GnRH antagonist in single-dose applications

Previous studies on ovarian stimulation have confirmed the efficacy of a single dose of the gonadotrophin-releasing hormone (GnRH) antagonist, Cetrorelix, in preventing premature LH surges. The single-dose protocol is easy to use and assures patient compliance. When compared with the long protocol using a depot administration of the GnRH agonist, triptorelin, the IVF results in patients treated with Cetrorelix showed a shorter treatment duration, reduced amount of human menopausal gonadotrophin (HMG) required and a lower occurrence of ovarian hyperstimulation syndrome (OHSS). The pregnancy rates did not differ significantly between the two treatments. The use of Cetrorelix in natural cycles associated with gonadotrophins reduced the rate of premature LH surges and, therefore, the cancellation rate. The stimulation was minimal and the preliminary pregnancy rates were satisfactory. If a larger study confirms the results of the natural cycle with HMG support, the single-dose administration of GnRH antagonist could represent an interesting first-choice IVF treatment in selected indications. The tolerance of Cetrorelix was excellent in all patients, with only mild and transitory reactions at the injection site. New GnRH antagonists are already available for clinical use in some countries, and they will certainly change ovarian stimulation protocols. If the pregnancy rates are confirmed, the main advantages of these new compounds are the reduction in side-effects and complications of the stimulation protocol; a clear benefit to the patients.     

GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis

Triggering final oocyte maturation with GnRH agonist during ovarian stimulation is feasible when inhibition of premature LH surge is performed with GnRH antagonists, and we aimed to systematically collate evidence on the clinical efficacy of GnRH agonist triggering in patients undergoing assisted reproduction in GnRH antagonist protocols. Twenty-three publications were identified by a comprehensive literature search that included PubMed, Embase and the Cochrane Library. Three publications out of 23 fulfilled the inclusion criteria for meta-analysis, which were (i) prospective, randomized controlled study design; (ii) stimulation with gonadotropins for induction of multifollicular development; (iii) suppression of endogenous LH by a GnRH antagonist; (iv) triggering of final oocyte maturation with GnRH agonist; (v) control group randomized to receive HCG for final oocyte maturation and (vi) any means of luteal phase support other than HCG. The participants were normoovulatory women undergoing IVF. The outcomes assessed were clinical pregnancy per randomized patient; number of oocytes retrieved; proportion of metaphase II oocytes; fertilization rate; embryo quality score; first trimester abortion rate; ovarian hyperstimulation syndrome (OHSS) incidence. Results are presented as combined standardized differences of the mean and combined odds ratios, as appropriate, with 95% confidence intervals. No significant difference was found for the number of oocytes retrieved (-0.94, -0.33-0.14), proportion of metaphase II oocytes (-0.03, -0.58-0.52), fertilization rate (0.15, -0.09-0.38) or embryo quality score (0.05, -0.18-0.29). No OHSS occurred in two of the studies, whereas in one study OHSS incidence was not reported. Thus from the available data, no conclusion can be drawn as regards OHSS incidence after GnRH agonist triggering. In comparison to HCG, GnRH agonist administration is associated with a significantly reduced likelihood of achieving a clinical pregnancy (0.21, 0.05-0.84; P = 0.03). The odds of first trimester pregnancy loss is increased after GnRH agonist triggering; however, the confidence interval crosses unity (11.51, 0.95-138.98; P = 0.05). In conclusion, the use of GnRH agonist to trigger final oocyte maturation in IVF, where inhibition of premature LH surge is achieved with GnRH antagonists, yields a number of oocytes capable to undergo fertilization and subsequent embryonic cleavage, which is comparable to that achieved with HCG. However, the likelihood of an ongoing clinical pregnancy after GnRH agonist triggering is significantly lower as compared to standard HCG treatment.     

The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice

BACKGROUND: It has remained controversial whether and in what way suppression of the pituitary-gonadal axis using GnRH analogues can reduce the destructive effects of chemotherapy on ovarian primordial follicles and thus prevent ovarian failure. GnRH antagonists suppress gonadotrophin levels immediately after administration. In this study we determined whether administration of the GnRH antagonist cetrorelix before exposure to increasing doses of cyclophosphamide (Cy) affected the number of surviving primordial follicles (PMF) in the mice ovary. METHODS: Highly inbred young Balb/c mice (114 females) were injected with 0, 50 and 75 mg/kg of Cy. In each treatment group, half of the females were injected daily with cetrorelix starting 9 days before and 7 days post-administration of Cy. In serial sequential ovarian sections the total number of PMF in both ovaries was counted. RESULTS: Ovaries exposed to Cy at doses of 50 and 75 mg/kg had significantly fewer PMF than those in the control group (P < 0.01). In each of the Cy groups used, pretreatment with cetrorelix resulted in significantly higher numbers of PMF: in the 50 mg/kg Cy group only 14% were destroyed (cetrorelix group) versus 53% (P < 0.001), while in the 75 mg/kg Cy group only 35% of PMF were destroyed versus 54% in animals treated only with Cy (P < 0.004). The interaction between the effect of cetrorelix and the different doses of Cy did not reach statistical significance (P = 0.089, two-way ANOVA). CONCLUSIONS: Administration of the GnRH antagonist cetrorelix to mice significantly decreases the extent of ovarian damage induced by the chemotherapeutic agent Cy. The use of different substerilizing doses of Cy suggested that the extent of protection achieved by the antagonist is dose-dependent and decreases with increasing Cy doses. The results of this study may suggest a possible similar beneficial effect in women undergoing chemotherapy, can explain the discrepancy in results of existing clinical studies and indicate possible pathways for ovarian GnRH agonist protection. Further research and clinical studies are needed in order to confirm these results.     

Clinical management of low ovarian response to stimulation for IVF: a systematic review

Poor response is not a rare occurrence in ovarian stimulation. Although not fully accepted, the most dominant criteria for poor ovarian response are small numbers of follicles developed or oocytes retrieved, and low estradiol (E2) levels after the use of a standard stimulation protocol. There is no ideal predictive test as the poor responder is revealed only during ovulation induction; however, increased levels of day 3 FSH and E2 as well as decreased levels of inhibin B can be used to assess ovarian reserve. Several protocols have been proposed for clinical management of low ovarian response in IVF. Although high doses of gonadotrophins have been used by the vast majority of authors, results have been controversial and prospective randomized studies have shown little or no benefit. The few available relevant studies do not indicate that recombinant FSH improves outcome. Flare-up GnRH agonist protocols (including all dosage varieties) produce better results than standard long luteal protocols. Luteal initiation GnRH agonist 'stop' protocols were shown to improve ovarian response according to prospective studies with historical controls, but this was not confirmed by well-designed prospective, randomized, controlled studies. The few available data obtained with GnRH antagonists have not shown any benefits. Adjuvant therapy with growth hormone (GH) or GH-releasing factors results in no significant improvement. The use of corticosteroids reduces the incidence of poor ovarian response in women undergoing IVF treatment. The limited data obtained with nitric oxide donors are encouraging. Pretreatment with combined oral contraceptives prior to stimulation may help ovarian response. No benefit was observed with standard use of ICSI or assisted hatching of zona pellucida. Finally, natural cycle IVF has produced results which are comparable with those obtained with stimulated cycles in true poor responders. Well-designed, large-scale, randomized, controlled trials are needed to assess the efficacy of these different management strategies.     

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.     

Controlled ovulation of the dominant follicle: a critical role for LH in the late follicular phase of the menstrual cycle

BACKGROUND: A method was sought to control ovulation of the dominant follicle and to test the importance of LH during the late follicular phase of the menstrual cycle. Menstrual cycles of rhesus monkeys were monitored, and treatment initiated at the late follicular phase (after dominant follicle selection, before ovulation). METHODS: The 2-day treatment consisted of GnRH antagonist plus either r-hFSH and r-hLH (1:1 or 2:1 dose ratio) or r-hFSH alone. In addition, half of the females received an ovulatory bolus of hCG. RESULTS: When treatment was initiated at estradiol levels >120 pg/ml, neither the endogenous LH surge, ovulation nor luteal function were controlled. However, when treatment was initiated at estradiol levels 80-120 pg/ml using either 1:1 or 2:1 dose ratios of FSH:LH, the LH surge was prevented, and ovulation occurred following hCG treatment. FSH-only treatment also prevented the LH surge, but follicle development appeared abnormal, and hCG failed to stimulate ovulation. CONCLUSIONS: Control over the naturally dominant follicle is possible during the late follicular phase using an abbreviated GnRH antagonist, FSH+LH protocol. This method offers a model to investigate periovulatory events and their regulation by gonadotrophins/local factors during the natural menstrual cycle in primates.     

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.     

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.     

Ovarian stimulation and ovarian tumours: a critical reappraisal

Increased interest has arisen recently about the possible associationbetween ovarian stimulation and ovarian tumours. In this article,the current knowledge on the epidemiology, pathogenesis andaetiology of ovarian tumours is extensively reviewed in relationto the existing literature on the relationship between ovulationinduction and ovarian neoplasia. The available data from epidemiologicalstudies and case reports do not support a direct causa] relationshipbetween ovarian stimulation and ovarian cancer. However, itis possible that ovarian stimulants may have an augmenting rolefor special categories of tumours, e.g. sex-cord stromal tumours.A definite answer to this important issue may be reached throughlarge prospective epidemiological studies or large retrospectivewell-designed case-control studies.     

Regulation of follicle development and novel approaches to ovarian stimulation for IVF

Current ovarian stimulation regimens for IVF are complex and not without risk. Increasing our knowledge of the physiology of follicle development and dominant follicle selection may enable the design of less complex, safer and cheaper ovarian stimulation regimens for IVF. Decremental serum FSH concentrations during the follicular phase of the menstrual cycle are required for single dominant follicle selection. Only the most mature follicle will continue its development due to increased sensitivity for stimulation by FSH. FSH stimulation becomes insufficient for less mature follicles and remaining cohort follicles will therefore go into atresia. The number of days during which FSH is above the threshold for stimulation of follicle development is limited, resulting in a narrow FSH window. More medium sized and large pre-ovulatory follicles and increased oestradiol output can be induced by the administration of small doses of exogenous FSH during the mid- to late follicular phase, preventing the physiological decrease in FSH stimulation. Intervention with decremental serum FSH concentrations in combination with gonadotrophin-releasing hormone (GnRH) antagonists to prevent a premature rise in serum LH may induce ongoing growth of multiple follicles sufficient for IVF. The benefits and risks of these minimal hyperstimulation protocols require further evaluation.     

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.     

Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovarian stimulation for conventional IVF or ICSI: a preliminary report

BACKGROUND: Gonadotrophin-releasing hormone (GnRH) antagonists have been proven safe and effective, with no adverse effects on offspring in animal studies. Careful study of pregnancy outcome in humans is mandatory. METHODS AND RESULTS: This preliminary report includes follow-up data of patients treated with the GnRH antagonist, ganirelix, during ovarian stimulation for IVF or ICSI. In total, 333 patients were randomized in a multicentre, double-blind, dose-finding study of ganirelix, at six different doses ranging from 0.0625 to 2 mg. In total, 68 vital intrauterine pregnancies were established that resulted in the birth of 46 singletons, 12 twins and one triplet. Follow-up of the 67 pregnant patients (one subject was lost to follow-up) revealed six miscarriages (9%). Of the 61 subjects with an ongoing pregnancy, two with a singleton pregnancy did not give birth to a live-born infant (one spontaneous abortion in week 19, and one intrauterine death in week 27). The mean gestational age was 39.4 weeks for singleton pregnancies, and 36.6 weeks for multiple pregnancies. In total, 73 infants (33 boys, 40 girls) were born. A birth weight <2500 g was reported for 8.7% and 54.2% of the infants resulting from singleton and twins delivery respectively. One major congenital malformation was diagnosed; a boy with Beckwith-Wiedemann syndrome (exomphalos and macroglossia). Seven minor malformations were reported among five infants. CONCLUSIONS: In this first follow-up study, the incidence of adverse obstetrical and neonatal outcome was comparable with reported incidences for IVF-embryo transfer pregnancies.     

A systematic review of tests predicting ovarian reserve and IVF outcome

The age-related decline of the success in IVF is largely attributable to a progressive decline of ovarian oocyte quality and quantity. Over the past two decades, a number of so-called ovarian reserve tests (ORTs) have been designed to determine oocyte reserve and quality and have been evaluated for their ability to predict the outcome of IVF in terms of oocyte yield and occurrence of pregnancy. Many of these tests have become part of the routine diagnostic procedure for infertility patients who undergo assisted reproductive techniques. The unifying goals are traditionally to find out how a patient will respond to stimulation and what are their chances of pregnancy. Evidence-based medicine has progressively developed as the standard approach for many diagnostic procedures and treatment options in the field of reproductive medicine. We here provide the first comprehensive systematic literature review, including an a priori protocolized information retrieval on all currently available and applied tests, namely early-follicular-phase blood values of FSH, estradiol, inhibin B and anti-Müllerian hormone (AMH), the antral follicle count (AFC), the ovarian volume (OVVOL) and the ovarian blood flow, and furthermore the Clomiphene Citrate Challenge Test (CCCT), the exogenous FSH ORT (EFORT) and the gonadotrophin agonist stimulation test (GAST), all as measures to predict ovarian response and chance of pregnancy. We provide, where possible, an integrated receiver operating characteristic (ROC) analysis and curve of all individual evaluated published papers of each test, as well as a formal judgement upon the clinical value. Our analysis shows that the ORTs known to date have only modest-to-poor predictive properties and are therefore far from suitable for relevant clinical use. Accuracy of testing for the occurrence of poor ovarian response to hyperstimulation appears to be modest. Whether the a priori identification of actual poor responders in the first IVF cycle has any prognostic value for their chances of conception in the course of a series of IVF cycles remains to be established. The accuracy of predicting the occurrence of pregnancy is very limited. If a high threshold is used, to prevent couples from wrongly being refused IVF, a very small minority of IVF-indicated cases (approximately 3%) are identified as having unfavourable prospects in an IVF treatment cycle. Although mostly inexpensive and not very demanding, the use of any ORT for outcome prediction cannot be supported. As poor ovarian response will provide some information on OR status, especially if the stimulation is maximal, entering the first cycle of IVF without any prior testing seems to be the preferable strategy.     

Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study

A total of 346 women with normal ovulatory function was stimulated with human menopausal gonadotrophins (HMG) to attain ovarian stimulation for IVF or intracytoplasmic sperm injection (ICSI). Stimulation with HMG started on cycle day 2 or 3. After 6 days of stimulation, Cetrorelix in its minimum effective multiple dose of 0. 25 mg/day, was administered daily until induction of ovulation. In total, 333 patients (96.2%) reached the day of HCG administration, and 324 (93.6%) underwent oocyte retrieval. A mean of 25.2 ampoules of HMG was applied for a mean of 10.4 days. Cetrorelix was administered for a mean time lapse of 5.7 days. The mean normal fertilization rate was 60% in the IVF group and 59% in the ICSI group. Seventy pregnancies were attained, reflecting an ongoing clinical pregnancy rate of 24% per transfer. The ongoing clinical implantation rate was 11.4%. Only three cases of raised luteinizing hormone (LH) (>/=10 IU/l) with increased progesterone secretion (>/=1 ng/ml) were observed after initiation of Cetrorelix administration, reflecting an incidence of premature luteinization of 0.9%. The abortion rate was 17%. The incidence of severe ovarian hyperstimulation syndrome (World Health Organization grade III) was as low as 0.6%.     

Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study

BACKGROUND: When administered in the late follicular phase to prevent an LH surge, GnRH antagonists induce a sharp decrease in serum LH levels that may be detrimental for assisted reproductive technology cycle outcome. Therefore, a prospective study was designed to assess the effects of recombinant human (r)LH supplementation during GnRH antagonist (cetrorelix) administration. METHODS: The protocol consisted of cycle programming with oral contraceptive pill, ovarian stimulation with rFSH and flexible administration of a single dose of cetrorelix (3 mg). A total of 218 patients from three IVF centres were randomized (by sealed envelopes or according to woman's birth date) to receive (n = 114) or not (n = 104) a daily injection of rLH 75 IU from GnRH antagonist initiation to hCG injection. RESULTS: The only significant difference was a higher serum peak E2 level in patients treated with rLH (1476 +/- 787 versus 1012 +/- 659 pg/ml, P < 0.001) whereas the numbers of oocytes and embryos as well as the delivery rate (25.2 versus 24%) and the implantation rate per embryo (19.1 versus 17.4%) were similar in both groups. CONCLUSIONS: These results show that in an unselected group of patients, there is no evident benefit to supplement GnRH antagonist-treated cycles with rLH.     

The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis

BACKGROUND: Milder ovarian stimulation protocols for in vitro fertilization(IVF) are being developed to minimize adverse effects. Mildstimulation regimens result in a decreased number of oocytesat retrieval. After conventional ovarian stimulation for IVF,a low number of oocytes are believed to represent poor ovarianreserve resulting in reduced success rates. Recent studies suggestthat a similar response following mild stimulation is associatedwith better outcomes. METHODS: This review investigates whether the retrieval of a low numberof oocytes following mild ovarian stimulation is associatedwith impaired implantation rates. Three randomized controlledtrials comparing the efficacy of the mild ovarian stimulationregimen (involving midfollicular phase initiation of FSH andGnRH co-treatment) for IVF with a conventional long GnRH agonistco-treatment stimulation protocol could be identified by meansof a systematic literature search. RESULTS: These studies comprised a total of 592 first treatment cycles.Individual patient data analysis showed that the mild stimulationprotocol results in a significant reduction of retrieved oocytescompared with conventional ovarian stimulation (median 6 versus9, respectively, P < 0.001). Optimal embryo implantationrates were observed with 5 oocytes retrieved following mildstimulation (31%) versus 10 oocytes following conventional stimulation(29%) (P = 0.045). CONCLUSIONS: The optimal number of retrieved oocytes depends on the ovarianstimulation regimen. After mild ovarian stimulation, a modestnumber of oocytes is associated with optimal implantation ratesand does not reflect a poor ovarian response. Therefore, thefear of reducing the number of oocytes retrieved following mildovarian stimulation appears to be unjustified.     

Minimal stimulation IVF with late follicular phase administration of the GnRH antagonist cetrorelix and concomitant substitution with recombinant FSH: a pilot study

BACKGROUND: The use of the natural cycle for IVF offers the advantage of a patient-friendly and low-risk protocol. Its effectiveness is limited, but may be improved by using a GnRH antagonist to prevent untimely LH surges. METHODS: In this pilot study, minimal stimulation IVF with late follicular phase administration of the GnRH antagonist cetrorelix and simultaneous substitution with recombinant FSH was applied for a maximum of three cycles per patient. Main outcome measures were pregnancy rates per started cycle and cumulative pregnancy rates after three cycles. RESULTS: A total of 50 patients completed 119 cycles (2.4 per patient). Fifty-two embryo transfers resulted in 17 ongoing pregnancies [14.3% per started cycle; 32.7% per embryo transfer; 95% confidence interval (CI) 7.9-20.7% and 19.7-45.7%, respectively]. One dizygotic twin pregnancy occurred after transfer of two embryos, the other pregnancies were singletons. The cumulative ongoing pregnancy rate after three cycles was 34% (95% CI 20.6-47.4%). Live birth rate was 32% per patient (95% CI 18.8-45.2%). CONCLUSIONS: Pregnancy rates after IVF with minimal, late follicular phase stimulation are encouraging. Considering the low-risk and patient-friendly nature of this protocol, it may be a feasible alternative to IVF with ovarian hyperstimulation.     

Ovarian tissue cryopreservation and transplantation: a review

The review covers current options for ovarian tissue cryopreservation and transplantation and provides a systematic review of the existing literature from the last 10 years, taking into account all previously published reviews on the subject. The different cryopreservation options available for fertility preservation in cancer patients are embryo cryopreservation, oocyte cryopreservation and ovarian tissue cryopreservation. The choice depends on various parameters: the type and timing of chemotherapy, the type of cancer, the patient's age and the partner status. The different options and their results are discussed, as well as their putative indications and efficacy. The review concludes that advances in reproductive technology have made fertility preservation techniques a real possibility for patients whose gonadal function is threatened by premature menopause, or by treatments such as radiotherapy, chemotherapy or surgical castration.     

Direct ovarian effects and safety aspects of GnRH agonists and antagonists

In in-vitro fertilization programmes, gonadotrophin releasing hormone (GnRH) agonists are now routinely used in order to prevent the undesired pre-ovulatory spontaneous luteinizing hormone surge. The first publications are now appearing in which GnRH antagonists are used with the same purpose. More attention should be addressed to the safety aspects of these drugs. This review aims to summarize studies on direct ovarian effects of GnRH agonists and GnRH antagonists in non-primates and primates with respect to the functional and morphological aspects in-vitro as well as in-vivo. We conclude that there is a wide variety of functional and morphological effects of GnRH analogues on the ovary. The sometimes paradoxical effects indicate that a variety of factors may be involved in the various processes. Those factors are: (i) the type and dose of the analogue, (ii) the different regimens of administration, (iii) ovarian status at the time of exposure, (iv) ovarian cell types in in-vitro systems, (v) hormonal pre-treatment of these cultures, (vi) the type of hormonal stimulation added to the in-vitro culture, (vii) further methodological differences in the experiments and finally (viii) physiological variations in GnRH receptor abundance which depends on species and/or timing in the cycle. With the increasing number of patients using GnRH analogues in assisted reproduction treatments, there will be an increasing number of pregnancies exposed to these drugs. So far, there does not appear to be an increased risk of birth defects or pregnancy wastage in human pregnancies exposed to daily low-dose GnRH agonist therapy in the first weeks of gestation.