Evaluation of uterine receptivity after gonadotropin releasing hormone agonist administration as an oocyte maturation trigger: a rodent model.

In natural cycle or minimal stimulation cycle IVF, buserelin acetate (buserelin), a gonadotropin-releasing hormone agonist, is often used as a maturation trigger; however, its effect on pregnancy outcomes remains unclear. Therefore, in the present study, we compared uterine receptivity in buserelin-administered mice with that in human chorionic gonadotropin (hCG)-administered mice during the peri-implantation period. Implantation, decidualisation, and term-pregnancy were impaired following hCG, but not buserelin administration. hCG stimulated the synthesis and secretion of progesterone and oestradiol, whereas ovarian steroidogenesis in the buserelin-treated group was comparable with that in the control group. Furthermore, similar to the observation in controls, the buserelin-treated group exhibited activation of progesterone receptor signalling and inhibition of oestrogen receptor signalling in the endometrial epithelium on the day of implantation. However, epithelial progesterone signalling was not detected, and a high expression of genes downstream to oestrogen was observed on day 4 following hCG administration. These results suggest that buserelin administration does not impact uterine receptivity as it did not affect ovarian steroidogenesis and endometrial steroid signalling. Therefore, buserelin is preferred as an oocyte maturation trigger to optimise uterine receptivity during treatments involving timed intercourse, intrauterine insemination, or fresh embryo transfer following in vitro fertilisation.

[Does fertility treatment increase the risk of breast cancer? Current knowledge and meta-analysis]. / Les traitements inducteurs de l'ovulation augmentent-t-ils le risque de cancer du sein ? Mise au point et méta-analyse.

OBJECTIVE: The objective of this review was to assess the level of risk of breast cancer for women exposed to ovulation-inducing therapy (OIT). METHODS: The 25 selected studies were extracted from the PUBMED database from January 2000 until March 2016 with the following key-words: "fertility agents", "infertility treatments", "clomiphene citrate", "buserelin", "ovarian stimulation", "assisted reproductive technology" and "breast cancer". Our meta-analysis was performed using Review Manager software, Cochrane Collaboration, 2014. The results were calculated by type of OIT, as well as globally. RESULTS: The analysis of these published epidemiological studies confirms that exposition to OIT is not a breast cancer risk factor, but the results are contradictory. Two studies have shown a significantly increased risk of breast cancer in a population of infertile women, while two others have found a significant decrease of this risk. The twenty others did not show any impact of IOT over this risk. Our meta-analysis of 20 selected studies has not identified a significant association between exposition to OIT and breast cancer risk (relative risk=0,96; IC 95: (0,81-1,14) for cohort studies and odds ratio=0,94; IC 95% (0,81-1,10) for case-control studies). CONCLUSION: Exposition to OIT is not an identified risk factor for breast cancer. A message reassuring about a possible risk of OIT-related breast cancer should be given to these women. Exposition to OIT is therefore not an indication of increased breast surveillance.

Short-term buserelin administration induces apoptosis and morphological changes in adult rat testes.

PURPOSE: To investigate the effect of buserelin on gonadal structure and function in adult male rats. METHODS: Twenty-four adult Wistar male rats were divided into three groups: two treated groups and controls. The first and second treated groups received 300 (low dose) and 500 (high dose) µg/kg buserelin, respectively, and the control group received normal saline. All groups were treated subcutaneously for five days. RESULTS: The seminiferous tubular epithelial thickness was significant decreased in the treated groups compared with those in the control. There was a significant increase in apoptotic cell death in high dose treated group compared with low dose treated and control groups. No significant difference in serum testosterone level was observed after one month in the three groups. CONCLUSION: Buserelin induces apoptotic cell death and decreased diameter and epithelium thickness of seminiferous tubules in the adult rat testes.

Short-term buserelin administration induces apoptosis and morphological changes in adult rat testes

Abstract Purpose: To investigate the effect of buserelin on gonadal structure and function in adult male rats. Methods: Twenty-four adult Wistar male rats were divided into three groups: two treated groups and controls. The first and second treated groups received 300 (low dose) and 500 (high dose) µg/kg buserelin, respectively, and the control group received normal saline. All groups were treated subcutaneously for five days. Results: The seminiferous tubular epithelial thickness was significant decreased in the treated groups compared with those in the control. There was a significant increase in apoptotic cell death in high dose treated group compared with low dose treated and control groups. No significant difference in serum testosterone level was observed after one month in the three groups. Conclusion: Buserelin induces apoptotic cell death and decreased diameter and epithelium thickness of seminiferous tubules in the adult rat testes.

Minodronic acid suppresses gonadotropin-releasing hormone agonist-induced bone remodeling biomarkers: a retrospective pilot study.

BACKGROUND: Estrogen deprivation therapy for myoma/adenomyosis decreases bone mineral density and can only be applied in the short term, as temporizing measures in the premenopausal woman. OBJECTIVE: To examine the effects of bisphosphonate minodronic acid on markers of bone turnover over a 6-month period in women receiving gonadotropin-releasing hormone agonist (GnRHa). METHODS: We retrospectively analyzed the medical records of 19 premenopausal patients with myoma/adenomyosis, who received GnRHa (leuprolide acetate, 1.88 mg/month or buserelin acetate, 900 µg/day) for 6 months from January 2014 to December 2014. Eight patients concomitantly received minodronic acid 50 mg every month during GnRHa therapy, and 11 treated with GnRHa alone. To compare these data in a case-controlled study, we analyzed an age-matched group of seven (premature or natural) menopausal women treated with minodronic acid. The primary outcome was percent changes in bone turnover markers in urine at 6 months. RESULTS: In menopausal women group, minodronic acid (50 mg once-monthly) for 6 months decreased urinary deoxypyridinoline (DPD) and cross-linked N-telopeptides of type 1 collagen (NTX). Women receiving a GnRHa had a significant increase in urinary DPD and TNX at 6 months while minodronic acid during GnRHa therapy improved urinary levels of DPD and NTX to near baseline. CONCLUSION: Minodronic acid treatment appears to be promising in women with secondary bone loss receiving GnRHa treatment.

Buserelin treatment to rats causes enteric neurodegeneration with moderate effects on CRF-immunoreactive neurons and Enterobacteriaceae in colon, and in acetylcholine-mediated permeability in ileum.

BACKGROUND: The gonadotropin-releasing hormone (GnRH) analog buserelin causes enteric neuronal loss. Acute stress or injection of corticotropin-releasing factor (CRF) affects motility, secretion, and barrier function of the gastrointestinal tract. The aim of the study was to characterize the CRF immunoreactivity in enteric neurons after buserelin treatment, and to evaluate possible effects of enteric neuropathy on gut microbiota, intestinal permeability, and stress response behavior. RESULTS: Sixty rats were given buserelin (20 µg) or saline subcutaneously for 5 days, repeated four times with 3 weeks in-between. At the study end, enteric neuronal density, enteric expression of CRF, gut microbial composition, and plasma levels of adrenocorticotropic hormone (ACTH) and CRF were analyzed. Intestinal permeability was examined in Ussing chambers and the reaction to stressful events was measured by behavior tests. Buserelin treatment reduced the number of neurons along the entire gastrointestinal tract, with increased relative numbers of CRF-immunoreactive submucosal and myenteric neurons in colon (p < 0.05 and p < 0.01, respectively). The overall microbial diversity and relative abundance did not differ between groups, but Enterobacteriaceae was decreased in colon in buserelin-treated rats (p = 0.020). Basal intestinal permeability did not differ between groups, whereas carbachol stimulation increased ileum permeability in controls (p < 0.05), but not in buserelin-treated rats. Buserelin did not affect stress behavior. CONCLUSIONS: Although buserelin treatment leads to enteric neuronal loss along the gastrointestinal tract with an increased percentage of CRF-immunoreactive neurons in colon, the physiology is well preserved, with modest effects on colon microbiota and absence of carbachol-induced permeability in ileum as the only observed changes.

Rescue hCG to treat empty follicle syndrome after the use of a GnRH agonist as oocyte maturation trigger: First report on fresh embryo transfer and clinical pregnancy.

We present a case series and literature review on the use of rescue human chorionic gonadotropin (hCG) in cases of empty follicle syndrome (EFS) after a gonadotropin-releasing hormone agonist (GnRHa) trigger. EFS was diagnosed after failure to collect any oocytes from one ovary. In such cases, a single dose of hCG was administered and the oocyte retrieval was repeated 36 h later. The main outcome measures were the number of mature oocytes (M2) and embryos (2PN), incidence of hospitalisation for severe ovarian hyperstimulation syndrome (OHSS) and clinical pregnancy when fresh embryo transfers occurred. Our population consisted of 322 patients, who had a GnRH agonist as oocyte maturation trigger (2-mg subcutaneous buserelin). Six patients (1.8%) developed EFS after the use of a GnRHa trigger. Mature oocytes were retrieved in 5 patients after the use of rescue hCG. One patient developed severe OHSS. Two patients had a fresh embryo transfer and one clinical pregnancy was reported. This is the first case series to report fresh embryo transfers and a clinical pregnancy with the use of rescue hCG after failure of the GnRHa trigger.

Ovarian hyperstimulation syndrome: a clinical report on 4894 consecutive ART treatment cycles.

BACKGROUND: Although a large number of studies have been dedicated to ovarian hyperstimulation syndrome (OHSS) none gave full embryological and clinical outcomes comparing oocyte trigger with human chorionic gonadotrophin (HCG) versus with a gonadotrophin-releasing hormone (GnRH) agonist (Buserelin) in cases with suspicious OHSS. The aim of the present study was thus to analyze 4894 consecutive assisted reproductive treatment cycles to undercover associated risk factors for development of OHSS, and the effects of the use of Buserelin as ovulation trigger on embryological and clinical outcomes. METHODS: In the 51 cases that developed OHSS, ovulation trigger was performed with HCG as indicators were not suspicious for OHSS. These were compared against two types of groups: 71 cases where Buserelin was used for ovulation induction due to suspicious development of OHSS; and those remaining 4772 cases where ovulation trigger was currently performed with HCG (control). RESULTS: Of the cases treated with Buserelin the oocyte maturation rate and the ongoing pregnancy rate were significantly lower, with higher rates of ectopic pregnancy and newborn malformations, but none developed OHSS. Of the OHSS cases, 23 needed hospitalization, with no major complications. CONCLUSIONS: Young age, lower time of infertility, lower basal follicle stimulating hormone levels, higher number of cases with female factor and polycystic ovarian syndrome, high number of follicles and higher estradiol concentrations were the risk factors found associated with OHSS. Cases with OHSS also presented higher follicle count but the estradiol levels were within the normal range. It thus remains to develop more strict criteria to avoid all cases with OHSS.

Choroidal neovascular membrane following hormonal stimulation for in vitro fertilization.

PURPOSE: To report the onset of choroidal neovascularization (CNV) following hormonal stimulation for in vitro fertilization (IVF) in a healthy young woman. METHODS: A 31-year-old woman presented with visual impairment following hormonal stimulation for IVF. Clinical history was collected and best-corrected visual acuity (BCVA), complete eye examination, optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography were -performed. RESULTS: Clinical history was negative with the exception of the use of medications for IVF in the previous weeks. Ocular examination revealed the presence of a CNV in the right eye, confirmed by OCT and FA, with a BCVA of 0.7 decimal units. Possible ocular and systemic diseases associated with CNV development were investigated and excluded. Treatment with 3 monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) was effective in reducing CNV size and restoring visual acuity. CONCLUSIONS: This is the first report describing the development of CNV following hormonal stimulation for IVF. The development of CNV may be associated with changes of sex hormones, cytokines, and angiogenic factor levels, including VEGF, induced by hormonal stimulation.

Autoantibodies and gastrointestinal symptoms in infertile women in relation to in vitro fertilization.

BACKGROUND: Prior reports suggest a link between gonadotropin-releasing hormone (GnRH) and gastrointestinal function. The aim of the study was to prospectively investigate women subjected to in vitro fertilization (IVF) using the GnRH analog buserelin, taking into account gastrointestinal symptoms and antibody development against buserelin, GnRH, luteinizing hormone (LH), and their receptors. METHODS: Gastrointestinal symptoms were registered by the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS) before and after IVF treatment, and five years later. Health-related quality of life was evaluated by the 36-item Short-Form questionnaire (SF-36). ELISA was used for antibody analyses before and after treatment. Data were compared with women from the general population. RESULTS: In total, 124 patients were investigated before and after IVF, and 62 were re-evaluated after five years. Buserelin treatment led to significant impairment of constipation (p = 0.004), nausea and vomiting (p = 0.035), psychological well-being (p = 0.000), and the intestinal symptoms' influence on daily life (p = 0.027). At 5-year follow-up, abdominal pain was worsened (p = 0.041), but psychological well-being was improved (p = 0.036), compared to prior treatment, and 15% had an observable deterioration in gastrointestinal symptoms. None developed severe dysmotility. Patients had higher prevalence of IgG antibodies against LH (p = 0.001) and its receptor (p = 0.016), and IgM antibodies against the GnRH receptor (p = 0.001) prior treatment compared with controls, but no antibody development was observed after IVF. CONCLUSION: Patients experience gastrointestinal symptoms during buserelin treatment, and abdominal pain is still increased after five years, but buserelin does not increase antibody formation against GnRH, LH or their receptors.

Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG.

STUDY QUESTION: Is severe early ovarian hyperstimulation syndrome (OHSS) completely prevented with the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol? SUMMARY ANSWER: Severe early OHSS can occur even after the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol. WHAT IS KNOWN ALREADY: Prior studies including over 200 women who received the GnRH agonist trigger and 1500 hCG luteal rescue protocol have reported complete prevention of severe early OHSS. Only a few late OHSS cases have been reported and it has been suggested that this protocol can be safely applied to any women under risk. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included all women who were at high risk of OHSS and were given the GnRH agonist trigger plus hCG luteal rescue protocol between December 2008 and August 2012 in the two participating centers. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 23 women with a mean estradiol level of 4891 ± 2214 pg/ml and a mean number of >12 mm follicles of 20 ± 6 on the day of ovulation triggering. OHSS was categorized according to the Golan criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Overall 6 of the 23 (26%) women developed severe OHSS. Five women had severe early OHSS requiring ascites drainage and hospitalization and three of these women did not undergo embryo transfer. The number of follicles measuring 10-14 mm on the day of triggering was significantly different between women who developed severe early OHSS and those who did not. LIMITATIONS, REASONS FOR CAUTION: The small number of women with severe early OHSS may have prevented identification of other significant risk factors. WIDER IMPLICATIONS OF THE FINDINGS: Although the GnRH agonist plus 1500 IU hCG luteal rescue protocol significantly decreases the risk of severe OHSS, this life threatening complication can still occur in high-risk patients. It would be prudent to avoid hCG luteal rescue and freeze all embryos for future transfer in such women particularly when there are ≥18 follicles with 10-14 mm diameters even with few larger follicles.

Outcomes from ovarian hyperstimulation following the sole administration of gonadotrophin-releasing hormone agonist in the context of in vitro fertilization: report of two cases and review of the literature.

OBJECTIVE: To report the outcomes from two cases of ovarian stimulation following the sole administration of gonadotrophin-releasing hormone agonist (GnRHa) in the context of in vitro fertilization (IVF). DESIGN: A case study was conducted. SETTING: National Referral Unit of Reproductive Medicine. PATIENTS: Two infertile women undergoing IVF participated in the study. INTERVENTIONS: Controlled ovarian hyperstimulation using a long protocol. GnRHa (Buserelin) was started in the luteal phase, in a dose of 600 µg/day, for 12 days. MAIN OUTCOME MEASURES: Number of retrieved oocytes, fertilization rate, number of embryos transferred, implantation rate, ongoing pregnancy, and live birth. RESULTS: Both women underwent egg retrieval and transfer of good quality embryos. One of them conceived and recently gave birth to a healthy full-term baby. CONCLUSIONS: The ovarian hyperstimulation after the sole administration of GnRHa is a rare condition. Oocyte retrieval may be a reasonable treatment under these circumstances instead of cycle cancellation. As far as it is known, this is the third case reported of a live birth following the sole administration of GnRHa in the context of IVF.

Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis--a randomized, double-blind, multicenter, controlled trial.

OBJECTIVE: To compare the efficacy and safety of dienogest (DNG) with intranasal buserelin acetate (BA) in patients with endometriosis. DESIGN: Phase III, randomized, double-blind, multicenter, controlled trial. SETTING: Twenty-four study centers in Japan. PATIENT(S): Two hundred seventy-one patients with endometriosis. INTERVENTION(S): Dienogest (2 mg/day, orally) or BA (900 microg/day, intranasally) for 24 weeks. MAIN OUTCOME MEASURE(S): The pre- to posttreatment changes in the scores of five subjective symptoms during nonmenstruation (lower abdominal pain, lumbago, defecation pain, dyspareunia, and pain on internal examination) and two objective findings (induration in the pouch of Douglas and limited uterine mobility). RESULT(S): Dienogest reduced the scores of all symptoms and findings at the end of treatment, and the mean changes in the scores of all symptoms and findings except induration in the pouch of Douglas were comparable to those obtained with BA. Compared with BA, DNG was associated with irregular genital bleeding more frequently and with fewer hot flushes. The reduction in bone mineral density (BMD) during DNG treatment was significantly lower than that during BA treatment. CONCLUSION(S): DNG is as effective as intranasal BA in alleviating endometriosis, and causes less BMD loss.

Chronic intestinal pseudo-obstruction due to buserelin-induced formation of anti-GnRH antibodies.

BACKGROUND & AIMS: A 30-year-old woman, treated with buserelin, an analogue of gonadotropin-releasing hormone (GnRH) (also called luteinizing hormone-releasing hormone, LH-RH), developed chronic intestinal pseudo-obstruction (CIPO). The sudden onset of this disease in a previously healthy woman perplexed us. CIPO refers to a gastrointestinal disorder that can have a variety of causes, such as drugs, among others. Thus, we wanted to examine whether in this patient the development of CIPO is related to the treatment with buserelin. METHODS: The patient was examined using esophagogastroduodenoscopy, esophageal, and antroduodenojejunal manometry, gastric emptying tests, and histologic analyses and immunohistochemistry on full-thickness biopsies including staining with anti-GnRH antibody. Plasma samples were examined by the standard serologic analyses and specifically for the occurrence of anti-GnRH antibodies by enzyme-linked immunosorbent assay methods. RESULTS: CIPO was diagnosed based on symptoms (abdominal pain, vomiting, and constipation), and the results of the clinical examinations, such as signs of esophageal aperistalsis, delayed gastric emptying, and small intestinal bursts. Histologic examination revealed a decreased number of myenteric neurons as well as increased neuronal degeneration and an abnormal immune profile. There was a loss of GnRH-containing neurons. The patient had high plasma titers of anti-GnRH antibodies, which occurred on the occasions of the treatment with buserelin. CONCLUSIONS: Our findings suggest that the patient has developed CIPO due to buserelin-induced formation of anti-GnRH antibodies destroying GnRH-producing neurons of the myenteric plexus.

A randomised study of GnRH antagonist (cetrorelix) versus agonist (busereline) for controlled ovarian stimulation: effect on safety and efficacy.

OBJECTIVE: To assess safety and efficacy of cetrorelix utilisation in controlled ovarian stimulation (COS). STUDY DESIGN: Phase III, randomized, single center study of 131 patients undergoing COS and IVF with or without ICSI, in a University affiliated Hospital. Sixty-six patients were allocated to the protocol with antagonist and 65 to the agonist protocol arm. The Student's t-test, the Mann-Whitney test and the chi-square test were applied as required, using SPSS for Windows with a two-sided 5% significance level. RESULTS: The mean (+/-S.D.) duration of stimulation was 9.5+/-1.7 days in the antagonist group and 10.6+/-2.1 days in the agonist group (P=0.02). The mean (+/-S.D.) duration of suppression was 4.6+/-1.3 days in the antagonist group and 27.3+/-5.2 days in the agonist group (P<0.0001). No significant differences were noted in other outcome measures: amount of rFSH required, estradiol level on hCG day, number of follicles>or=15 mm and endometrial thickness on oocyte retrieval day, number of oocytes retrieved, fertilization rate and number of OHS cases. Clinical pregnancy rates per-attempt and per-transfer were 15.1% and 17.0% in the antagonist group and 16.9% and 20.0% in the agonist group (P=0.79 and 0.71, respectively). CONCLUSIONS: GnRH antagonists are an effective, safe and well tolerated alternative to agonists for COS.

Achievement of pregnancy three times in the same patient during luteal GnRH agonist administration.

Gonadotrophin-releasing hormone agonist (GnRHa) administration from the mid-luteal phase onwards is considered the gold standard of ovarian stimulation for IVF treatment. It might, however, coincide with an implanting spontaneous pregnancy. Concerns have therefore been raised with regard to the evolution of the resulting pregnancies and long-term outcome of the children born. The current case report describes the achievement of three pregnancies in the same patient during luteal administration of GnRHa. One pregnancy ended in spontaneous abortion and the other two resulted in the delivery of two female infants. The children have so far been followed for 3.5 and 7 years. The physical examination of both children was unremarkable. However, the older child has recently been diagnosed with attention deficit hyperactivity disorder and dyslexia.

Central precocious puberty: current treatment options.

Central precocious puberty (CPP) is characterized by early pubertal changes, acceleration of growth velocity, and rapid bone maturation that often result in reduced adult height. An onset of pubertal signs before the age of 8 years in girls and 9 years in boys should always be evaluated. A combination of clinical signs, bone age, pelvic echography in girls, and hormonal data are required to diagnose CPP and make a judgment concerning progression and prognosis. Not all children with apparently true CPP require medical intervention. The main reasons for treatment are to prevent compromised adult height and to avoid psychosocial or behavioral problems. The need for treatment for auxologic reasons is based on estimation of predicted adult height, with the finding of a reduced height potential, which may require a follow-up. Indication for treatment on the basis of psychologic and behavioral anomalies has to be determined on an individual basis. The main short-term aims of therapy are to stop the progression of secondary sex characteristics and menses (in girls) and to treat the underlying cause, when known. Long-term goals are to increase final adult height and to promote psychosocial well-being. Once it has been decided that treatment is appropriate, it should be initiated immediately with depot gonadotropin-releasing hormone (GnRH) agonists. The effective suppression of pituitary gonadal function is achieved with these compounds in practically all CPP patients. Long-term data are now available from 2 decades of GnRH agonist treatment for patients with CPP. Treatment preserves height potential in the majority of patients (especially in younger patients) and improves the final adult height of children with rapidly progressing CPP, with a complete recovery of the hypothalamic-pituitary-gonadal axis after treatment. GnRH agonist treatment using depot preparations is useful and has a good safety profile, with minimal adverse effects and no severe long-term consequences. Although further data are need, there may be a role in the future for combining somatropin (growth hormone) and GnRH agonist treatment for some patients with significantly impaired growth velocity. The introduction of GnRH antagonists is likely to improve the treatment options for CPP.