Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists

When gonadotrophin-releasing hormone (GnRH) was discovered, the agonist and antagonist of GnRH were developed to control the release of FSH and LH by the gonadotrophs. More than 10 years of research were needed to develop a GnRH antagonist free of histamine release. Recent studies have shown that these GnRH antagonists are effective in preventing a rise in LH during ovarian stimulation in IVF. However, a decrease in ongoing pregnancies seems to suggest that implantation rates per transferred embryo are reduced in GnRH antagonist-stimulated cycles. In my opinion, these data highlight an area less well known to clinicians: the role of the GnRH antagonist at the cellular level in extrapituitary tissues. There are sufficient data in the literature suggesting that GnRH antagonist is an inhibitor of the cell cycle by decreasing the synthesis of growth factors. Given that, for folliculogenesis, blastomere formation and endometrium development, mitosis is everything; the interaction between the GnRH antagonist and the GnRH receptor (present in all these cells and tissues) may compromise the mitotic programme of these cells. This is the Rubicon for the GnRH antagonist: to demonstrate irrevocably that, at the minimal doses necessary to suppress LH release, it does not affect processes such as implantation, embryo development and folliculogenesis.     

Embryo implantation and GnRH antagonists: GnRH antagonists do not activate the GnRH receptor

Recent suggestions that gonadotrophin-releasing hormone (GnRH) antagonists activate the GnRH receptor are discussed. Most of the studies cited in support of this suggestion are in-vitro studies, testing supra-pharmacological doses of GnRH analogues in cancer cell lines, whereas GnRH antagonists, e.g. ganirelix or cetrorelix, do not affect the steroidogenesis of human granulosa cells in vitro. In patients treated with GnRH antagonists prior to IVF or intracytoplasmic sperm injection (ICSI), oocyte maturity and fertilization rates are equal to those achieved following a long protocol of GnRH agonists. Although there is a tendency towards a lower pregnancy rate (not statistically significant) in the initial trials using GnRH antagonist with either recombinant FSH or human menopausal gonadotrophin (HMG) for ovarian stimulation, this new treatment option of GnRH antagonists facilitates short and simple treatment and improves the convenience and safety for the patient. As with GnRH agonists in the past, the clinical outcome of GnRH antagonist treatment will improve with time as more clinical experience is gained (learning curve) and the treatment protocol is optimized. Moreover, a GnRH agonist instead of human chorionic gonadotrophin (HCG) may be used for triggering ovulation and will decrease the cancellation rate and minimize the risk for developing ovarian hyperstimulation syndrome (OHSS).     

Embryo implantation and GnRH antagonists: the search for the human placental GnRH receptor

Hypothalamic gonadotrophin-releasing hormone (GnRH) plays a major role in the endocrine control of reproduction. Acting through its high affinity receptors on pituitary gonadotrophs, it regulates the secretion of gonadotrophins. In addition, GnRH also functions as a local regulator in a number of other cell lines and tissues, including the placenta. In a manner analogous to hypothalamic GnRH stimulation of LH and FSH from the anterior pituitary, GnRH was found to cause a dose-dependent release of human chorionic gonadotrophin (HCG) from the placenta. So began the search for a putative GnRH receptor in the human placenta. Although early radio-receptor studies reported specific binding, the properties of these 'putative' GnRH binding sites were found to differ significantly from those of their pituitary counterparts in several important respects. This was followed by a series of contradictory reports that led to more questions and opened up avenues for further investigations. Even after nearly two decades of research, the human placental GnRH receptor has not been characterized beyond all reasonable doubt. This review recalls the discovery, the controversies and unanswered questions concerning the human placental GnRH receptor.     

The use of GnRH antagonists in ovarian stimulation

GnRH antagonists induce a rapid decrease in LH and FSH, preventing and interrupting LH surges. Their properties do not require a desensitization period, and this allows their use in the late follicular phase. GnRH antagonists could replace GnRH agonists in controlled ovarian stimulation without their side-effects and their long desensitization period. Two protocols for assisted reproduction technology (ART) cycles were designed: the single-dose protocol allies simplicity and efficacy, while the multiple-dose protocol is efficient and could reduce monitoring of the cycle, though compliance is mandatory. A review of the available literature on GnRH antagonists in ART cycles is presented, focusing on phase III controlled trials and ART results. Both protocols using GnRH antagonists were associated with the need for a smaller dose of gonadotrophin, a shorter stimulation period and a lower incidence of ovarian hyperstimulation syndrome (OHSS), albeit with statistically comparable pregnancy rates. A trend is observed in all studies showing a lower pregnancy rates in GnRH antagonist cycles as compared with GnRH agonist cycles. The role of the lower number of embryos, and the potential adverse effects of GnRH antagonists on endometrium or follicle must be studied. More cycles using GnRH antagonists are necessary to confirm their equivalent pregnancy rates. There is room for improvement in both protocols with regard to scheduling, antagonist dose level and the timing of its administration. Until further studies have been conducted, luteal support seems to remain mandatory. Perinatal outcome appears similar to that with other stimulation regimens. Triggering of ovulation can be obtained with GnRH agonist for patients at risk of OHSS. With regard to GnRH antagonists, questions remain regarding pregnancy rates, the indications of their use in patients with polycystic ovary syndrome or poor responders, and in ovarian stimulation outside IVF.     

GnRH antagonists in ovarian stimulation for IVF

The present review describes, on the basis of the currently available evidence, the consensus reached by a group of experts on the use of gonadotropin-releasing hormone (GnRH) antagonists in ovarian stimulation for IVF. The single or multiple low-dose administration of GnRH antagonist during the late-follicular phase effectively prevents a premature rise in serum luteinizing hormone (LH) levels in most women. Although controversy remains, most comparative studies suggest a slight, not significant reduction in the probability of pregnancy after IVF using GnRH antagonist versus GnRH agonist co-treatment. Published meta-analyses suggest that this slight difference in pregnancy rates is not attributed to chance. Further studies applying varying treatment regimens and outcome measures are required. Data are not in favour of a need to modify the starting dose of gonadotropins. Data are not in favour of increasing gonadotropin dose at GnRH antagonist initiation. The addition of LH from the initiation of ovarian stimulation or from GnRH antagonist administration does not appear to be necessary. Replacement of human chorionic gonadotropin (HCG) by GnRH agonist for triggering final oocyte maturation is associated with a lower probability of pregnancy. The optimal timing for HCG administration needs to be explored further. GnRH antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14-16 mm, although earlier GnRH antagonist administration is worth further evaluation. Luteal phase supplementation in GnRH antagonist protocols remains mandatory in IVF. Effects of GnRH antagonist co-treatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present in favour of the GnRH antagonists. The role of GnRH antagonists in ovarian stimulation for IVF appears to be promising, although many questions regarding preferred dose regimens and effects on clinical outcomes remain.     

The impact of ovarian stimulation on implantation and fetal development in mice

The objective of this study was to evaluate, using an embryo donation model, whether impaired oocyte/embryo developmental competence and/or changes in uterine milieu are responsible for the previously observed adverse effects of superovulation with gonadotrophins on implantation and fetal development in mice. Embryos from superovulated and non-stimulated females were transferred to separate uterine horns within the same superovulated or non-stimulated pseudopregnant recipient mice. Embryo development was impaired as a significantly higher proportion of normal embryos from control donors (61%) were blastocysts on transfer day compared with superovulated donors (41%; P = 0.001). The implantation rate in control recipients was significantly reduced after transfer of embryos from superovulated donors (12%) compared with control donors (25%; P = 0.001). Uterine receptivity was impaired in superovulated recipients. The implantation rate of control embryos was significantly higher in control (25%) than in superovulated recipients (7%; P = 0.001). Transfer of embryos recovered from superovulated donors resulted in significantly higher post-implantation fetal mortality in superovulated recipients (69%) than in control recipients (36%; P = 0.01), and the mean weight of live fetuses was significantly lower for fetuses obtained from superovulated recipients (0.51 g) compared with that of fetuses obtained from control recipients (0.72 g; P = 0.006). Hence, ovarian stimulation appears to impair oocyte/embryo quality as well as uterine milieu.     

Embryo quality and uterine receptivity in in-vitro fertilization cycles with or without agonists of gonadotrophin-releasing hormone

The proportion of abnormal oocytes or embryos per recovered oocyte in in-vitro fertilization (IVF) cycles had no influence on the occurrence of pregnancy following the transfer of normal embryo(s) derived from oocytes capable of fertilization. There were more implantations per transferred embryo in stimulated IVF cycles using long-acting buserelin (30.0%) compared with short-acting decapeptyl (17.3%) or no gonadotrophin-releasing hormone agonist (GnRHa, 15.2%) treatments. However, the chances of implantation per embryo transferred being in excess of one in patients who became pregnant tended to be higher in non-GnRHa (23.5%) compared to buserelin- (16.4%) or decapeptyl- (13.3%) treated IVF cycles. Moreover, frozen--thawed embryos had a higher implantation rate (P less than 0.05) when originating from IVF cycles without GnRHa (11.7%) compared to GnRHa-treated cycles (buserelin, 4.3%; decapeptyl, 5.9%). It can be concluded that GnRHa associated with gonadotrophins produced embryos of a poorer aptitude for development than stimulation treatments without GnRHa. The clinical efficacy of GnRHa in IVF--ET cycles could be the result of an improved uterine receptivity to the transferred embryos.     

Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF

BACKGROUND: The significance of suppressed LH levels in GnRH antagonist cycles for IVF outcome is currently unknown. The purpose of this study was to evaluate prospectively the association between LH levels and ongoing pregnancy achievement after GnRH antagonist initiation in IVF cycles. METHODS: Ovarian stimulation with a fixed dose of 200 IU recombinant FSH and daily GnRH antagonist (ganirelix) 0.25 mg from day 6 of stimulation was initiated in 116 women. Patients were not pretreated with an oral contraceptive. Induction of final oocyte maturation was performed with HCG 10,000 IU as soon as three follicles of > or =17 mm were present in ultrasound, and was followed by oocyte pick-up, conventional IVF or ICSI, and embryo transfer. The luteal phase was supplemented with vaginal progesterone. RESULTS: A significant decrease of both ongoing pregnancy rate and implantation rate was present across groups of patients with increasing LH levels. The highest implantation rate and ongoing pregnancy rate was present in those patients with LH levels on day 8 of stimulation < or =0.5 IU/l. CONCLUSIONS: Profound suppression of LH on day 8 of stimulation is associated with a significantly higher chance of achieving an ongoing pregnancy. More studies are necessary to evaluate this phenomenon further.     

GnRH antagonists followed by a decline in serum estradiol results in adverse outcomes in donor oocyte cycles

BACKGROUND: The aim of this retrospective study was to assess clinical outcomes using GnRH antagonists in oocyte donation cycles. METHODS: Between July 2000 and June 2001, 40 recipient cycles generated from donor oocytes were evaluated. Controlled ovarian hyperstimulation (COH) was started on cycle day 2 using recombinant gonadotrophins (225 IU daily). GnRH antagonist was started on cycle day 6 of COH. All recipients were synchronized to donors using GnRH agonist followed by estrogen and progesterone supplementation. Main outcome measures were days of stimulation (DOS), number of ampoules used, peak serum estradiol, number of oocytes, fertilization rate, embryo score, clinical on-going pregnancy rate and implantation rate. RESULTS: Thirty-seven donor cycles (93%) underwent oocyte retrieval, resulting in 36 embryo transfers. Fourteen cycles (35%) had decreased serum estradiol after initiation of GnRH antagonist. No differences were seen in numbers of FSH ampoules, DOS, peak serum estradiol, number of retrieved oocytes, fertilization rate and embryo quality. However, clinical pregnancy rate per initiated cycle [14% (2/14) versus 54% (14/26)], ongoing pregnancy rate per initiated cycle [7% (1/14) versus 46% (12/26)] and implantation rate (4 versus 24%) were all significantly less (P <0.05) following a decrease in serum estradiol after initiation of GnRH antagonist. No clinical predictor, including donor age, basal day 2 FSH or estradiol, ovarian morphology or serum estradiol prior to GnRH antagonist, was predictive of a decline in serum estradiol following GnRH antagonist. CONCLUSION: These data demonstrate an adverse effect on clinical outcome in cycles, resulting in a decline in serum estradiol after GnRH antagonist administration. This effect was unpredictable and provided a simplified protocol for oocyte donation cycles; nonetheless, further study is needed to clarify the adverse effects of GnRH antagonists in oocyte donation cycles.     

GnRH agonist versus GnRH antagonist in oocyte donation cycles: a prospective randomized study

BACKGROUND: The specific role of LH in folliculogenesis and oocyte maturation is unclear. GnRH antagonists, when administered in the late follicular phase, induce a sharp decrease in serum LH which may be detrimental for IVF outcome. This study was performed to evaluate whether the replacement of GnRH agonist (triptorelin) by a GnRH antagonist (ganirelix; NV Organon) in oocyte donation cycles has any impact on pregnancy and implantation rates. METHODS: A total of 148 donor IVF cycles was randomly assigned to use either a GnRH antagonist daily administered from the 8th day of stimulation (group I) or a GnRH agonist long protocol (group II) for the ovarian stimulation of their donors. The primary endpoints were the pregnancy and the implantation rates. RESULTS: The clinical pregnancy rate per transfer (39.72%, 29/73 versus 41.33%, 31/75) based on transvaginal scan findings at 7 weeks of gestation, the implantation rate (23.9 versus 25.4%) and the first trimester abortion rate (10.34 versus 12.90%) were similar in the two groups. CONCLUSION: In oocyte donation cycles the replacement of GnRH agonist by a GnRH antagonist appears to have no impact on the pregnancy and implantation rates when its administration starts on day 8 of stimulation.     

Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles

BACKGROUND: GnRH agonist was recently suggested as a novel luteal-phase support that may act at different levels, including the pituitary gonadotrophs, the endometrium and the embryo itself. This prospective randomized study evaluates the effect of GnRH agonist administered in the luteal phase on ICSI outcomes in both GnRH agonist- and GnRH antagonist-treated ovarian stimulation protocols. METHODS: Six hundred women about to undergo ovarian stimulation for ICSI (300 using a long GnRH agonist protocol and 300 using a GnRH antagonist protocol) were enrolled in this study. Patients treated with each of these two protocols were randomly assigned to receive a single injection of GnRH agonist or placebo 6 days after ICSI. Implantation and live birth rates were the primary outcomes. RESULTS: Administration of 0.1 mg of GnRH agonist triptorelin on day 6 after ICSI led to a significant improvement of implantation and live birth rates after ICSI as compared with placebo. In GnRH antagonist-treated ovarian stimulation cycles, luteal-phase GnRH agonist also increased ongoing pregnancy rate. Moreover, luteal-phase GnRH agonist administration increased luteal-phase serum HCG, estradiol and progesterone concentrations in both ovarian stimulation regimens. CONCLUSIONS: Luteal-phase GnRH agonist administration enhances ICSI clinical outcomes after GnRH agonist- and GnRH antagonist-treated ovarian stimulation cycles, possibly by a combination of effects on the embryo and the corpus luteum.     

Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists

BACKGROUND: The purpose of this study was to investigate whether luteal estradiol (E(2)) administration reduces follicular size discrepancies and enhances ovarian response in recombinant FSH (r-FSH)/GnRH antagonist protocols. METHODS: We studied prospectively 90 IVF-embryo transfer (ET) candidates who were randomly pre-treated with 17beta-E(2) (4 mg/day) from day 20 until next cycle day 2 (E(2) group, n = 47) or served as controls (control group, n = 43). On day 3, all women started r-FSH treatment. A single 3 mg dose of GnRH antagonist was administered eventually according to follicular maturation. Outcome measures were magnitude of size discrepancy of growing follicles on day 8 of r-FSH treatment and number of follicles >or=16 mm in diameter on the day of HCG. RESULTS: On day 8, follicles were smaller (9.9 +/- 2.5 versus 10.9 +/- 3.4 mm, P < 0.001) and their size discrepancies attenuated (P < 0.001) in the E(2) group compared with the control group. This was associated with more >or=16 mm follicles, mature oocytes and embryos in the E(2) group. CONCLUSIONS: Luteal E(2) administration reduces the pace of growth, improves size homogeneity of antral follicles on day 8 of r-FSH treatment and increases the number of follicles reaching maturation at once. Coordination of follicular development optimizes ovarian response to r-FSH/GnRH antagonist protocols and may constitute an attractive approach to improving their outcome.     

Comparison between a GnRH antagonist and a GnRH agonist flare-up protocol in oocyte donors: a randomized clinical trial

BACKGROUND: Little information is available on the outcome of controlled ovarian hyperstimulation (COH) using GnRH antagonist in oocyte donation cycles especially in comparison with the short GnRH agonist protocol. This study was aimed at comparing the two stimulation protocols in oocyte donation (OD) cycles. METHODS: A total of 113 donors randomly received COH using either GnRH antagonist or GnRH agonist. The primary endpoint was the mean number of mature oocytes retrieved per started donor cycle. Secondary endpoints were the mean number of cumulus-oocyte-complexes (COCs) retrieved, the mean proportion of mature oocytes, pregnancy and implantation rates in recipients. RESULTS: Oocytes were distributed to 166 recipients. The mean number (+/- SD) of COC (11.6 +/- 5.8 versus 12.1 +/- 6.7), mature oocytes (8.4 +/- 4.4 versus 8.9 +/- 5.3) and the proportion of mature oocytes (70.8 versus 75.7%) retrieved per started donor cycle were similar in the antagonist and agonist groups, respectively. The implantation rate (26.1 versus 30.1%), clinical (40.2 versus 45.6%) and ongoing pregnancy rate per recipient cycle (32.2 versus 37.9%) were comparable in antagonist and agonist protocols, respectively. CONCLUSIONS: Similar mean number of mature oocytes and comparable pregnancy rates are achieved after OD in which donors received COH using GnRH antagonist or short GnRH agonist protocols.     

Enhancement of embryo developmental potential by a single administration of GnRH agonist at the time of implantation

BACKGROUND: Several reports have shown that inadvertent administration of a GnRH agonist in the luteal phase does not compromise pregnancy. Moreover, some studies suggested that, unexpectedly, the embryo developmental potential is improved in these conditions. This prospective controlled study was designed to test this hypothesis. METHODS: In an oocyte donation programme, oocytes from each donor (n = 138) were shared by two recipients, one of whom was given a single dose of a GnRH agonist (0.1 mg triptorelin) 6 days after ICSI, and the other received placebo at the same time. RESULTS: Oocyte recipients treated with GnRH agonist 6 days after ICSI had higher implantation (36.9 versus 25.1%), twin pregnancy (16.7 versus 3.6%), twin delivery (13.8 versus 2.2%) and birth (31.1 versus 21.5%) rates and similar miscarriage and abortion rates as compared with the placebo group. CONCLUSIONS: GnRH agonist administration at the time of implantation enhances embryo developmental potential, probably by a direct effect on the embryo.     

Long-term GnRH analogue treatment is equivalent to laparoscopic laser diathermy in polycystic ovarian syndrome patients with severe ovarian dysfunction

This prospective, randomized study included 18 polycystic ovarian syndrome (PCOS) patients with severe ovarian dysfunction, who were evaluated by standard clomiphene and FSH stimulation. In this group of patients, a 6 month down-regulation with gonadotrophin-releasing hormone (GnRH) analogues gave outcomes similar to laparoscopic ovarian laser diathermy with respect to stimulatory outcome and pregnancy rate. Clomiphene stimulation with 50 mg of clomiphene/day and FSH stimulation in a low-dose, step-up protocol with purified FSH did not result in oligofollicular development; thus patients were divided into two subgroups: one subgroup received laparoscopic laser drilling and the other received 6 months of therapy with GnRH analogues plus add-back therapy after diagnostic laparoscopy. Subsequently, three cycles of low-dose, step-up stimulation with recombinant FSH were started. In both groups, approximately 30% of cycles still remained anovulatory. In the down-regulated subgroup, this mainly happened in the first cycle. In each group, ovulation was achieved in 14 cycles, intrauterine insemination was performed, and five pregnancies were obtained. This resulted in a pregnancy rate of 36% per ovulatory cycle in both groups. Overall, 50% of the formerly unreactive patients in both groups overcame childlessness. In achieving this, long-term treatment with GnRH analogues was as successful as laparoscopic laser diathermy.     

Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in-vitro fertilization

In 1673 treatment cycles stimulated with buserelin and HMG, for IVF, GIFT or ZIFT, the severe ovarian hyperstimulation syndrome (OHSS) occurred in 10 cycles (0.6%). Eight patients were hyperandrogenic and showed an increased ovarian response to HMG. After replacement of a maximum of three embryos or zygotes, seven women became pregnant. Three women had a multiple gestation. All patients recovered uneventfully with conservative treatment. Support with progesterone or continuation of the agonist during the luteal phase did not prevent OHSS, confirming that the ovulatory HCG dose is the most important factor in inducing this severe complication. Luteal supplementation with HCG and/or HCG production during implantation could exacerbate OHSS.     

GnRH antagonist-induced inhibition of the premature LH surge increases pregnancy rates in IUI-stimulated cycles. A prospective randomized trial

BACKGROUND: Our prospective randomized controlled trial was designed to assess whether the use of GnRH antagonists can improve the success rate of controlled ovarian stimulation (COS)/intrauterine insemination (IUI) treatments, via inhibition of the premature LH rise. METHODS: A total of 104 patients were randomly divided, using a randomization list, into two groups: in group A (n = 52), recombinant FSH (rFSH) was given with GnRH antagonist Cetrorelix, and in group B (n = 52), the patients received rFSH alone in a manner similar to that of group A. The primary outcome measure was clinical pregnancy rate per couple. RESULTS: The pregnancy rate per patient was 53.8% in group A and 30.8% in group B (P = 0.017). The rate of premature LH surge was 7% in group A and 35% in group B (P < 0.0001). A premature luteinization was observed in two cycles of 144 in group A (1.4%) and in 16 cycles of 154 in group B (10.4%) (P = 0.001). The mean values of LH and progesterone were significantly lower in patients receiving GnRH antagonist than in those who did not (3.3 +/- 3.3 mIU/ml in group A versus 9.9 +/- 7.9 mIU/ml in group B, P < 0.0001, for LH; 1.3 +/- 1.1 ng/ml versus 2.1 +/- 1.9 ng/ml for group A and B, respectively, P < 0.0001, for progesterone). CONCLUSION: The use of GnRH antagonist in COS/IUI cycles improves pregnancy rate, preventing the premature LH rise and luteinization.     

Menstruation-free interval and ongoing pregnancy in IVF using GnRH antagonists

BACKGROUND: The purpose of this study was to evaluate prospectively the association between the achievement of ongoing pregnancy and the time interval from the end of menstruation until the administration of HCG (menstruation-free interval) in patients treated by IVF. METHODS: A fixed dose of 200 IU of recombinant FSH (rFSH) was started in 90 patients on day 2 of the menstrual cycle and daily GnRH antagonist was initiated on day 6 of stimulation. Triggering of final oocyte maturation was performed with 10,000 IU of HCG as soon as three follicles of > or =17 mm were present at ultrasound. RESULTS: Single embryo transfer was performed in 64.6% of the patients who reached embryo transfer (53/82). Ongoing pregnancy rate per embryo transfer was 18.3% (95% CI 11.4-28.0%). The menstruation-free interval significantly predicted the probability of ongoing pregnancy in a logistic regression analysis, controlling for female age and LH on day 1 of stimulation (odds ratio for the menstruation-free interval: 0.70; 95% CI: 0.54-0.92). CONCLUSION: The longer the interval from the end of menstruation until the administration of HCG, the lower the probability of ongoing pregnancy in patients stimulated with recombinant FSH and GnRH antagonist for IVF.     

Endocrinology: Insulin actions on ovarian steroidogenesis are not modulated by metformin

Metformin, an agent used in treatment of non-insulin-dependentdiabetes mellitus, is believed to act by potentiating the effectsof insulin on glucose metabolism. This study was designed todetermine whether metformin affects the actions of insulin onovarian steroidogenic capability. Rat thecal—interstitial(T—I) and granulosa (G) cells were cultured in chemicallydefined media for 144 h with or without gonadotrophins [luteinizinghormone (LH) at 100 ng/ml or follicle stimulating hormone (FSH)at 100 ng/ml], insulin (1 µg/ml) and/or metformin (1 and5 µg/ml). Production of testosterone and progesteroneby T—I cells, and 17-oestradiol and progesterone by Gcells were assessed. Insulin potentiated LH-dependent stimulationof testosterone production by T—I cells and FSH-dependentstimulation of 17-oestradiol production by G cells, but didnot significantly affect progesterone production by T—Icells or G cells in the presence or absence of gonadotrophins.Metformin did not affect any of the actions of insulin on steroidogenesis.These results suggest that insulin may modulate ovarian steroidogenesisvia a pathway separate from that modulating glucose metabolism.Actions of insulin on steroidogenesis are selective with regardto stimulation of specific aspects of steroidogenesis and donot simply amplify gonadotrophin effects.     

Comparable clinical outcome using the GnRH antagonist ganirelix or a long protocol of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation

This multicentre, randomized study was performed to assess theefficacy and safety of 0.25 mg ganirelix (Orgalutran^®, Antagon^TM)treatment, using triptorelin (Decapeptyl^®) in a long protocolas a reference treatment. In total, 236 subjects were randomizedto treatment with ganirelix (0.25 mg, s.c.) and 119 to triptorelin(0.1 mg, s.c.) treatment (treatment ratio 2:1). Treatment withganirelix started on day 6 of stimulation, whereas treatmentwith triptorelin started on menstrual cycle day 21 to 24 ofthe previous cycle (i.e. the midluteal phase). The ganirelixregimen was on average 17 days shorter (9 versus 26 days) comparedto the triptorelin regimen. The median total dose of recombinantFSH (Puregon^®) used was 450 IU less (1350 versus 1800 IU)in the ganirelix protocol. The initial follicular growth wasfaster and, consequently, oestradiol concentrations were higherin the ganirelix group. On the day of human chorionic gonadotrophin(HCG), the mean number of follicles 11 mm was 10.1 and 10.7and the median serum oestradiol concentration was 1090 and 1370pg/ml in the ganirelix and triptorelin groups respectively.Per attempt, 7.9 and 9.6 oocytes (mean) were retrieved in theganirelix and triptorelin groups respectively. The fertilizationrates (64.0% ganirelix and 64.9% triptorelin) and the mean numberof good quality embryos (2.7 and 2.9) were comparable in bothtreatment groups. The implantation rate was identical (22.9%).The ongoing pregnancy rate per attempt was 31.0 and 33.9% inthe ganirelix and triptorelin groups respectively. The ganirelixregimen showed an improved local tolerance in that the percentageof subjects with at least one local skin reaction was 2-foldlower than in the triptorelin group (11.9 versus 24.1%). Takingall data together, it may be concluded that ganirelix offersa new treatment regimen in ovarian stimulation that is short,safe and well-tolerated, optimizing convenience for the patient.