Overlapping biosimilar and originator follitropin alfa preparations: How much closer can they get?

Unfounded skepticism relating to biosimilars, arising from the assertion that they are not molecularly identical to their original counterpart, fails to acknowledge that no biological medicine, including Gonal-f® (from Merck Serono) is identical to itself. Molecular differences between the biosimilar and the reference medicines are irrelevant and clinically undetectable as long as they are contained within the accepted variability for the original medicine. Accordingly, the minor differences in 'ongoing pregnancy rate' and 'live birth' rate reported in a recent meta-analysis of biosimilars of Gonal-f® from Chua et al. are probably driven by product-unrelated factors, notwithstanding the fact that of the four products under analysis, only Ovaleap® (from Theramex UK Ltd) and Bemfola® (from Gedeon Richter Plc) can unambiguously be considered to be biosimilars. The EU Biosimilars model has proven successful, but some healthcare professionals, building on highly arguable premises, voice a distrust in biosimilars. Only if such scientifically unfounded distrust is reverted, the full promise of rFSH alfa biosimilars for reproductive medicine patients is likely to be fulfilled.

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study.

Background: Ovaleap® (follitropin alfa), a recombinant human follicle stimulating hormone, is a biosimilar medicinal product to Gonal-f® and is used for ovarian stimulation. The main objective of this study was to assess the safety and effectiveness of Ovaleap® compared to Gonal-f® in one treatment cycle in routine clinical practice. Methods: Safety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies (SOFIA) was a prospective cohort study conducted in six European countries. Eligible patients were infertile women undergoing superovulation for assisted reproductive technology, who were administered Ovaleap® or Gonal-f® for ovarian stimulation and were naïve to follicle stimulating hormone treatment. The recruitment ratio was 1:1. The primary endpoint was incidence proportion of ovarian hyperstimulation syndrome (OHSS) and the secondary endpoint was OHSS severity (Grades I, II, III). The effect of risk factors or potential confounders on the odds ratio for OHSS incidence as well as treatment effect on OHSS incidence was explored using univariate logistic regression. Pregnancy and live birth rates were also assessed. Results: A total of 408 women who were administered Ovaleap® and 409 women who were administered Gonal-f® were eligible for analysis. The incidence proportion of OHSS was 5.1% (95% CI: 3.4, 7.7) in the Ovaleap® cohort and 3.2% (95% CI: 1.9, 5.4) in the Gonal-f® cohort. This difference in OHSS incidence proportion between the two cohorts was not statistically significant neither before (p = 0.159) nor after univariate adjustment for each potential confounder (p > 0.05). The incidence proportion of OHSS severity grades was similar in the two treatment groups (3.4% versus 2.0% for Grade I, 1.2% versus 1.0% for Grade II, and 0.5% versus 0.2% for Grade III, in the Ovaleap® and Gonal-f® cohorts, respectively), without a significant statistical difference (p = 0.865, for each grade). Among patients who had embryo transfer, clinical pregnancy rates were 33% and 31% and live birth rates were 27% and 26%, in the two cohorts, respectively. Conclusions: Findings from the SOFIA study indicate that the incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, are similar between Ovaleap® and Gonal-f® treatments and corroborate the safety and effectiveness of Ovaleap® as a biosimilar to Gonal-f®.

A multi-centre international study of salivary hormone oestradiol and progesterone measurements in ART monitoring.

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.

Functionality of a novel follitropin alfa pen injector: results from human factor interactions by patients and nurses.

OBJECTIVE: The main objective of this user experience testing study was to evaluate the impact of human factors on the use of a disposable pen containing follitropin alfa by patients and nurses with special focus on the convenience, safety and ease of use, in different types of stimulation protocols. METHODS: Infertile women trying to conceive, and specialist nurses were recruited across 6 European countries. In total 18 patients and 19 nurses took part in the testing, which included both nurse-patient pairings and in-depth interviews. A standardized list of expected and pre-defined critical steps according to the Instructions for Use (IFU), was used to assess the correct handling of the pen. RESULTS: During the user experience testing, no critical errors, related to the use of the pen, which could affect the success of the injection process were identified. In general, both nurses and patients found the pen very easy to learn, use and would be confident using the pen for self-injection. Nurses also found the pen very easy to train the patients. CONCLUSIONS: The study provides valuable information on the pen from both patient and nurse perspectives in different simulated scenarios reflecting standard practice.

Randomized trial comparing luteinizing hormone supplementation timing strategies in older women undergoing ovarian stimulation.

In this open-label study, women aged 36-40 years undergoing ovarian stimulation were randomized to recombinant human FSH (rhFSH) plus recombinant human luteinizing hormone (rhLH) from stimulation day 1 (group A; n = 103), or rhFSH alone (days 1-5) followed by rhFSH plus rhLH from day 6 (group B; n = 99). The primary objective was equivalence in number of oocytes retrieved per patient. The mean (±SD) number of oocytes retrieved was 9.7 (±6.9) in group A and 10.9 (±6.5) in group B; the estimated difference between groups (-1.28 oocytes [95% confidence interval: -3.15 to 0.59]) did not reach the predefined limit of equivalence (±3 oocytes). The study's primary objective was therefore not met. In both groups, a mean (±SD) of 1.9 (±0.6) embryos were transferred per patient. Implantation rates were 24.7% in group A and 13.3% in group B. Clinical pregnancy rates per started cycle and per embryo transfer were 31.6% and 34.4% in Group A, 17.2% and 18.9% in Group B. Ovarian hyperstimulation syndrome was reported in four (group A) and five (group B) patients. The potential benefit of initiating LH supplementation earlier during ovarian stimulation in older women is of interest, warranting further exploration.

Anti-Müllerian hormone versus antral follicle count for defining the starting dose of FSH.

This pilot study compared the efficacy and safety of two simple dosing algorithms, one based on anti-Müllerian Hormone (AMH) and the other on the antral follicle count (AFC), to determine the starting dose of recombinant FSH (rFSH) for ovarian stimulation in 348 women. Patients were randomized to a predefined AMH- or AFC-based algorithm. The proportion of cycles with the desired response was similar when rFSH dose was determined using AMH or AFC (35.2% versus 28.4%). There was a significant difference between the groups in the proportion of cycles with a hyperresponse (8.6% and 17.4%, but the incidence of ovarian hyperstimulation syndrome was similar (1.1% and 4.6%). There were no significant differences between two groups in outcomes, including implantation (19.3% versus 19.0%), clinical pregnancy (38.0% versus 46.9%), multiple pregnancy (16.5% versus 15.2%) and miscarriage (7.0% versus 8.3%). However, statistically significant differences in ovarian response were evident among the AMH and AFC subgroups: for AMH, Desired and Hypo; for AFC, Hypo and Hyper. This pilot study provides information for developing protocols to further validate the use of either AMH or AFC to guide the starting dose of rFSH in ovarian stimulation. The ideal outcome for couples undergoing IVF treatment is the birth of a healthy baby. One factor that might influence this is retrieving an adequate number of eggs, which are obtained using various treatment protocols. A group of drugs called gonadotrophins have been used for more than 20years to stimulate the ovaries to produce eggs. However, the dose to start treatment has not been clearly defined. A few studies have looked at ways to use the best gonadotrophin dose for each woman, but to be useful in the clinic any approach needs to be simple and easy to use. This study compared the effectiveness and safety of two simple approaches to determining the starting dose of recombinant FSH (rFSH) for ovarian stimulation in women undergoing IVF. One was based on the concentration of a hormone secreted by developing eggs (anti-Müllerian hormone; AMH) and the other on the number of developing follicles (antral follicle count; AFC). The number of cycles achieving the desired response in terms of number of eggs was similar when rFSH dose was guided using AMH or AFC, and the incidence of ovarian hyperstimulation syndrome was also similar. In addition, rates of clinical pregnancy, multiple pregnancy and miscarriage did not differ between the two groups. However, patients with low AMH concentrations or low AFC had a poor response to ovarian stimulation. This pilot study provides useful information from which new studies can further assess these approaches to personalizing treatment during IVF.

Ovarian stimulation protocols in assisted reproductive technology: an update.

Controlled ovarian stimulation (COS) with gonadotropins to produce multiple follicular development and high-quality oocytes is the cornerstone of assisted reproductive technology. Today, recombinant human follicle-stimulating hormone (r-hFSH) is widely used for COS. A long-acting r-hFSH and a combination of r-hFSH and recombinant human luteinizing hormone have recently become available. Formulations of purified urinary FSH with or without luteinizing hormone activity (provided by human chorionic gonadotropin) are also available. COS protocols can now be individualized to optimize efficacy and safety - defined as singleton pregnancies with a low incidence of ovarian hyperstimulation syndrome. This is facilitated by an estimation of ovarian response using the antral follicle count and/or serum anti-Müllerian hormone levels; anti-Müllerian hormone is viewed as the most reliable single marker. However, an efficient management strategy for poor responders to COS is still required. Developments in biomarkers and other techniques for accurate identification of viable oocytes and embryos and optimal uterine receptivity are expected.

Conventional ovarian stimulation no longer exists: welcome to the age of individualized ovarian stimulation.

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.

The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders.

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 ≥ 16 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.

The antral follicle count: practical recommendations for better standardization.

OBJECTIVE: To provide recommendations for the standardized use of the Antral follicle count (AFC) which is used to predict ovarian response to gonadotrophin stimulation during assisted reproductive technology treatment. However, the nature of the follicles that are visualized by ultrasound and the competence of the oocytes held within are largely unknown. In addition, there is considerable variability in the clinical definitions and technical methods used to count and measure antral follicles in both published studies and clinical practice. DESIGN AND SETTING: In December 2007, specialist reproductive medicine clinicians and scientists attended a workshop in an effort to address these issues. Literature concerning the physiology and measurement of ovarian antral follicles was reviewed, clinical and technical considerations regarding antral follicle measurement were discussed, and an operational definition of AFC was developed. PATIENT(S): None. INTERVENTION(S): None. OUTCOME MEASURES: Simple recommendations were established for the standardization of AFC assessment in routine clinical practice. The basic clinical and technical requirements required for AFC evaluation were agreed upon, and a systematic method of measuring and counting antral follicles in routine practice was proposed. CONCLUSION(S): The use of a standardized approach according to the practical recommendations for antral follicle counting as presented is encouraged in future clinical trials and routine practice. The authors also advocate a systematic evaluation of these recommendations as standardized study data become available.

Biological versus chronological ovarian age: implications for assisted reproductive technology.

BACKGROUND: Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of delayed childbearing and reduced fecundity with increasing age has resulted in an increased number and proportion of women of greater than or equal to 35 years of age seeking assisted reproductive technology (ART) treatment. METHODS: Literature searches supplemented with the authors' knowledge. RESULTS: Despite major advances in medical technology, there is currently no ART treatment strategy that can fully compensate for the natural decline in fertility with increasing female age. Although chronological age is the most important predictor of ovarian response to follicle-stimulating hormone, the rate of reproductive ageing and ovarian sensitivity to gonadotrophins varies considerably among individuals. Both environmental and genetic factors contribute to depletion of the ovarian oocyte pool and reduction in oocyte quality. Thus, biological and chronological ovarian age are not always equivalent. Furthermore, biological age is more important than chronological age in predicting the outcome of ART. As older patients present increasingly for ART treatment, it will become more important to critically assess prognosis, counsel appropriately and optimize treatment strategies. Several genetic markers and biomarkers (such as anti-Müllerian hormone and the antral follicle count) are emerging that can identify women with accelerated biological ovarian ageing. Potential strategies for improving ovarian response include the use of luteinizing hormone (LH) and growth hormone (GH). When endogenous LH levels are heavily suppressed by gonadotrophin-releasing hormone analogues, LH supplementation may help to optimize treatment outcomes for women with biologically older ovaries. Exogenous GH may improve oocyte development and counteract the age-related decline of oocyte quality. The effects of GH may be mediated by insulin-like growth factor-I, which works synergistically with follicle-stimulating hormone on granulosa and theca cells. CONCLUSION: Patients with biologically older ovaries may benefit from a tailored approach based on individual patient characteristics. Among the most promising adjuvant therapies for improving ART outcomes in women of advanced reproductive age are the administration of exogenous LH or GH.

The role of preimplantation genetic diagnosis in diagnosing embryo aneuploidy.

PURPOSE OF REVIEW: Use of preimplantation genetic diagnosis to improve in-vitro fertilization outcomes is reviewed. RECENT FINDINGS: Many embryos produced in vitro contain chromosomal abnormalities and have little potential for forming a viable pregnancy. The most commonly used method for preimplantation genetic diagnosis involves embryo biopsy on day 3 of development, followed by fluorescence in-situ hybridization analysis of 5-12 chromosomes. However, positive results have been more common with single-cell biopsy and the analysis of nine or more chromosomes, including 15, 16, 21, and 22. Comparative genomic hybridization, array-comparative genomic hybridization, and single-nucleotide polymorphism arrays analyze all chromosomes and, although technically demanding and requiring experience for successful use, improve the selection potential of preimplantation genetic diagnosis and minimize error rates. Recent data suggest that biopsy at the blastocyst stage may allow sampling of representative genetic material without compromising embryo viability. The optimal strategy for aneuploidy screening using preimplantation genetic diagnosis seems to be blastocyst biopsy at 5 days and comprehensive chromosome analysis (comparative genomic hybridization, array-comparative genomic hybridization, single-nucleotide polymorphism array). SUMMARY: The use of preimplantation genetic diagnosis to assist the identification and preferential transfer of healthy euploid embryos should improve implantation rates, reduce miscarriages and trisomic offspring, and ultimately lead to an increase in live birth rates.

A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin.

OBJECTIVE: To compare the efficacy and safety of recombinant human FSH (r-hFSH) and hCG treatment for male hypogonadotropic hypogonadism (HH) in different populations and to identify characteristics predictive of spermatogenesis. DESIGN: A combined analysis of data from four clinical trials. SETTING: Phase III, open-label, noncomparative studies with similar designs conducted in Australia, Europe, Japan, and the United States. PATIENT(S): One hundred men with complete idiopathic or acquired HH. INTERVENTION(S): Pretreatment with hCG for 3-6 months, followed by combination therapy with hCG and r-hFSH (150 IU three times weekly) for up to 18 months. Doses of r-hFSH were adjusted according to spermatozoa count until the maximum dose was reached. MAIN OUTCOME MEASURE(S): The primary efficacy endpoint was a spermatozoa concentration of >or=1.5 x 10(6)/mL. RESULT(S): A total of 81 men remained azoospermic but achieved normal serum T concentrations after hCG pretreatment. Of these, 68 (84.0%) achieved spermatogenesis and 56 (69.1%) achieved spermatozoa concentrations >or=1.5 x 10(6)/mL. Large baseline mean testicular volume, low body mass index, and advanced sexual maturity were predictors of good response to therapy. Similar treatment responses were observed across different study populations. CONCLUSION(S): R-hFSH (combined with hCG) is effective for the restoration of fertility in the majority of men with HH.

Treatment strategies in assisted reproduction for women of advanced maternal age.

In a spontaneous menstrual cycle, during the follicular phase, only one follicle out of a cohort of 10-20 usually completes maturation and ovulates to release a mature oocyte. The aim of ovarian stimulation in assisted reproductive technology (ART) protocols is to overcome the selection of a dominant follicle and to allow the growth of a cohort of follicles. This strategy leads to an increase in the number of oocytes and hence embryos available for transfer, thereby increasing the chance of transferring up to three viable embryos. However, the chance of pregnancy and also live birth begins to dramatically decline after the age of 35, and successful treatment for these patients continues to be a major challenge in ART programs. Preimplantation genetic screening studies over the last decade have identified a dramatic increase in the rate of aneuploidy as a major contributor to the reduction in embryo viability in older patients. It has also been demonstrated that women of advanced maternal age may have oocytes that are compromised by a significant reduction in the amount of mitochondrial DNA in their cytoplasm. The strategies outlined in this review may provide a means of augmenting follicular recruitment and cytoplasmic integrity by utilizing pharmacogenomics and manipulating endocrinology to improve the prognosis for these women. Recent studies indicate that androgen supplementation may be one area to explore further. The availability of recombinant human leutinizing hormone (rhLH) has made it possible to investigate the role of LH in the endocrinology of follicular recruitment: it appears that a defect in the balance of LH/ follicle-stimulating hormone (FSH) might be involved in the subtle age-related decline in follicular recruitment, and patients of older reproductive age undergoing ART might benefit from the addition of LH and/or hGH. Further studies are required to investigate the physiological mechanisms behind this observation and to assess the possible effect of LH and/or hGH supplementation on the age-related decline in pregnancy rate.

Optimizing the use of GnRH antagonists in ovarian stimulation protocols

Unlike the GnRH agonists, which have been routinely used in ovarian stimulation protocols for almost 20 years, the GnRH-antagonist acts via a dose-dependent competetive blockade of the pituitary GnRH receptors. This results in an immediate suppression of gonadotrophin secretion (in particular LH) from the anterior pituitary. Despite the new advantages of this new class of substances, the controversial discussion about the influence of the antagonist of the implantation and embryo quality has been ongoing for the last few years. New data from recent meta analysis have demonstrated that the clinical pregnancy rate per cycle is equivalent between antagonist protocols, however there is a sugnificant reduction in the amount of FSH used and the incidence of OHSS. Recently, flexible protocols where the GnRH antagonist is applied according to leading follicle size rather than a fixed of stimulation have been developed in order to prevent a premature LH surge. A recent meta-analysis of four randomised trials comparing fixed vs flexible starting day for the GnRH antagonist concluded there was no statistically significant difference in pregnancy rates, but a significant reduction in the amount of FSH utilized in favour of the flexible protocol. A series of studies have however raised concern about late administration of the GnRH antagonist, as used in a flexible protocol. In the three studies, the implantation and pregnancy rates were higher when the antagonist was initiated on a fixed day (stimulation day 6) compared to administration in a flexible protocol according to follicle size (-15mm). Whilst Kolibianakis, et al. reported no difference in overall pregnancy rate in flexible over fixed day antagonist administration, the implantation rate was lower in the flexible protocol, when there were no follicles of -15mm on the stimulation day 6. In this group, higher concentrations of LH and oestradiol were observed to antagonist administration. In a second study, Kolibianakis, et al reported that profound suppression of LH after GnRH antagonist suppression was associated with a significantly higher ongoing pregnancy rate. They argued that exposure of the genital tract/oocyte to LH may adversely affect the implantation rate, mainly by altering endometrial receptivity. One issue here that ma have complicated the interpretation of the results is the very late administration of the GnRH antagonist (-15mm). It is generally recommended that the antagonist should administered when the leading follicle is 14mm at he very latest. Co-treatment with oral contraceptive pill (OCP) programming can also be utilized with GnRH antagonists in order to facilitate scheduling the start of FSH therapy, rather than waiting for the patient to have spontaneous menses. There are now a number of studies reporting the use of OCP pill programming with either daily 0.25mg or single dose 3mg Cetrotide in routine ART and also poor responder patients. Future studies in this area are needed to elucidate the optimal preparation protocol in GnRH antagonist cycles. However, the data that are emerging seem to support that previous cycle preparation can make a clinical contribution to the outcome of the antagonist treatment cycle.

Treatment strategies for women of advanced maternal age undergoing ART

In the follicular phase of the spontaneous menstrual cycle, only one follicle, out of a cohort of 10-20, usually completes maturation and ovulates to release a mature oocyte. The aim of ovarian stimulation in ART protocols is to overcome the selection of a dominant follicle and to allow the growth of a cohort of follicles, thus increasing the number of oocytes and hence embryos available, thereby increasing the chance of replacing, up to 3 viable embryos. However, a major challenge in ART programs is the treatment of patients in their mid 30's and over, as the chance of pregnancy and also live birth begins to dramatically decline. Preimplantation Genetic Screening studies over the last decade have identified that a major contributor to the reduction in embryo viability in older patients is the dramatic increase in the rate of eneuploidy. It has also been demonstrated that in women of advanced maternal age, the amount of mitochondrial DNA in the oocyte cytoplasm is significantly reduced. Additionally, some recent studies suggest that the ovarian stimulation regimen may also play an important role on improving embryo viability as tailoring ovarian stimulation with supplemental LH in the mid to late follicular phase may be beneficial to this older patient group. What could be the mechanisms by which LH supplementation may have an effect? In a recent study of Foong, et al. on low to poor respondrs to r-hFSH only stimulation, intra-follicular estradiol was significantly lower progesterone was significantly higher in poor to low responders to FSH. Previously, it has been demonstrated that in vitro, estradiol plays an important role in human oocyte cytoplasmic maturation manifesting itself im improved fertilization and cleavage rates. On the contrary, androstenedione can irreversibly block the effect of E2. Additionally in the ovine, E2 is assoiciated with upregulation of oocyte DNA repair enzymes. Studies carried out playing an aromatase inhibitor in the late stages of follicular development in the rhesus monkey, just prior to the period pf ovulation, showed reduced capacity on the oocyte to mature and a reduced rate of in vitro fertilization. Overall, it seems that LH may have a beneficial effect through a mechanism, which improves oocyte cytoplasmic maturation, either through E2 or some other intraovarian factor.

The place of gonadotrophin-releasing hormone antagonists in reproductive medicine.

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.