Randomized, controlled, open-label, non-inferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa.

In this randomized, controlled, open-label, phase IV study, ovarian response after a follitropin alfa starting dose determined by the CONSORT calculator was compared with a standard dose (150 IU). Normo-ovulatory women (aged 18-34 years) eligible for assisted reproductive techniques were recruited (23 centres: nine European countries and Chile); 200 women were randomized (CONSORT [n = 96]; standard dosing [n = 104]). Significantly lower mean daily (121.5 versus 167.4 IU; P < 0.001) and total (1288.5 versus 1810.0 IU; P < 0.001) doses of follitropin alfa were administered in the CONSORT group. Clinical pregnancy rates were CONSORT (36.0%) and standard dosing (35.5%); estimated difference (confidence interval 0.6%; -13.5 to 14.6). Ovarian hyperstimulation syndrome occurred in 6.3% and 12.5% of patients in the CONSORT and standard-dosing groups, respectively. The primary efficacy analysis found a significantly lower mean [SD] number of oocytes retrieved in the CONSORT (10.0 [5.6]; P = 0.037) versus standard-dosing group (11.8 [5.3]). Although the CONSORT calculator was statistically inferior to standard dosing in the number of oocytes retrieved, clinical pregnancy rates (fresh embryo transfers) were similar in both groups, and incidence of ovarian hyperstimulation syndrome was lower in the CONSORT group.

Health outcomes of children born after IVF/ICSI: a review of current expert opinion and literature.

The Sixth Evian Annual Reproduction (EVAR) Workshop Group Meeting was held to evaluate the impact of IVF/intracytoplasmic sperm injection on the health of assisted-conception children. Epidemiologists, reproductive endocrinologists, embryologists and geneticists presented data from published literature and ongoing research on the incidence of genetic and epigenetic abnormalities and congenital malformations in assisted-conception versus naturally conceived children to reach a consensus on the reasons for potential differences in outcomes between these two groups. IVF-conceived children have lower birthweights and higher peripheral fat, blood pressure and fasting glucose concentrations than controls. Growth, development and cognitive function in assisted-conception children are similar to controls. The absolute risk of imprinting disorders after assisted reproduction is less than 1%. A direct link between assisted reproduction and health-related outcomes in assisted-conception children could not be established. Women undergoing assisted reproduction are often older, increasing the chances of obtaining abnormal gametes that may cause deviations in outcomes between assisted-conception and naturally conceived children. However, after taking into account these factors, it is not clear to what extent poorer outcomes are due to the assisted reproduction procedures themselves. Large-scale, multicentre, prospective epidemiological studies are needed to investigate this further and to confirm long-term health consequences in assisted-conception children. Assisted reproduction treatment is a general term used to describe methods of achieving pregnancy by artificial means and includes IVF and sperm implantation. The effect of assisted reproduction treatment on the health of children born using these artificial methods is not fully understood. In April 2011, fertility research experts met to give presentations based on research in this area and to look carefully at the evidence for the effects of assisted reproduction treatment on children's health. The purpose of this review was to reach an agreement on whether there are differences in the health of assisted-conception children with naturally conceived children. The researchers discovered no increased risk in birth defects in assisted-conception children compared with naturally conceived children. They found that IVF-conceived children have lower birth weights and higher fat under the skin, higher blood pressure and higher fasting glucose concentrations than naturally conceived children; however, growth, development and cognitive function are similar between groups. A very low risk of disorders of genetic control was observed in assisted-conception children. Overall, there did not appear to be a direct link between assisted reproduction treatment and children's health. The researchers concluded that the cause of some differences in the health of children conceived using assisted reproduction treatment may be due to the age of the woman receiving treatment. Large-scale, research studies are needed to study the long-term health of children conceived using assisted reproduction treatment.

Contemporary genetic technologies and female reproduction.

BACKGROUND: The Fifth Evian Annual Reproduction (EVAR) Workshop Meeting discussed knowledge regarding contemporary genetics in female reproduction. METHODS: Specialist reproductive medicine clinicians and geneticists delivered presentations based on published literature and current research. The content of this report is based on the expert presentations and subsequent group discussions that took place during this Workshop. RESULTS: Numerous ovarian genes with a role in infertility have been identified. Future challenges for genetic screening of patients, such as those with polycystic ovary syndrome, primary ovarian insufficiency or endometriosis, include the identification of high-throughput strategies and how to apply these findings to infertile patients. The identification of high-quality embryos in IVF using objective technologies remains a high priority in order to facilitate single-embryo transfer. Gene expression profiling of cumulus cells surrounding the oocyte, and proteomic and metabolomic approaches in embryo culture media may significantly improve non-invasive embryo quality assessment. CONCLUSIONS: The way forward in advancing the knowledge of genes involved in reproduction was considered to be through genome-wide association studies involving large numbers of patients. Establishing international collaboration is required to enable the application of such technologies in sufficient numbers of patients.

Recombinant gonadotrophins in reproductive medicine: the gold standard of today.

Since the early 1980s when gonadotrophins were first routinely used in ovarian stimulation regimens, there have been important advances in pharmaceutical product development, leading to the availability today of highly purified and consistent human gonadotrophins produced by recombinant technology, that have benefited cycle management and treatment outcomes. This 'evolution' has introduced scientifically robust and 'state of the art' processes and equipment to ensure that the product is consistent, pure and safe, and is the optimal way to reduce risk of any viral, protein, and bacterial contamination. Production of human proteins by recombinant technology has resulted in improvements in product purity, consistency and delivery as well as enabling the design of future generations of gonadotrophins (e.g. longer-acting forms and orally active mimetics).

Factors related to successful ovulation induction in patients with WHO group II anovulatory infertility.

To identify baseline characteristics related to successful ovulation induction, data were analysed from oligo- or anovulatory patients undergoing their first cycle of human recombinant FSH (r-hFSH; follitropin alfa) in a chronic low-dose (75 IU starting dose), step-up protocol in two clinical trials (n=446). Patients were grouped according to response: group A, ovulated within 14 days (75 IU follitropin alfa); group B, ovulated after 14 days (>75 IU follitropin alfa); group C, not administered human chorionic gonadotrophin (HCG) because of poor response; group D, cycle cancelled due to over-response (HCG not administered); group E, spontaneous ovulation prior to obtaining criteria for administration of HCG. Mean body mass index (BMI) of group A (25.0 kg/m(2)) was significantly lower than groups B (27.1 kg/m(2), P<0.001) or C (28.2 kg/m(2), P<0.0001), but similar to group D (24.3 kg/m(2)). Mean antral follicle count (AFC) of group A was also significantly lower than group C (18.3 versus 22.7; P=0.018), but not significantly different from groups B (21.5) or D (19.5); group E had the highest mean AFC (35.7). Comparatively low BMI, low AFC and higher (although still within the normal range) FSH concentration at baseline were associated with successful ovulation induction in infertile women undergoing a chronic low-dose, step-up stimulation protocol.

Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study.

The CONSORT dosing algorithm individualizes recombinant human FSH (r-hFSH) doses for assisted reproduction technologies, assigning 37.5 IU increments according to patient characteristics: basal FSH, body mass index, age and antral follicle count. A prospective, uncontrolled, international, 18-centre, pilot study of normo-ovulatory women aged 18-34 years inclusive undergoing a long agonist treatment protocol was performed. Follitropin alpha filled-by-mass (GONAL-f) dose was assigned by the algorithm and was intended to be altered only for risk of ovarian hyperstimulation syndrome (OHSS). Primary end-point was number of oocytes retrieved. Dose groups containing >or=5 patients were analysed: 75 IU (n = 48), 112.5 IU (n = 45), 150 IU (n = 34), 187.5 IU (n = 24), 225 IU (n = 10). Cancellations due to inadequate response were higher than expected in the 75 IU group (12/48). Overall, a median of 9.0 oocytes were retrieved (8.5, 8.0, 10.0, 12.0 and 8.0 in the 75, 112.5, 150, 187.5 and 225 IU groups respectively). Clinical pregnancy rates/cycle started were 31.3, 31.1, 35.3, 50.0 and 20.0%, respectively (overall, 34.2%). Two patients had severe OHSS. Use of the CONSORT algorithm achieved an adequate oocyte yield and good pregnancy rates in this preliminary study. Adjustment of the algorithm could reduce cancellation rates.

Progesterone supplementation during cryopreserved embryo transfer cycles: efficacy and convenience of two vaginal formulations.

Sequential exogenous oestradiol and progesterone are often used to prepare the endometrium in frozen embryo transfer (FET) cycles. This open-label, randomized study compared the efficacy and acceptability of self-administered once daily vaginal progesterone gel and vaginal micronized progesterone tablets (three times daily) for luteal support in FET cycles. An Asian population of women (aged < or = 45 years) were assigned randomly to receive progesterone gel (90 mg, once daily, n= 100) or vaginal micronized progesterone tablets (200 mg, three times daily, n= 100). All received oestradiol from day 2 of the menstrual cycle, for at least 10 days (or until endometrial thickness was > or =8 mm), before self-administering progesterone for 2 days before FET and up to 14 weeks afterwards if pregnancy occurred. Clinical pregnancy rates (31% for gel and 28% for tablets) and implantation rates (9.8% and 8.8%, respectively) were not significantly different between the treatment groups. Asian women using once daily progesterone gel found the gel easy to use and comfortable, and preferred it to their previous experience of vaginally administered tablets. In summary, once-daily vaginal progesterone gel has similar efficacy to vaginal tablets and is associated with high patient satisfaction.

Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation.

BACKGROUND: The role of LH in sensitizing antral follicles to FSH is unclear. LH is required for normal hormone production and normal oocyte and embryo development, but follicular responses to LH may depend upon the stage of development. Potential roles at the early follicular phase were explored in a clinical setting by employing a sequential approach to stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist. METHODS: We employed a multi-centre, prospective, randomized approach. Women (n = 146) were treated in a long course high-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured at the start of r-hLH treatment, on FSH stimulation Days 0 and 8 and at the time of HCG administration. RESULTS: The LH treatment was associated with increased small antral follicles prior to FSH stimulation (P = 0.007), and an increased yield of normally fertilized (2 PN) embryos (P = 0.03). There was no influence of the r-hLH pretreatment upon hormone profiles or ultrasound assessments during the FSH phase. Anti-mullerian hormone increased in both groups during the week prior to FSH stimulation (P = 0.002). CONCLUSIONS: This sequential approach to the use of r-hLH in standard IVF showed a possible modest clinical benefit. The results support other recent work exploring up-regulated androgen drive upon follicular metabolism indicating that clinical benefit may be obtainable after further practical explorations of the concept.

The use of a decremental dose regimen in patients treated with a chronic low-dose step-up protocol for WHO Group II anovulation: a prospective randomized multicentre study.

BACKGROUND: In women with chronic anovulation, the choice of the FSH starting dose and the modality of subsequent dose adjustments are critical in controlling the risk of overstimulation. The aim of this prospective randomized study was to assess the efficacy and safety of a decremental FSH dose regimen applied once the leading follicle was 10-13 mm in diameter in women treated for WHO Group II anovulation according to a chronic low-dose (CLD; 75 IU FSH for 14 days with 37.5 IU increment) step-up protocol. METHODS: Two hundred and nine subfertile women were treated with recombinant human FSH (r-hFSH) (Gonal-f) for ovulation induction according to a CLD step-up regimen. When the leading follicle reached a diameter of 10-13 mm, 158 participants were randomized by means of a computer-generated list to receive either the same FSH dose required to achieve the threshold for follicular development (CLD regimen) or half of this FSH dose [sequential (SQ) regimen]. HCG was administered only if not more than three follicles >or=16 mm in diameter were present and/or serum estradiol (E(2)) values were <1200 pg/ml. The primary outcome measure was the number of follicles >or=16 mm in size at the time of hCG administration. RESULTS: Clinical characteristics and ovarian parameters at the time of randomization were similar in the two groups. Both CLD and SQ protocols achieved similar follicular growth as regards the total number of follicles and medium-sized or mature follicles (>/=16 mm: 1.5 +/- 0.9 versus 1.4 +/- 0.7, respectively). Furthermore, serum E(2) levels were equivalent in the two groups at the time of hCG administration (441 +/- 360 versus 425 +/- 480 pg/ml for CLD and SQ protocols, respectively). The rate of mono-follicular development was identical as well as the percentage of patients who ovulated and achieved pregnancy. CONCLUSIONS: The results show that the CLD step-up regimen for FSH administration is efficacious and safe for promoting mono-follicular ovulation in women with WHO Group II anovulation. This study confirms that maintaining the same FSH starting dose for 14 days before increasing the dose in step-up regimen is critical to adequately control the risk of over-response. Strict application of CLD regimen should be recommended in women with WHO Group II anovulation.

Predictive factors and a corresponding treatment algorithm for controlled ovarian stimulation in patients treated with recombinant human follicle stimulating hormone (follitropin alfa) during assisted reproduction technology (ART) procedures. An analysis of 1378 patients.

BACKGROUND: Identifying parameters that can accurately predict the response to controlled ovarian stimulation (COS) would be of great benefit in assisted reproductive technology (ART) procedures. An analysis was undertaken with the objective of determining whether specific factors could optimally predict a response to stimulation in ART, and to then develop a corresponding treatment algorithm that could be used to calculate the optimal starting dose of recombinant human follicle stimulating hormone (r-hFSH; follitropin alfa) for selected patients. METHODS: The overall population consisted of 2280 normo-ovulatory ART patients from 11 randomised clinical trials. However, for the final analysis population, only patients less than 35 years of age who received r-hFSH monotherapy (N = 1378) were included. RESULTS: Backwards stepwise regression modelling indicated that predictive factors for ovarian response included basal FSH, BMI, age and number of follicles < 11 mm at baseline screening. The concordance probability index was 59.5% for this model. CONCLUSIONS: In the largest data series so far analysed to determine predictive factors of ovarian response, basal FSH, BMI, age and number of follicles < 11 mm at screening were the most important variables in ART patients less than 35 years of age who were treated with r-hFSH monotherapy. Using these four predictive factors, a follitropin alfa starting dose calculator was developed that can be used to select the FSH starting dose required for an optimal response. The relevance of this dose calculator will be evaluated in a prospective clinical trial.

Recombinant gonadotrophins in reproductive medicine: the gold standard of today.

Since the early 1980s when gonadotrophins were first routinely used in ovarian stimulation regimens, there have been important advances in pharmaceutical product development, leading to the availability today of highly purified and consistent human gonadotrophins produced by recombinant technology, that have benefited cycle management and treatment outcomes. This 'evolution' has introduced scientifically robust and 'state of the art' processes and equipment to ensure that the product is consistent, pure and safe, and is the optimal way to reduce risk of any viral, protein, and bacterial contamination. Production of human proteins by recombinant technology has resulted in improvements in product purity, consistency and delivery as well as enabling the design of future generations of gonadotrophins (e.g. longer-acting forms and orally active mimetics).

Safety and efficacy of a 3 mg dose of the GnRH antagonist cetrorelix in preventing premature LH surges: report of two large multicentre, multinational, phase IIIb clinical experiences.

Gonadotrophin-releasing hormone antagonists are effective and safe in preventing premature LH surges, a leading cause of cycle cancellation or failure during assisted conception. Two studies assessed two administration regimens for cetrorelix (as Cetrotide): the multiple-dose (MD, 0.25 mg/day, n = 1066) and single-dose (SD, 3 mg, n = 541) protocols. Patient outcomes were very similar: >90% reached criteria for human chorionic gonadotrophin (HCG) administration and underwent oocyte retrieval; embryo transfer was performed in 83-84%; failure to retrieve oocytes was rare (0.8%); on average, 11 follicles > or =10 mm in diameter were seen on the day of HCG administration. The SD protocol was associated with higher numbers of oocytes retrieved and available for insemination, although the numbers of embryos obtained or transferred were comparable. A total of 251 and 121 pregnancies were reported in the MD and SD groups respectively. Pregnancy rates per embryo transfer were 27 and 28% respectively. Severe ovarian hyperstimulation syndrome (OHSS) occurred in <1% of cycles. Twelve per cent of patients reported local reactions to injections in the MD group, compared with 8% in the SD group; none was serious or led to discontinuation. Seventy-three per cent of patients in the SD group received only one injection. These two studies therefore show that the single-dose cetrorelix protocol offers equal efficacy and safety to the MD regimen, while having the advantage of requiring only one injection in most patients.

No influence of body weight on pregnancy rate in patients treated with cetrorelix according to the single- and multiple-dose protocols.

The question of whether adjustment to body weight is necessary in in-vitro fertilization (IVF) cycles using GnRH antagonists is currently under discussion. Therefore, a data analysis of five prospective studies using either the single- or the multiple-dose antagonist protocol with cetrorelix (Cetrotide) was performed. The influence of stimulation procedure, gonadotrophins and body weight on pregnancy rate was evaluated in a linear logit model. The effect of the stimulation procedure and body weight on the cumulus-oocyte complex (COC) and follicle number was explored in an ANOVA model. Cetrorelix plasma concentrations were tested for any correlation with body weight. Baseline and outcome parameters in different body weight groups (<50 kg, 50-59 kg, 60-69 kg, 70-79 kg, > or =80 kg) were assessed for human menopausal gonadotrophin and recombinant human FSH stimulation separately. Cetrorelix plasma concentrations were correlated with body weight, but no influence of the type of stimulation or body weight on pregnancy rate was found. Body weight did not influence cetrorelix plasma concentrations. In contrast, body weight significantly influenced the number of retrieved COC as well as the number of follicles on the day of human chorionic gonadotrophin administration. Body weight does not influence the outcome of treatment in cetrorelix cycles.

Cost-effectiveness modelling of recombinant FSH versus urinary FSH in assisted reproduction techniques in the UK.

BACKGROUND: The purpose of this study was to undertake an economic evaluation to compare the cost-effectiveness of recombinant (r)FSH with urinary (u)FSH for attaining clinical pregnancy with assisted reproduction. METHODS: Mathematical modelling was utilized incorporating a Markovian decision framework and a Monte Carlo simulation. Statistical representations of recurrent events over time were incorporated into a decision analysis involving fresh and frozen cycles in any sequence (after the first fresh embryo transfer cycle) over three successive assisted reproduction attempts. The mean values of transition probabilities were derived from randomized controlled clinical trials and published reports. The distributions of these transition probabilities were agreed upon by a panel of experts. Cost data for procedures and drugs were derived and validated according to the perspectives of the National Health Service and private clinics in the UK. RESULTS: The study involved 5000 Monte-Carlo simulations of treatment on a Markov cohort of 100 000 patients. The total number of pregnancies attained was significantly higher in the rFSH (40 575) compared with the uFSH (37 358) group. The cost per successful pregnancy was significantly lower for rFSH (5906 pounds sterling) compared with uFSH (6060 pounds sterling) and overall, fewer cycles of treatment were required with rFSH to achieve an ongoing pregnancy. The incremental cost-effectiveness ratio is 4148 pounds sterling for each additional clinical pregnancy with rFSH. CONCLUSIONS: In addition to the increased effectiveness of rFSH in ART, this study demonstrated that it is more cost-effective and more efficient than uFSH in attaining an ongoing pregnancy.

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.

Role of LH and FSH in ovarian function.

Human gonadotrophin preparations have been used in the treatment of infertility for almost four decades. The earliest preparations were derived from urine from postmenopausal women and contained approximately equal amounts of follicle stimulating hormone (FSH) and luteinizing hormone (LH) activities. However, with the recognition that FSH is the principal regulator of follicular growth and maturation, these have been largely superseded by highly purified urinary FSH preparations and, more recently, recombinant human FSH (r-hFSH). Because of its complexity, r-hFSH is expressed in mammalian cells grown in culture and, from a manufacturing stand point, offers superior purity and batch-to-batch consistency, compared with urinary preparations. A number of clinical trials have compared the efficacy of r-hFSH and urinary FSH in women undergoing assisted reproductive technologies (ART). In general, these have shown that fewer FSH ampoules are required to achieve ovarian stimulation with r-hFSH, while the number of oocytes retrieved and embryos produced are higher than with urinary FSH. Additionally, the results of a recent meta-analysis have also shown that the clinical pregnancy rate per cycle started is significantly higher with r-hFSH, compared with urinary FSH. Furthermore, in poor responder patients, higher implantation rates were seen in patients treated with r-hFSH than in those treated with urinary FSH, suggesting that embryo viability is increased following use of the recombinant preparations. The finding that FSH preparations produce effective ovarian stimulation compared to human menopausal gonadotrophins in women undergoing ART raises the question of whether LH is required for ovarian stimulation. This has been investigated in a number of recent studies. For example, results have suggested that implantation rates may actually be lower in women who received exogenous LH. Such studies suggest, therefore, that in normogonadotrophic women, the addition of LH to an r-hFSH regimen does not add any further clinical benefit and may actually be detrimental. Hence, it appears that LH administration is necessary only in women with hypogonadotrophic hypogonadism. In conclusion, r-hFSH is a consistently pure and high quality gonadotrophin preparation and contributes to increasing the successful outcome of an ART cycle. Together with careful auditing of routine clinical practice, and the application of evidence-based medicine to facilitate clinical decision making, this means that a total quality management approach can be applied to optimize the outcome of assisted reproduction.

A double-blind, randomized study to compare recombinant human follicle stimulating hormone (FSH; Gonal-F) with highly purified urinary FSH (Metrodin) HP) in women undergoing assisted reproductive techniques including intracytoplasmic sperm injection. The French Multicentre Trialists.

This prospective, double-blind, randomized, multicentre study compared the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH; Gonal-F((R))) versus highly purified urinary FSH (u-hFSH HP; Metrodin((R)) HP) in women undergoing ovarian stimulation for in-vitro fertilization, including intracytoplasmic sperm injection. A total of 278 patients began a long gonadotrophin-releasing hormone agonist protocol, then 139 received r-hFSH and 139 u-hFSH HP, 150 IU/day administered s.c., for the first 6 days of treatment. On day 7, the dose was adjusted, if necessary, according to ovarian response. Human chorionic gonadotrophin (HCG, 10 000 IU, s.c.) was administered once there was more than one follicle 18 mm in diameter and two others >/=16 mm. Oocyte retrieval was performed 36-38 h after HCG injection: 128 patients (92%) receiving r-hFSH and 113 (81%) receiving u-hFSH HP had at least one oocyte retrieved. Among patients receiving r-hFSH, there was a significantly higher mean (+/- SD) number of oocytes retrieved (11.0 +/- 5.9 versus 8.8 +/- 4.8 with u-hFSH HP; P = 0. 002) and mean number of embryos obtained (5.1 +/- 3.7 versus 3.5 +/- 2.9 with u-hFSH HP; P = 0.0001). With r-hFSH, significantly fewer FSH treatment days (11.7 +/- 1.9 versus 14.5 +/- 3.3) and 75 IU ampoules (27.6 +/- 10.2 versus 40.7 +/- 13.6) were required than with u-hFSH HP (P = 0.0001). Embryo replacement on day 2-3 after oocyte retrieval resulted in 36 liveborn children in the Gonal-F((R)) group and 33 in the Metrodin HP((R)) group (not significant). There were seven cases (5.0%) of ovarian hyperstimulation syndrome in the r-hFSH group and three (2.2%), in the u-hFSH HP group (not significant). It is concluded that r-hFSH is more effective than u-hFSH in inducing multiple follicular development.

Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements.

Low-dose follicle stimulating hormone (FSH) regimens for induction of ovulation for women with polycystic ovaries have succeeded in reducing the rate of ovarian hyperstimulation syndrome (OHSS) almost to nil and the rate of multiple pregnancies to a minimum of 6%. This has been achieved by reaching, but not exceeding, the threshold level of FSH, starting with a daily dose of 75 IU for 14 days, using small incremental dose rises where necessary, and inducing uniovulation in 70% of cycles. Conception rates are as good, if not better, than those achieved with conventional therapy. The miscarriage rate is still relatively high (20-25%) and obese women fare worse. Serum oestradiol concentrations and the number of large and intermediate follicles on the day of human chorionic gonadotrophin administration are much lower, in parallel with lower serum FSH concentrations. Inhibin values increase with the rise in serum FSH concentrations but those of luteinizing hormone decrease steadily throughout the follicular phase. New data using recombinant hFSH (rhFSH), rather than urinary gonadotrophin as the ovarian stimulant, demonstrate that treatment time is shortened. However, the ideal regimen has still to be formulated.

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.

A comparative prospective study of a chronic low dose versus a conventional ovulation stimulation regimen using recombinant human follicle stimulating hormone in anovulatory infertile women.

The efficacy and safety of a chronic low dose (group A) and a conventional (group B) stimulation regimen of recombinant human follicle stimulating hormone (r-HFSH) were compared in 103 WHO Group II infertile women with clomiphene citrate-resistant anovulation. Mono- or bifollicular development was induced in 88.1% of patients in group A compared with 76.1% in group B. Ovulation and pregnancy rates were higher in group A (71.4% and 33.3%, respectively) than in group B (63.0% and 20%), but these differences were not statistically significant. Additionally, the total number of follicles that were >10 mm diameter was lower in group A than group B (3.0+/-2.6 versus 6.3+/-6.5; P < 0.0001), as was the oestradiol concentration (504+/-477 pg/ml versus 988+/-740 pg/ml; P < 0.03). The median dose of FSH (75 IU ampoules) used per cycle was 11 ampoules in group A and 12.5 in group B. In terms of the incidence of ovarian hyperstimulation syndrome, no differences were recorded between the two groups. The results demonstrated that r-HFSH is effective and safe in both these treatment protocols. The chronic low dose regimen was associated with a trend towards a higher rate of mono- or bifollicular development, without jeopardizing the incidence of pregnancy.