotrophins was initiatedwhen the serum oestradiol concentration decreased to <30pg/ml. The serum follicle stimulating hormone (FSH)/luteinizinghormone (LH) ratio, rather than serum FSH or LH concentrationsduring GnRHa-induced pituitary desensitization, showed a significantpositive correlation with age and the total dose of exogenousgonadotrophins. The FSH/LH ratio also showed a significant negativecorrelation with oestradiol response and the number of retrievedoocytes, and was significantly lower in pregnant women comparedwith the non-pregnant group during pituitary desensitization.Our results indicate that, even under pituitary desensitizationwith GnRHa, the serum FSH/LH ratio influences individual ovarianresponsiveness and the state of the intra-ovarlan hormonal environment.Our results suggest that the FSH/LH ratio may be a useful clinicalpredictor of the ovarian response to exogenous gonadotrophinsunder pituitary desensitization.     

LH serum levels during ovarian stimulation as predictors of ovarian response and assisted reproduction outcome in down-regulated women stimulated with recombinant FSH

BACKGROUND: There has been much debate about the effect of 'residual' LH levels in normogonadotrophic women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH ovarian stimulation. The aim of this prospective study, where receiver-operating characteristic (ROC) analysis was used, was to assess further the usefulness of serum LH levels as predictors of ovarian response, assisted reproduction treatment outcome, and the outcome of pregnancy when measured throughout the ovarian stimulation period in a large cohort of such assisted reproduction treatment women. METHODS: A total of 246 consecutive women undergoing their first cycle of IVF or ICSI treatment were included in this study. Blood samples for hormone analyses were obtained on day S0 (the day when pituitary suppression was evidenced) and every other day from stimulation day 5 (S5) until the day of hCG injection. RESULTS: LH serum levels throughout ovarian stimulation treatment were similar for cancelled (n =32) versus non-cancelled (n = 214) cycles, non-conception (n = 132) versus conception (n = 82) cycles, and ongoing pregnancy (n = 66) versus early pregnancy loss (n = 16) groups. There was no correlation between LH serum levels in non-cancelled cycles and parameters of ovarian response and assisted reproduction treatment outcome. ROC analysis showed that serum LH concentration during ovarian stimulation was unable to discriminate between cancelled and non-cancelled cycles, conception versus non-conception cycles, or early pregnancy loss versus ongoing pregnancy groups. CONCLUSIONS: Serum LH measurements during ovarian stimulation with recombinant FSH under pituitary suppression in normogonadotrophic women undergoing assisted reproduction treatment cannot predict ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy. Thus, there is little underlying physiological support for the addition of LH in stimulation protocols if daily doses of an appropriate GnRH agonist (leuprolide or triptorelin having lower potency than buserelin) and a step-down regimen of recombinant FSH administration are used.     

Recombinant follicle stimulating hormone is effective in poor responders to highly purified follicle stimulating hormone

Ovarian stimulation in cases of poor ovarian responsiveness is an important challenge in in-vitro fertilization (IVF) programmes. Despite improvements in oocyte number and quality, an ideal ovarian stimulation strategy has yet to be defined. Here, the results of ovarian stimulation with recombinant follicle stimulating hormone (rFSH) in 28 poor responders to highly purified FSH (FSH-HP) with high basal concentrations of FSH are reported. The protocols used on the FSH-HP and rFSH cycles were identical with the sole exception of the FSH preparation: triptorelin 0.1 mg/day (gonadotrophin-releasing hormone, GnRH-agonist short protocol) and the starting FSH dose of 300 IU/day were administered from day 2 of the menstrual cycle. Ovarian outcome was classified as 'normal', 'intermediate' and 'poor', depending on the number of mature oocytes retrieved and the peak serum oestradiol concentration. Nine of the 28 subjects had an intermediate ovarian response to re-stimulation with rFSH. In the 26 patients who received human chorionic gonadotrophin on both cycles, re-stimulation resulted in a significant increase (P < 0.05) in the mean number of mature oocytes (2.4 +/- 1.4 versus 1.7 +/- 0.8), mean peak oestradiol concentration (606 +/- 252 versus 443 +/- 32 pg/ml) and fertilization rate (73.0 versus 53.3%). Four pregnancies were achieved. It is concluded that rFSH in a GnRH-agonist short protocol improves the ovarian outcome in poor responders to FSH-HP with high basal concentrations of FSH.     

Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study

Gonadotrophin-releasing hormone agonists (GnRHa) are routinely used in IVF programmes to prevent an unwanted LH surge and consequent ovulation. Despite its widespread use in IVF, a convincing dose recommendation for GnRHa in IVF does not exist. In our opinion, the lowest possible dose of GnRHa should be used. Thus, we performed a prospective, randomized, double-blind, placebo-controlled study to determine the minimal daily dose of triptorelin acetate needed to suppress a premature LH surge during IVF treatment in a long protocol. A total of 240 women (60 in each group) was randomized to either placebo or to one of three doses of triptorelin, i.e. 15, 50 or 100 microg daily. Ovarian stimulation was performed with two or three ampoules of FSH daily. A premature LH surge occurred in 23% of placebo-treated patients, but in none of the triptorelin acetate-treated patients. There were significantly more oocytes and embryos in the 50 and 100 microg triptorelin groups. There was no dose relationship in rates of either implantation, pregnancy, ongoing pregnancy, live birth or baby take-home. In this study we showed that daily administration of 15 microg triptorelin is sufficient to prevent a premature LH surge, and that 50 microg is equivalent to 100 microg in terms of IVF results.     

Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation

BACKGROUND: To compare the clinical results and the cost-effectiveness of using the aromatase inhibitor, letrozole, in conjunction with FSH and FSH alone for controlled ovarian stimulation (COS) in patients undergoing intrauterine insemination (IUI) for a variety of indications. METHODS: Four hundred and thirty-two consecutive patients who underwent 872 IUI cycles were included. The study population was composed of two groups. Group I included 308 patients who underwent 589 IUI cycles with letrozole and FSH for the following indications: anovulation (143 cycles), male factor infertility (147 cycles), unexplained infertility (250 cycles), endometriosis (18 cycles) and combined indications (31 cycles). Group II included 124 patients who underwent 283 IUI cycles who received FSH only for the following indications: ovarian factor infertility (82 cycles), male factor infertility (66 cycles), unexplained infertility (114 cycles), endometriosis (13 cycles) and other indications (8 cycles). Main outcome measures included number of mature follicles >16 mm in diameter, dose of FSH used per cycle, clinical pregnancy rate and cost-effectiveness ratio per pregnancy. RESULTS: FSH dose required for ovarian stimulation was significantly lower when letrozole was used (P < 0.0001). Although a significantly higher number of follicles >16 mm and endometrial thickness at the day of hCG administration (P < 0.0001) were observed in Group II, pregnancy rate per started (14.4 versus 15.9%) and per completed cycles (15.77 versus 18.07%) was the same in Group I and Group II, respectively. IUI cancellation rate was significantly lower with letrozole treatment (P = 0.05%). The cost per cycle was significantly lower in Group I versus Group II (468.93 Can dollars +/- 418.18 versus 1067.28 +/- 921.43; P < 0.0001). The cost-effectiveness ratio was 3249.42 dollars in the letrozole group and 6712.00 dollars in the FSH-only group. CONCLUSION: A letrozole-FSH combination could be an effective ovarian stimulation protocol in IUI cycles. Such a protocol may be more cost-effective than FSH alone because of the difference of FSH dose and cost. A randomized controlled trial is needed to further substantiate this finding.     

A comparative randomized trial to assess the impact of oral contraceptive pretreatment on follicular growth and hormone profiles in GnRH antagonist-treated patients

BACKGROUND: This randomized controlled trial was designed to assess the impact of oral contraceptive (OC) scheduling with a GnRH antagonist (ganirelix) regimen on the ovarian response of women undergoing recombinant FSH (rFSH) stimulation for IVF, compared with a non-scheduled ganirelix regimen and a long GnRH agonist (nafarelin) protocol. METHODS: A total of 110 women was treated with an OC and ganirelix, 111 with ganirelix alone and 111 with nafarelin. The OC (containing 30 microg ethinylestradiol/150 microg desogestrel) was taken for 14-28 days and stopped 2 days prior to the start of rFSH treatment. Primary efficiency parameters were the number of cumulus-oocyte complexes (per attempt) and the number of grade 1 or 2 embryos (per attempt). RESULTS: In terms of follicular growth and hormone profiles, the OC-scheduled antagonist regimen mimicked the agonist regimen rather than the (non-scheduled) GnRH antagonist regimen. In the OC-scheduled GnRH antagonist group and the nafarelin group (versus the non-scheduled antagonist group), pituitary suppression was more profound at the start of stimulation (P < or = 0.001), there was a slower start of follicular growth (P < or = 0.001), longer stimulation was required (11.7 and 10.3 days respectively versus 9.4; P < or = 0.001), and more rFSH was used (2667 and 2222 IU versus 1966 IU; P < or = 0.001). In the three groups, the number of oocytes was similar (13.1, 12.9 and 11.5 respectively; not significant) as well as the number of good quality embryos (5.1, 5.7 and 5.0 respectively; not significant). CONCLUSION: OC treatment prior to the rFSH/ganirelix regimen can be successfully applied to schedule patients, although more days of stimulation and more rFSH are required than with a non-scheduled GnRH antagonist regimen.     

Ovarian stimulation during assisted reproduction treatment: a comparison of recombinant and highly purified urinary human FSH. On behalf of The Feronia and Apis study group

This randomized, single-blind, multicentre, multinational study compared recombinant human FSH (rhFSH, Gonal-F) with highly purified urinary human FSH (uhFSH, Metrodin HP) in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). Following desensitization in a long gonadotrophin-releasing hormone (GnRH) agonist protocol, patients received s.c. Gonal-F or Metrodin HP, at a fixed dose of 150 IU, until there was adequate follicular development. Of 496 women randomized, 232 and 231 in the Gonal-F and Metrodin HP groups respectively received human chorionic gonadotrophin (HCG). The duration of FSH treatment was significantly shorter with Gonal-F than with Metrodin HP (11.6 +/- 1.9 days versus 12. 4 +/- 2.7 days; P < 0.0001) and significantly fewer ampoules were required (mean 22.6 +/- 5.0 versus 24.3 +/- 5.1, P < 0.0002). There were, however, significantly more follicles > or =10 mm in diameter with Gonal-F (15.6 +/- 8.2 versus 13.6 +/- 7.1, P < 0.01) and oocytes retrieved (13.1 +/- 7.7 versus 11.4 +/- 7.6, P < 0.002). Although no statistical difference in pregnancy rate was recorded, patients receiving Gonal-F had a higher pregnancy rate per cycle than patients given Metrodin HP (25.1 versus 20.1%). Moderate to severe ovarian hyperstimulation syndrome occurred in 2.8 and 1.2% of Gonal-F and Metrodin HP patients respectively (not significant). In conclusion, FSH stimulation in combination with a long GnRH agonist protocol is effective in inducing multiple follicular development and embryos with a high implantation potential. However, Gonal-F is clearly more effective than Metrodin HP in inducing multifollicular development.     

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.     

Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH

BACKGROUND: Treatment of poor-responder patients to controlled ovarian stimulation for assisted reproduction, who have normal basal FSH concentrations, is one of the most difficult challenges in reproductive medicine. This study investigated the usefulness of testosterone pretreatment in such patients. METHODS: Prospective, therapeutic, self-controlled clinical trial including 25 consecutive infertile patients who had a background of the first and second IVF treatment cycle cancellations due to poor follicular response, in spite of vigorous gonadotrophin ovarian stimulation and having normal basal FSH levels. In the third IVF attempt, all patients received transdermal testosterone treatment (20 microg/kg per day) during the 5 days preceding gonadotrophin treatment. RESULTS: Twenty patients (80%) showed an increase of over fivefold in the number of recruited follicles, produced 5.8+/-0.4 (mean+/-SEM) oocytes, received two or three embryos and achieved a clinical pregnancy rate of 30% per oocyte retrieval. There were 20% cancelled cycles. CONCLUSION: Pretreatment with transdermal testosterone may be a useful approach for women known to be low responders on the basis of a poor response to controlled ovarian stimulation but having normal basal FSH concentrations.     

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.     

Serum IGF-1 concentrations following pituitary desensitization do not predict the ovarian response to gonadotrophin stimulation prior to IVF

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is known to play a role in ovarian follicular development augmenting the action of FSH. Low intrafollicular concentrations have been detected in women who respond poorly to gonadotrophins. This study addresses the relationship between serum IGF-1 levels following pituitary desensitization and ovarian response to gonadotrophin stimulation. METHODS: This is a case-control study of 78 patients undergoing IVF-embryo transfer treatment. Thirty-nine strictly-defined poor responder patients requiring 50 or more ampoules (75 IU FSH) to reach oocyte retrieval were compared with 39 age-matched normal responders, requiring fewer than 50 ampoules. IGF-1 concentrations were determined by extraction radioimmunoassay on serum samples obtained after pituitary desensitization but prior to gonadotrophin stimulation. RESULTS: Despite highly significant differences in measures of ovarian response between groups, the mean serum IGF-1 concentration was not statistically significantly different between poor and normal responders [(31.5 nmol/l [95% confidence interval (CI) 28.5-34.5] versus 34.5 nmol/l (95% CI 31.8-37.2)] respectively. No correlation between oocyte number or total gonadotrophin used and serum IGF-1 concentration was observed. CONCLUSION: Whilst IGF-1 influences ovarian follicular development this study suggests that serum IGF-1 does not predict ovarian response and does not differentiate between critically-defined poor and normal responders.     

Does growth hormone-releasing factor assist follicular development in poor responder patients undergoing ovarian stimulation for in-vitro fertilization?

Treatment with growth hormone-releasing factor (GRF) has been reported to improve the ovarian response to gonadotrophins in women who respond poorly to ovarian stimulation during in-vitro fertilization (IVF). The efficacy and tolerability of GRF were studied in a randomized, double-blind, placebo-controlled trial involving 196 patients. Following down-regulation with a gonadotrophin-releasing hormone agonist (GnRHa), patients were randomized to receive GRF (500 microg twice daily; n = 96) or placebo (n = 100) in addition to follicle stimulating hormone (FSH); treatment was continued until human chorionic gonadotrophin was given, or for a maximum of 14 days. GRF had no significant effect on the mean number of follicles with a diameter of >/=16 mm (GRF: 3.26 +/- 2.29; placebo: 3.27 +/- 2.30; P = 0.95), the number of FSH ampoules required to achieve ovarian stimulation (GRF: 55.2 +/- 16. 4; placebo: 54.9 +/- 17.2; P = 0.50), or on secondary measures of ovarian response and treatment outcome. There were, however, significant increases in circulating growth hormone (GH) and insulin-like growth factor (IGF)-1 concentrations. GRF was well tolerated. It is concluded that, despite producing significant increases in GH and IGF-1, concomitant treatment with GRF does not improve the ovarian response to FSH in poorly responsive women undergoing IVF.     

Dose-finding study for the use of long-acting gonadotrophin-releasing hormone analogues prior to ovarian stimulation for IVF

Gonadotrophin-releasing hormone (GnRH) analogues improve the outcome of treatment with IVF by increasing the number and quality of oocytes retrieved and by reducing cycle cancellation rates. Whilst short-acting GnRH analogues are most commonly used, depot preparations are now available that are more convenient for patient use. Some studies have reported that pregnancy rates with depot GnRH analogues are similar to those of short-acting preparations, but others have suggested that the more profound down-regulation seen with depot GnRH analogues results in inferior embryo quality. The purpose of this study was to determine whether a lower than conventional dose of a depot GnRH analogue may be more appropriate for use in ovarian stimulation prior to IVF. Sixty patients were randomized to receive either 3.75 mg (conventional dose) or 1.87 mg (low dose) triptorelin prior to ovarian stimulation for IVF. Suppression was measured using serum concentrations of LH measured 2 and 3 weeks after the administration of the GnRH analogues, the dose of gonadotrophin used and the time to resumption of menses. Mean concentrations of LH were 2.2 +/- 1.0 and 1.1 +/- 0.6 IU/l in the conventional dose group and 3.5 +/- 5.5 and 2.7 +/- 1.9 IU/l in the low dose group (P < 0.05 at 2 and 3 weeks). There were no significant differences between the doses of gonadotrophins used, the number of oocytes and embryos available and the time to resumption of menses, nor in the pregnancy rates. Although the degree of suppression as measured biochemically was more profound with the conventional dose, this did not affect the IVF outcome. The use of a lower dose therefore appears to be equally effective and could contribute to a reduction in the cost of treatment.     

Differences in ovarian function parameters between Chinese and Caucasian oocyte donors: do they offer an explanation for lower IVF pregnancy rates in Chinese women?

BACKGROUND: IVF outcomes in Chinese women are inferior to those of Caucasian patients. Reflecting prematurely diminished ovarian function, women with elevated age-specific baseline (b-) FSH levels are designated to suffer from premature ovarian aging (POA). We investigated if the prevalence of POA differs between these two ethnic populations. METHODS: We compared patient characteristics and first IVF cycle outcomes in 29 consecutive, Caucasian and 17 Asian-Chinese oocyte donors. POA was diagnosed in a donor if her b-FSH levels exceeded the 95% confidence interval (CI) for her age group. RESULTS: There was no age difference between Chinese and Caucasian groups (26.2 +/- 4.9 versus 25.7 +/- 3.1 years, respectively). Chinese women demonstrated, however, a higher cycle cancellation rate (5/17, 29.4%), either before cycle start or during stimulation (0/29; relative risk 1.42, 95% CI 1.04-1.9; P < 0.01), fewer oocytes per initiated cycle (9.3 +/- 9.7 versus 15.3 +/- 7.1, respectively; P < 0.05) (difference disappeared for only cycles that reached retrieval) and higher b-FSH levels (7.5 +/- 1.9 versus 5.1 +/- 1.7 mIU/ml, respectively; P = 0.004). Nine out of 17 (53%) of Chinese and only 1/26 (4%) of Caucasian donors met b-FSH level criteria for a presumptive POA diagnosis. Their odds of meeting POA criteria were approximately 30-times greater (odds ratio 31.5; 95% CI 3.5-18.7; P < 0.0001). CONCLUSIONS: These data suggest a possible explanation for lower IVF pregnancy rates in Chinese women. Preceding treatment, Chinese women at all ages should be carefully investigated to detect occult POA. Ethnicity may have to be considered an additional outcome variable in fertility studies.     

Age-specific FSH levels as a tool for appropriate patient counselling in assisted reproduction

BACKGROUND: The purpose of this study was to assess whether, even within a normal FSH range (< or =10 mU/ml), age-specific FSH levels are predictive of ovarian reserve. METHODS: Between January 1998 and December 2001, 535 women, undergoing controlled ovarian stimulation with 225 IU of recombinant (rec) FSH and 75 IU of recLH, were included in this retrospective cohort study. Criteria for enrolment were: age 25-40 years, basal FSH (b-FSH) < or =10 mU/ml and basal LH < or =12 mU/ml. Patients were assigned to three age groups (group I: 25-29 years; group II: 30-35 years; and group III: 36-40 years). Each age group was divided into quartiles according to b-FSH levels, comparing the lowest and highest b-FSH quartiles for basal hormonal patterns and outcome-related parameters. RESULTS: At ages 25-35 years, women in the lowest FSH quartiles demonstrated significantly increased numbers of oocytes at retrieval (group I: low b-FSH quartile 8.4 +/- 3.7 versus high b-FSH quartile 6.4 +/- 2.7, P < 0.02; group II: 7.5 +/- 4.0 versus 6.3 +/- 3.0, P < 0.047), whereas no difference with regard to oocyte yield was observed in patients above age 35 (group III: low b-FSH quartile 5.5 +/- 3.1 versus high b-FSH quartile 5.6 +/- 3.5). No statistical correlation was found between FSH quartiles and clinical pregnancy rates or miscarriage. CONCLUSIONS: In young women, age-specific high b-FSH levels, even within normal ranges, are associated with significantly reduced numbers of oocytes retrieved. B-FSH concentrations should, therefore, be interpreted in an age-specific manner to allow for appropriate patient counselling in IVF.     

Inhibin A and inhibin B reflect ovarian function in assisted reproduction but are less useful at predicting outcome

To test the hypothesis that dimeric inhibin A and/or inhibin B concentrations represent improved markers of in-vitro fertilization (IVF) outcome over follicle stimulating hormone (FSH), 78 women who achieved pregnancy within three assisted reproduction treatment cycles were matched to 78 women who underwent at least three assisted reproductive treatment cycles and failed to achieve pregnancy. Baseline serum inhibin B and FSH were obtained between days 1 and 4 in a cycle prior to ovarian stimulation, and inhibin A and B were measured immediately before the ovulatory stimulus and in follicular fluid from the lead follicle. Comparing pregnant and non-pregnant subjects at baseline, younger age (34.0 +/- 0.5 versus 36.0 +/- 0.5 years; P < 0.003) and a combination of FSH lower than the median value (11.2 IU/l) and inhibin B higher than the median value (76.5 pg/ml) were associated with pregnancy (P < 0.03), but FSH (11.7 +/- 0.5 versus 12.9 +/- 0.9 IU/ml) and inhibin B (89.0 +/- 10.2 versus 79.7 +/- 7.7 pg/ml) were not independently associated. At the time of the ovulatory stimulus, serum inhibin A (52.8 +/- 3.8 versus 40.0 +/- 2.7 IU/ml; P < 0.004), inhibin B (1623.8 +/- 165.1 versus 859.2 +/- 94.8 pg/ml; P < 0.0009) and the number of oocytes retrieved (14.6 +/- 0.8 versus 10.1 +/- 0.6; P < 0.0001) were predictive of pregnancy when controlled for age. Inhibin A was correlated with the number of embryos (r = 0.4; P < 0.0001). However, neither inhibin A nor inhibin B provided additional information in predicting successful outcome over age and number of oocytes. We conclude that: (i) in patients undergoing assisted reproductive technology, age and number of oocytes retrieved are the strongest predictors of success; (ii) of the parameters available prior to cycle initiation, a combination of lower FSH and higher inhibin B was associated with a greater chance for a successful outcome but an absolute cut-off could not be defined; and (iii) during ovarian stimulation, higher concentrations of inhibin A and inhibin B in serum are associated with successful IVF and mark ovarian reserve as a measure of oocyte number and quality.