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Research question Ovarian stimulation during IVF cycles involves close monitoring of oestradiol, progesterone and ultrasound measurements of follicle growth. In contrast to blood draws, sampling saliva is less invasive. Here, a blind validation is presented of a novel saliva-based oestradiol and progesterone assay carried out in samples collected in independent IVF clinics. Design Concurrent serum and saliva samples were collected from 324 patients at six large independent IVF laboratories. Saliva samples were frozen and run blinded. A further 18 patients had samples collected more frequently around the time of HCG trigger. Saliva samples were analysed using an immunoassay developed with Salimetrics LLC. Results In total, 652 pairs of saliva and serum oestradiol were evaluated, with correlation coefficients ranging from 0.68 to 0.91. In the European clinics, a further 237 of saliva and serum progesterone samples were evaluated; however, the correlations were generally poorer, ranging from –0.02 to 0.22. In the patients collected more frequently, five out of 18 patients (27.8%) showed an immediate decrease in oestradiol after trigger. When progesterone samples were assessed after trigger, eight out of 18 (44.4%) showed a continued rise. Conclusions Salivary oestradiol hormone testing correlates well to serum-based assessment, whereas progesterone values, around the time of trigger, are not consistent from patient to patient.

The prediction of extremes of ovarian response to stimulation and the irreversibility of reduced ovarian reserve remain important clinical and basic science research issues of IVF treatment. Recommending commencement of ovarian stimulation using any of the available exogenous compounds without knowledge of individual ovarian potentials is simplistic and dangerous because of the possible adverse consequences for the woman. The identification of groups of patients likely to benefit from one protocol than another is central to the workup process of IVF. Determining the agents for ovarian stimulation as well as the combination of them, the daily dose and duration according to some background information should be seen as the way to enhance safety and cost-effectiveness. This discussion paper aims to introduce the concept of individualized ovarian stimulation in routine clinical practice and to generate interest for tailored stimulation protocols.

Objective: To investigate the effectiveness of treatment with transdermal testosterone gel (TTG) before controlled ovarian stimulation (COS) using GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection (ICSI). Design: Prospective randomized controlled trial. Setting: University-affiliated infertility clinic. Patient(s): A total of 110 low responders, who were defined as patients who failed to produce %3 follicles with a mean diameter of R16 mm with the result that %3 oocytes were retrieved despite the use of a high gonadotropin dose (>2,500 IU) in a previous failed IVF/ICSI cycle. Intervention(s): Patients were randomized into TTG pretreatment group or control group. For TTG pretreatment group, 12.5 mg TTG were applied daily for 21 days in the cycle preceding COS for IVF. Main Outcome Measure(s): COS results and IVF outcome. Result(s): There were no differences in patients’ characteristics between the two groups. Total dose and days of rhFSH used were significantly fewer in the TTG pretreatment group than in the control group. The numbers of oocytes retrieved, mature oocytes, fertilized oocytes, and good-quality embryos were significantly higher in the TTG pretreatment group. Embryo implantation rate and clinical pregnancy rate per cycle initiated also were significantly higher in the women pretreated with TTG. No patient reported adverse effects attributed to TTG use. Conclusion(s): TTG pretreatment might be beneficial in improving both response to COS and IVF outcome in low responders undergoing IVF/ICSI. (Fertil Steril� 2011;95:679‐83. � 2011 by American Society for Reproductive Medicine.)

In their quest for a child, infertile couples embark on a journey that is full of expectations and hopes. Over recent years, treatment procedures for assisted conception have become safer and more efficient. However, couples undergoing treatment can still experience some degree of emotional stress due to disappointment if pregnancy is not achieved, or if treatment cycles may have to be cancelled due to a low- or hyper-response. Strategies aimed at minimizing the variability of ovarian response or overall treatment outcome can be expected to significantly reduce this emotional stress. New developments have led to the production of follitropin alfa filled by mass. This is a highly consistent FSH preparation improving the consistency of ovarian response and reducing the risk of cycle cancellation. The impact of this new FSH preparation for assisted reproduction treatments is discussed in this review.

Gonadotrophin-releasing hormone (GnRH) antagonists have recently been introduced into clinical practice. They appear to offer a promising alternative to the long-established GnRH agonist regimens for prevention of a premature LH surge during ovarian stimulation for assisted reproductive techniques. Clinical outcomes achieved with antagonists are comparable with those of a long GnRH agonist protocol, while treatment times and gonadotrophin requirements are reduced and safety is improved. In particular, the antagonists appear to be associated with a lower risk of ovarian hyperstimulation syndrome (OHSS) than do agonists. Patient surveys suggest a preference for antagonist over agonist treatment cycles. These benefits suggest that GnRH antagonists have the potential to replace agonists as the treatment of choice in ovarian stimulation for assisted reproductive techniques. Two agents, cetrorelix and ganirelix, are currently in clinical use. Cetrorelix is available in single- and multiple-dose formulations, offering increased flexibility compared with ganirelix.

Objective: To compare the efficacy and the safety of recombinant human FSH (hFSH) with urinary hFSH for stimulating follicular development in women undergoing IVF-ET. Design: Multicenter, prospective, randomized, open, parallel group, clinical study. Setting: Eight European academic IVF units and one private IVF unit. Patient(s): Infertile female patients aged 18 to 38 years suffering from tubal disease, mild endometriosis, or unexplained infertility. Intervention(s): Pretreatment with buserelin acetate was followed by recombinant or urinary hFSH treatment started at an initial dose of 225 IU FSH/d. Dose adjustment was allowed after 5 days of FSH. After administration of hCG, a standard IVF-ET procedure was performed. Main Outcome Measure(s): Follicular development, oocyte retrieval, fertilized oocytes, duration and dose of FSH, and pregnancy. The hypothesis formulated before the study was that no difference was expected between the two FSH preparations. Result(s): Sixty patients were treated with recombinant hFSH and 63 with urinary hFSH. The mean number (±SD) of growing follicles (mean diameter >10 mm) was 10.3 ± 4.9 and 11.2 ± 5.2, of follicles (mean diameter >14 mm) was 7.8 ± 3.6 and 9.2 ± 4.5, of retrieved oocytes was 9.3 ± 5.0 and 10.7 ± 5.3, and of fertilized oocytes was 5.6 ± 3.8 and 6.5 ± 4.3, for recombinant and urinary hFSH, respectively. The duration of FSH treatment was 9.9 ± 2.3 and 9.4 ± 1.8 days and the average total dose was 2270 ± 714 and 2095 ± 591 IU of FSH, for recombinant and urinary hFSH, respectively. Thirteen pregnancies were recorded in the recombinant hFSH group and 11 in the urinary hFSH group. Nine patients delivered 13 live infants in the recombinant hFSH group and eight delivered 13 live infants in the urinary hFSH group. In terms of safety, no difference was recorded between the groups and no anti-FSH antibodies were found in any of the patients. Conclusion(s): This clinical study shows that recombinant hFSH is as safe and effective as urinary hFSH in stimulating ovarian follicular development.

Objective: To analyze the role of serum LH and of E 2 secretion on IVF-ET outcome in patients stimulated with FSH. Design: Using data from three studies, we analyzed ovarian response to FSH and IVF-ET outcome from two standpoints: [1] serum LH and [2] serum E 2 on the day of hCG administration divided by the number of retrieved oocytes. Setting: Twenty-six academic and private clinical centers. Patient(s): Three hundred twenty-three ovulatory patients eligible for IVF-ET. Intervention(s): Patients were treated with a GnRH agonist and FSH and underwent IVF-ET. Main Outcome Measure(s): Follicular development, embryos, and pregnancy rate (PR). Result(s): Serum LH levels did not correlate significantly with number of oocytes retrieved, E 2 -oocyte ratio, fertilization rate, or PR. Five patient subpopulations were identified on the basis of E 2 -oocyte ratios: 0 to 70 (A), 70 to 140 (B), 140 to 210 (C), 210 to 280 (D), and >280 (E) pg/mL per oocyte (conversion factor to SI unit, 3.671). Pregnancy rates were significantly different, i.e., 5.3%, 31.3%, 18.1%, 23.9%, and 20.4% for groups A, B, C, D, and E, respectively. Groups were not different in terms of baseline characteristics, number of follicles, fertilization rates, and number of embryos transferred. Conclusion(s): Patients with very low levels of LH respond to FSH alone as well as those with higher LH. The E 2 -oocyte ratio is a strong index of success rate.