In-vivo ovarian androgen responses to recombinant FSH with and without recombinant LH in polycystic ovarian syndrome

BACKGROUND: Effects of exogenous LH on ovarian androgen secretion during ovulation induction have not been clearly characterized in polycystic ovarian syndrome (PCOS). The purpose of this study was to compare androgen secretion in PCOS women during ovarian stimulation with either recombinant FSH (rFSH) alone or combined with recombinant LH (rLH). METHODS: Clomiphene-resistant women with PCOS were allocated, in a factorial study design, to receive either daily injections of rFSH (n = 24) or rFSH + rLH (n = 24) in a 1:1 ratio starting: (i) on day 2-3 of progestogen-induced menses (n = 8); (ii) after 6 weeks of GnRH agonist treatment (nafarelin, 400 micro g twice daily; n = 8); or (iii) after nafarelin treatment as in (ii) plus dexamethasone (n = 8). The effects of rFSH with rFSH + rLH under these three hormone conditions on serum LH, 17alpha-hydroxyprogesterone (17-OHP), androstenedione (DeltaDelta(4)) and testosterone were contrasted by analysis of variance with specific treatment days as a repeated measures factor. RESULTS: Pre-study hormone levels were similar for all groupings. Nafarelin significantly suppressed LH levels, which remained at the lower limit of assay sensitivity (0.5 IU/l) during stimulation with rFSH but increased significantly to >1 but <2 IU/l when rLH was added. As expected, 17-OHP, DeltaDelta(4) and testosterone levels fell following nafarelin treatment. Dexamethasone further suppressed 17-OHP, DeltaDelta(4) and testosterone levels and unmasked a small but significant rise in these ovarian steroids 24 h following the first dose of rFSH + rLH, a rise that was absent with rFSH alone. Secretion of these steroids then appeared to 'catch-up' after 5 days of rFSH stimulation. CONCLUSIONS: Despite profound LH, 17-OHP, DeltaDelta(4) and testosterone suppression, comparable E(2) response, follicle development and successful pregnancies in PCOS subjects receiving rFSH alone to those receiving rFSH + rLH would argue that circulating LH at levels as low as 0.5 IU/l are sufficient to sustain adequate follicle development and function when FSH is present in abundance. Whether the observed dichotomy between rFSH and rFSH + rLH treatment in temporal secretion patterns reflects a greater reliance on evolving paracrine mechanisms as the follicles mature under profound LH suppression remains to be explored but may influence the optimal LH threshold for ovulation induction in PCOS.     

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.     

Endocrine profile in serum and follicular fluid differs after ovarian stimulation with HP-hMG or recombinant FSH in IVF patients

BACKGROUND: Highly purified menotrophin (HP-hMG) has been associated with fewer oocytes retrieved and a higher proportion of top-quality embryos compared with recombinant FSH (rFSH). METHODS: A randomized, assessor-blind, multinational trial in 731 women undergoing IVF after stimulation with HP-hMG (MENOPUR) (n = 363) or rFSH (GONAL-F) (n = 368) following a long GnRH agonist protocol was conducted. Blood was collected before, during and after stimulation. Fluid was collected from follicles > or =17 mm. RESULTS: Serum androstenedione, total testosterone and free androgen index (FAI) were higher (P < 0.001) with HP-hMG than with rFSH after starting stimulation. At the end of stimulation, serum estradiol was higher (P = 0.031) with HP-hMG, whereas progesterone was higher (P < 0.001) with rFSH, even after adjusting for ovarian response. Serum LH was not different between treatments. Mean mid- and end-follicular hCG levels in the HP-hMG group were 2.5 and 2.9 IU/l, respectively. Follicular fluid levels of FSH, LH, hCG, androstenedione, testosterone, FAI and estradiol and ratios of estradiol:androstenedione, estradiol:total testosterone and estradiol:progesterone were higher (P < 0.001) with HP-hMG, whereas progesterone was higher (P < 0.001) with rFSH. CONCLUSION: Major differences in serum and follicular fluid endocrine profile exist after stimulation with HP-hMG or rFSH. Exogenous LH activity induces a differential endocrine environment influencing oocyte quantity and quality, which may be of relevance for clinical outcome.     

Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO Group II anovulatory infertility: a randomized controlled study

BACKGROUND: The contribution of the LH activity in menotrophin preparations for ovulation induction has been investigated in small trials conducted versus FSH preparations. The objective of this study was to demonstrate non-inferiority of highly purified urinary menotrophin (HP-HMG) versus recombinant FSH (rFSH) with respect to the primary outcome measure, ovulation rate. METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-HMG (n=91) or rFSH (n=93) using a low-dose step-up protocol. RESULTS: The ovulation rate was 85.7% with HP-HMG and 85.5% with rFSH (per-protocol population), and non-inferiority was demonstrated. Significantly fewer intermediate-sized follicles were observed in the HP-HMG group (P<0.05). The singleton live birth rate was comparable between the two groups. The frequency of ovarian hyperstimulation syndrome and/or cancellation due to excessive response was 2.2% with HP-HMG and 9.8% with rFSH (P=0.058). CONCLUSIONS: Stimulation with HP-HMG is associated with ovulation rates at least as good as a rFSH in anovulatory WHO Group II women. LH activity modifies follicular development so that fewer intermediate-sized follicles develop. This could have a positive impact on the safety of ovulation induction protocols.     

A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility

BACKGROUND: Controlled ovarian hyperstimulation with intrauterine insemination (IUI) is a widely accepted treatment for unexplained and male subfertility. No consensus exists about the drug of first choice to be used as hyperstimulation. This randomized multicentre trial using a parallel design compares the efficacy of clomiphene citrate (CC) with that of recombinant FSH (rFSH). METHODS: Couples with primary unexplained or male subfertility were randomized to receive CC or rFSH for ovarian hyperstimulation. The treatment was continued for up to four cycles unless pregnancy occurred. Cycles with more than three follicles were cancelled. Cumulative pregnancy rates and live birth rates were primary outcomes. Cancellation during treatment and multiple birth rates are secondary outcomes. Results were analysed following the intention-to-treat principle. RESULTS: Seventy couples with male subfertility and 68 couples with unexplained subfertility were included. Seventy-one women received CC, and 67 received rFSH. Twenty-seven pregnancies were observed in the CC group (38%) and 23 in the rFSH group (34.3%) relative risk (RR) 1.11 [95% confidence interval (95% CI) 0.71-1.73]. The live birth rate was 28.2% (20/71) and 26.9% (18/67) for CC and rFSH, respectively, RR 1.05 (95% CI 0.61-1.80). Overall, the live birth rates per cycle were 10% for CC-stimulated and 8.7% for rFSH stimulated cycles. The total multiple pregnancy rate was 6.0%. Thirty-five cycles (8.6%) were cancelled because of four or more follicles (CC, n = 17; rFSH, n = 18). CONCLUSIONS: In couples with primary unexplained or male subfertility participating in an IUI program, ovarian hyperstimulation can be achieved by CC or rFSH. No significant difference in live birth rates between CC and rFSH was observed. Being less expensive, CC seems the more cost-effective drug and therefore, can be offered as drug of first choice.     

Suppression of LH during ovarian stimulation: effects differ in cycles stimulated with purified urinary FSH and recombinant FSH

There has been much debate about the role of luteinizing hormone (LH) during follicle stimulating hormone (FSH)-treated ovarian stimulation for assisted reproduction, where the endogenous LH is suppressed using a gonadotrophin-releasing hormone analogue. The requirement for LH in oestradiol biosynthesis is established, but other effects of 'insufficiency' are less clear, and little attention has been paid to the specific origin of the FSH used. The aim of this study was to examine the roles of profoundly suppressed circulating LH concentrations in cycles of ovarian stimulation for IVF, which were affected in two large separate cohorts of patients undergoing assisted reproduction. They were stimulated by either purified urinary FSH (MHP) or recombinant human FSH (rFSH). Within each dataset, outcomes were examined with respect to the circulating concentrations of LH in the mid-follicular phase, as plasma samples were stored prospectively, and assayed retrospectively. Patients with profoundly suppressed LH showed much reduced oestradiol concentrations at mid-follicular phase and at human chorionic gonadotrophin administration in cycles treated with either MHP or rFSH. However, gross ovarian response, as became evident by FSH dose demands, duration of stimulation, and also oocyte and embryo yields and embryo cryopreservation were influenced only in cycles treated with MHP. Furthermore, no effect upon pregnancy survival was observed. Thus, it is concluded that there is a demand for additional exogenous LH treatment only in cycles treated with purified urinary FSH where the LH is profoundly suppressed.     

The effect of gonadotrophins with differing LH/FSH ratios on the secretion of the various species of inhibin in women receiving IVF

We have measured secretory patterns of inhibin A, B, total alpha inhibin, pro-alphaC inhibin and oestradiol in women following pituitary suppression who were randomised into two groups to receive either urinary gonadotrophin (25:75 IU/ampoule of luteinizing hormone (LH) and follicle stimulating hormone (FSH; Normegon; n = 11) or recombinant (r)FSH (75 IU/ampoule of FSH alone, n = 16). The women were of similar age (approximately 33 years) and length of infertility (approximately 4 years) and had a normal endocrine evaluation. Plasma FSH, LH, oestradiol, inhibin A, B, pro-alphaC and total alpha inhibin were measured by immunoassay prior to and following gonadotrophin stimulation. Immunoactive FSH, LH and oestradiol blood concentrations following pituitary down regulation were similar in the two groups being <2.0, <3.6 IU/l and <82 pmol/l respectively. The units of FSH given (2230 versus 2764 IU; Normegon versus rFSH), duration of treatment (9.1 versus 9.4 days) and number of follicles of > or =14mm on the day of human chorionic gonadotrophin (HCG) administration (17 versus 14) were also similar. Inhibin A or B concentrations rose similarly during Normegon or rFSH administration, peaking at days 9-11. Total alpha and pro-alphaC inhibin concentrations were lower (P < 0.05) in the rFSH group during days 10 and 11 of treatment being 18.9 +/- 15.9 ng/ml (Normegon) and 4.6 +/- 2.8 ng/ml (rFSH) for total alpha inhibin and 8.5 +/- 6.8 ng/ml (Normegon) and 2.8 +/- 1.6 ng/ml (rFSH) for pro-alphaC inhibin on day 10. Overall, higher total alpha inhibin concentrations were associated with more mature follicles and oocytes, greater fertilization rates and better quality embryos. We conclude that inhibin A and B secretion was similar in both groups and is primarily controlled by FSH, whereas total alpha inhibin and pro-alphaC increased preferentially in the Normegon group over the rFSH group, indicating that they are, in part, stimulated by LH.     

Clinical evidence for an LH 'ceiling' effect induced by administration of recombinant human LH during the late follicular phase of stimulated cycles in World Health Organization type I and type II anovulation

BACKGROUND: The objective of these studies was to test the hypothesis that over-dosing with recombinant human LH (rLH) during the late follicular phase would suppress the development of follicles. METHODS: Two double-blind studies were conducted. In study A, WHO I anovulatory patients received treatment with rFSH and rLH. When at least one follicle reached a mean diameter of 10-13 mm, patients were randomized using a computer-generated randomization list (stratified by centre) to rFSH and rLH (225 IU/day) (n = 8) or rLH alone (n = 6) or rFSH alone (n = 6). In study B, WHO II anovulatory patients with a hyper-responsive FSH were randomized to rLH (225 IU/day) (n = 4) or rLH 450 IU/day (n = 8) or placebo (n = 5). RESULTS: Study A: the mean number of follicles >/=11 mm was 4.2 +/- 0.3 in the rFSH group, 1.5 +/- 0.7 in the rLH group and 6.0 +/- 2.3 in the rFSH/rLH group (P = 0.07). 0/8 patients presented follicular growth arrest in the rFSH group, but 4/6 in the rLH group and 1/6 in the rFSH/rLH did. Study B: 5/12 patients presented follicular growth arrest in the rLH groups, but none in the placebo group. The mean number of follicles >/=11 mm was 4.6 +/- 1.8 for the placebo group, 2.5 +/- 1.9 for the rLH 225 IU group and 4.2 +/- 1.4 in the rLH 450 IU group (not significant). CONCLUSIONS: Results of this pilot study suggest that rLH alone can trigger follicular growth arrest in a significant number of patients, suggesting the existence of an 'LH ceiling' during late follicular maturation.     

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.     

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.     

Recombinant LH supplementation to recombinant FSH during the final days of controlled ovarian stimulation for in vitro fertilization. A multicentre, prospective, randomized, controlled trial

BACKGROUND: The purpose of this multicentre, multinational trial was to study whether rLH supplementation to recombinant FSH (rFSH) during the late follicular phase increased pregnancy rates. METHODS: After down-regulation with nafarelin, 526 women were randomized on Day 1 of stimulation to use either rFSH (Gonal-F) alone (n = 261) or to continue after Day 6 of stimulation with both rFSH (Gonal-F) and rLH (Luveris) (n = 265) from Day 6. The starting dose of rFSH was 150-225 IU/day according to age below or above 35 years. RESULTS: Ongoing pregnancy rate at week 10-12 was 28.7% after rFSH alone and 27.2% after rFSH + rLH. This showed no evidence of a difference. Administration of rLH significantly (P< 0.001) increased serum LH. Ongoing pregnancy rates in patients with low LH levels (<33 percentile) on Days 1 and 6 of stimulation showed no difference between the group treated with rFSH only (23.9% low Day 1 LH; 22.1% low Day 6 LH) versus rFSH + rLH (25.0% low Day 1 LH; 28.9% low Day 6 LH). CONCLUSIONS: Supplementing rFSH with daily doses of 75-150 IU of rLH during the second half of the follicular phase showed no evidence of increasing the ongoing pregnancy rates in the general population. (ClinicalTrials.gov, trial number: KF02-035/03).     

Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH

BACKGROUND: It has been recently suggested that gonadotrophin-releasing hormone agonist down-regulation in some normogonadotrophic women may result in profound suppression of LH concentrations, impairing adequate oestradiol synthesis and IVF and pregnancy outcome. The aims of this study, where receiver-operating characteristic (ROC) analysis was used, were: (i) to assess the usefulness of serum LH measurement on stimulation day 7 (S7) as a predictor of ovarian response, IVF outcome, implantation, and the outcome of pregnancy in patients treated with recombinant FSH under pituitary suppression; and (ii) to define the best threshold value, if any, to discriminate between women with 'low' or 'normal' LH concentrations. METHODS: A total of 144 infertile women undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment were included. Seventy-two consecutive patients having a positive pregnancy test (including 58 ongoing pregnancies and 14 early pregnancy losses) were initially selected. As a control non-pregnant group, the next non-conception IVF/ICSI cycle after each conceptual cycle in our assisted reproduction programme was used. RESULTS: The median and range of LH values in non-conception cycles, conception cycles, ongoing pregnancies, and early pregnancy losses, clearly overlapped. ROC analysis showed that serum LH concentration on S7 was unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.52; 95% CI: 0.44 to 0.61) or ongoing pregnancy versus early pregnancy loss groups (AUC(ROC) = 0.59; 95% CI: 0.46 to 0.70). To assess further the potential impact of suppressed concentrations of circulating LH during ovarian stimulation on the outcome of IVF/ICSI treatment, the three threshold values of mid-follicular serum LH proposed in the literature (<1, < or =0.7, <0.5 IU/l) to discriminate between women with 'low' or 'normal' LH were applied to our study population. No significant differences were found with respect to ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy between 'low' and 'normal' S7 LH women as defined by those threshold values. CONCLUSIONS: Our results do not support the need for additional exogenous LH supplementation in down-regulated women receiving a recombinant FSH-only preparation.     

Highly purified FSH is as efficacious as recombinant FSH for ovulation induction in women with WHO Group II anovulatory infertility: a randomized controlled non-inferiority trial

BACKGROUND: The objective of this study was to demonstrate non-inferiority of a highly purified urinary follicle stimulating hormone (HP-FSH) preparation compared with a recombinant (rFSH) preparation with respect to ovulation rate (primary end-point). METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-FSH (n=73) or rFSH (n=78) using a low-dose step-up protocol. The non-inferiority limit was prespecified at -20%. RESULTS: The ovulation rate was 85.2% (51/62) with HP-FSH and 90.9% (60/66) with rFSH (per-protocol population), and non-inferiority was demonstrated [95% confidence interval: -16.9; 5.6]. No differences were noted between groups in number of follicles>or=12 mm, >or=15 mm or >or=18 mm, mono-follicular development, pregnancy rates, endometrial thickness, number of ovarian stimulation syndrome cases or frequency of injection site reactions/pain. The singleton live birth rate was 15% in both groups (11/73 with HP-FSH and 12/78 with rFSH). CONCLUSIONS: This urinary HP-FSH preparation is non-inferior compared with a rFSH preparation with respect to ovulation rate in anovulatory WHO Group II women failing to ovulate or conceive on clomiphene citrate.     

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.     

Rescue of IVF cycles by HMG in pituitary down-regulated normogonadotrophic young women characterized by a poor initial response to recombinant FSH

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.     

A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). The ganirelix dose-finding study group

A multicentre, double-blind, randomized dose-finding study of Org 37462 (ganirelix) was conducted in 333 women undergoing ovarian stimulation with recombinant follicle stimulating hormone (rFSH; Puregon) to establish the minimal effective dose preventing premature luteinizing hormone (LH) surges during ovarian stimulation. For ovarian stimulation, rFSH was given in a fixed daily dose of 150 IU for 5 days from days 2 to 6 of the menstrual cycle. From cycle day 7 onward, up to and including the day of human chorionic gonadotrophin (HCG), Org 37462 (dosages 0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/0.5 ml) was administered once daily by s.c. injection, and the rFSH dose was adjusted depending on ovarian response. The lowest (0.0625 mg) and highest (2.0 mg) dose groups were terminated prematurely on the advice of an external independent advisory committee. Serum Org 37462 concentrations increased in a linear dose-proportional manner, whereas serum LH and increases of oestradiol fell with increasing Org 37462 dose. During Org 37462 treatment, serum LH concentrations > or =10 IU/l were observed in the lowest dose groups with incidences of 16% (0.0625 mg), 9% (0.125 mg) and 1.4 % (0.25 mg). On the day of HCG, the number of follicles > or =11, > or =15 and > or =17 mm were similar in the six dose groups, whereas serum oestradiol concentrations were highest in the 0.0625 mg group (1475 pg/ml) and lowest in the 2 mg group (430 pg/ml). The median daily dose of rFSH was between 150 and 183 IU and the overall median duration of Org 37462 treatment was approximately 5 days in the six treatment groups. Overall, Org 37462 treatment appeared to be safe and well tolerated. The mean number of recovered oocytes and good-quality embryos was similar in all dose groups and ranged from 8.6 to 10.0 and 2.5 to 3.8, respectively. The mean number of replaced embryos in the different dose groups ranged from 2.3 to 2.7. The implantation rate was highest in the 0.25 mg group (21.9%) and lowest in the 2 mg group (1.5%). The early miscarriage rates (first 6 weeks after embryo transfer) were 11.9 and 13% in the 1 and 2 mg group respectively, whereas in the other dose groups this incidence was zero (0.0625%) up to a maximum of 3.7% (0.5 mg group). The vital pregnancy rate (with heart activity) at 5-6 weeks after embryo transfer was highest in the 0.25 mg group, i.e. 36.8 % per attempt and 40.3 % per transfer, and resulted in an ongoing pregnancy rate 12-16 weeks after embryo transfer of 33.8% per attempt and 37.1% per transfer. In conclusion, a daily dose of 0.25 mg Org 37462 prevented LH surges during ovarian stimulation and resulted in a good clinical outcome.      

A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction

BACKGROUND: Studies with the GnRH antagonist ganirelix in assistedreproduction have indicated that compared with traditional GnRHagonist downregulation protocols, slightly fewer oocytes areretrieved. In this study it was investigated whether an increasein the starting dose of recombinant FSH (rFSH) could compensatefor this loss. METHODS: A randomized, double-blind, multicentreclinical trial comparing a starting dose of 150 and 200 IUof rFSH (follitropin ), in women undergoing treatment with theGnRH antagonist ganirelix. RESULTS: In total, 257 women weretreated with rFSH, of whom 131 received 150 IU and 126women 200 IU. Overall, 10.3 oocytes were retrieved in the150 IU group and 11.9 in the 200 IU group (P = 0.051).This difference became significant when women with cycle cancellationbefore HCG administration were excluded. Nearly 500 IUof additional rFSH was given in the high-dose group (2014 versus1541 IU). In the low-dose group, 4.6 high-quality embryoswere obtained compared with 4.5 in the high-dose group. Vitalpregnancy rates were similar (31 and 25% in the 150 and 200 IU-treatedwomen, respectively). Serum concentrations of FSH, estradioland progesterone were significantly higher in the high-dosegroup at day 6 of rFSH treatment and on the day of HCG administration.In the high-dose group, serum LH concentrations were higherat day 6 of rFSH treatment but lower at the day of HCG administration.CONCLUSION: By increasing the starting dose from 150 to 200 IUof rFSH, slightly more oocytes can be retrieved in GnRH antagonistprotocols for assisted reproduction. However, because this didnot translate into a higher number of high quality embryos,the clinical relevance of such a dose increase may be questioned.     

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

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.     

A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a 'standard' dose of 150 IU/day in 'standard' patients undergoing IVF/ICSI treatment

BACKGROUND: The study aim was to compare the use of individual rFSH doses between 100 and 250 IU/day (calculated using the rFSH dose normogram) with a standard dose of rFSH of 150 IU/day. METHODS: This prospective randomized dual-centre clinical trial included 267 first IVF/ICSI cycles using the long agonist protocol in 'standard' patients. Following down-regulation, 262 patients were randomized using computer-generated lists using 'clusters of 10' into the individual dose (study) group (n = 131) or the standard dose (control) group (n = 131). RESULTS: In the study group, 101 patients (77.1%) had an appropriate response (defined as 5-14 oocytes), compared with 86 (65.6%) in the control group (P < 0.05). Fewer than five oocytes were retrieved in two patients (1.5%) in the study group, compared with 14 patients (10.7%) in the control group (P < 0.05). By comparison, >14 oocytes were retrieved from 27 patients (20.6%) in the study group and from 26 (19.8%) control patients (P = NS). Eighty-six per cent of the individual dose patients did not require any dose adjustment on day 8, compared with 45% of the standard dose patients (P < 0.01). The ongoing pregnancy rate per initiated cycle was 36.6% in the study group and 24.4% in the control group (P < 0.01). One patient (0.8%) in the study group, and four patients (3.1%) in the control group, were hospitalized due to ovarian hyperstimulation syndrome. CONCLUSIONS: An individual dose regimen in a well-defined 'standard' patient population increased the proportion of appropriate ovarian responses and decreased the need for dose adjustments during controlled ovarian stimulation. A higher ongoing pregnancy rate was observed in the individual dose group.     

Effects of profound suppression of luteinizing hormone during ovarian stimulation on follicular activity, oocyte and embryo function in cycles stimulated with purified follicle stimulating hormone

The effects of profound suppression of circulating luteinizing hormone (LH) during the follicular phase of in-vitro fertilization cycles were explored in normal women during treatment with a gonadotrophin- releasing hormone analogue and exogenous purified follicle stimulating hormone. Ovarian responses to treatment and the capacity of supernumerary embryos to undergo blastocyst formation were examined in groups of patients defined by the concentration of plasma LH in the mid- follicular phase. Concentrations < or = 0.5 IU/I diagnosed the group with profoundly suppressed LH (<LH, n = 20), which was compared with the remaining patients (nLH, n = 41). The <LH group showed lower oestradiol concentrations at human chorionic gonadotrophin administration, while the total follicular development estimated by the total follicular diameters was similar in both groups. The oestradiol secreted per follicle, estimated by the circulating concentration per mm total follicular diameter, was significantly lower in the <LH group. The combined effects of a trend to lower yield of oocytes (not significant) and a lower fertilization rate (not significant) resulted in a significantly reduced quantity of embryos available for cryopreservation after the fresh transfer. Supernumerary embryos were cultured for 7 days to determine blastocyst development rates, and the degree of LH suppression made no difference to embryo developmental competence (nLH, 23%; <LH, 27%), or the rates of blastocyst formation. The group of patients with profoundly suppressed mid-follicular phase LH showed a reduced yield of oocytes and embryos which resulted in significantly fewer embryos available for cryopreservation. However, the developmental potential of those embryos, represented by the ability to form blastocysts in vitro, was unaffected.