Cardiovascular adverse events-related to GnRH agonists and GnRH antagonists: analysis of real-life data from Eudra-Vigilance and Food and Drug Administration databases entries.

INTRODUCTION AND OBJECTIVES: GnRH agonists and GnRH antagonists are two of the mainstays of hormonal therapy (HT) for prostate cancer (PCa). These drugs are at increased risk of cardiovascular (CV) adverse events (AEs). Aim of our study was to compare real-life data on AEs associated with GnRH agonists and GnRH antagonists based on Eudra-Vigilance (EV) and Food and Drug Administration (FDA) reported AEs. MATERIALS AND METHODS: EV and FDA databases were queried and the number of CV adverse events (AEs) for degarelix, buserelin, goserelin, leuprorelin, triptorelin until September 2021 were recorded. Specific CV AEs were recorded and data were analyzed per age and severity. pooled relative risk (PRR) was used to compare data between drugs. RESULTS: CV events were reported in 315/5128 (6%) for Degarelix, in 55/628 for Buserelin (9%), in 843/12,145 (7%) for Goserelin, in 3395/71,160 (5%) for Leuprorelin and in 214/4969 (5%) for Triptorelin. In terms of specific CV disorders, Degarelix presented lower risk of hypertension (PRR 0.60 (95% CI 0.37-0.98), p = 0.04), of myocardial infarction (PRR 0.05 (95% CI 0.01-0.39), p < 0.01) and thrombosis (PRR 0.14 (0.02-1.07), p = 0.06) when compared to GnRH agonists. Overall, younger patients (<65 years) presented a very low risk of CV AEs. Side effects were classified as serious in 90-96% of the cases. Fatal AEs were 5-20% over the CV AEs and 0.2-1% over the total AEs. CONCLUSIONS: Real-life data are consistent with registry studies regarding side effects related to HT. Real-life data suggest GnRH agonists are associated with higher CV AEs when compared to GnRH antagonists. Clinicians should consider these data when prescribing HT especially in patients with CV comorbidities.

DuoStim: a new option for fertility preservation for a woman with Turner syndrome.

INTRODUCTION: Turner syndrome (TS) is associated with hypergonadotropic hypogonadism due to gonadal dysgenesis, which results in premature ovarian failure and subsequent infertility. Therefore, counseling and evaluation for fertility preservation are required as early as possible for women with TS. CASE PRESENTATION: A 23-year-old unmarried woman with mosaic TS (45, X [4/30] 46, XX [26/30]) presented to the pediatric department of our hospital for fertility counseling; she was accompanied by her mother. She was referred to the reproduction center of our hospital for ovarian reserve assessment and counseling regarding fertility preservation. We decided to retrieve oocytes using DuoStim as the controlled ovarian stimulation protocol. During the first and second oocyte retrievals, a total of 17 (9 and 8, respectively) mature metaphase II oocytes were cryopreserved. CONCLUSION: DuoStim may be a useful option for fertility preservation for women with TS and reduced ovarian reserve. This new strategy may obtain the required number of oocytes in the shortest time and preserve the future fertility of women with TS.

Suboptimal response to GnRH-agonist trigger during oocyte cryopreservation: a case series.

BACKGROUND: Random-start, controlled ovarian stimulation (COS) has advanced the field of fertility preservation, allowing patients to expedite fertility treatment and avoid further delays to their cancer therapy. This novel approach allows patients to initiate ovarian stimulation at any point, regardless of where they are in their menstrual cycle. Luteal-phase start (LPS) protocols describe treatment cycles where COS is initiated during the luteal-phase of the menstrual cycle. LPS protocols have not been studied or optimized to the same degree as conventional, early-follicular COS. Particularly, there is a paucity of evidence evaluating treatment outcomes using different trigger medications in LPS protocols. The present study aims to evaluate the efficacy of using a GnRH agonist (GnRH-a) trigger in patients undergoing oocyte cryopreservation in LPS protocols. METHODS: This descriptive case series describes two patients, recently diagnosed with cancer, who underwent oocyte cryopreservation using an LPS protocol and a GnRH-a trigger at a university-affiliated, academic center. RESULTS: The patients described in our case series both failed to adequately respond to a GnRH-a trigger, based on their serum levels of luteinizing hormone (LH) and progesterone 12 h after their GnRH-a trigger. They both required a single rescue dose of human chorionic gonadotropin (hCG). CONCLUSIONS: These findings highlight the potential risk of a suboptimal response to a GnRH-a trigger in patients undergoing LPS, controlled ovarian stimulation for oocyte cryopreservation. This risk might be attributed to the downregulation of GnRH receptors by elevated serum progesterone levels during the luteal phase. Currently, there is insufficient evidence to recommend for or against the use of a GnRH-a trigger during LPS controlled ovarian stimulation. This case series offers a number of management strategies to mitigate this risk and emphasizes the need for further research in this area.

Reproductive performance in dairy cows with cystic ovarian disease after single treatment with buserelin acetate or dinoprost.

The treatment of cystic ovarian disease (COD) in dairy cows is still controversial, and some researchers recommend using gonadotropin-releasing hormone (GnRH) regardless of the type of cysts. The aim of this study was to comparatively evaluate the reproductive performance of cows diagnosed with follicular or luteal cystic structures, after treatment with either buserelin acetate (GnRH agonist) or dinoprost (prostaglandin F2-alpha or PGF2α). The diagnosis was established by ultrasonographic examinations performed twice a month starting 40-45 days after calving, until the cows were diagnosed pregnant after artificial insemination. Both types of cysts were treated either with 21 µg buserelin acetate or 25 mg dinoprost, resulting in four subject groups. After treatment, the estrus rate in cows with follicular cysts treated with dinoprost (55.1%) was significantly lower (P<0.05) than in cows treated with buserelin acetate (77.5%) or in cows diagnosed with luteal cysts (77.2% for dinoprost and 72.4% for buserelin acetate). The conception rate was higher (P<0.05) in cows with follicular cysts treated with buserelin acetate (67.7%) than in those treated with dinoprost (60%) or in those with luteal cysts (56.9% for dinoprost and 47.5% for buserelin acetate). These results show that it is preferable to differentiate between the two types of ovarian cysts before treatment. Luteal cysts can be treated with either PGF2α or GnRH analogues, with better results when PGF2α is used. Contrastingly, follicular cysts are better treated with GnRH analogues. When differentiation is not possible, GnRH analogues are recommended over PGF2α.

Current Medical Strategies in the Prevention of Ovarian Hyperstimulation Syndrome

The purpose of this review is to analyze current medical strategies in the prevention of ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation for in vitro fertilization. Owing to contemporary preventive measures of OHSS, the incidence of moderate and severe forms of the syndrome varies between 0.18% and 1.40%. Although none of medical strategies is completely effective, there is high-quality evidence that replacing human chorionic gonadotropin (hCG) by gonadotropin-releasing hormone (GnRH) agonists after GnRH antagonists and moderate- quality evidence that GnRH antagonist protocols, dopamine agonists and mild protocols reduce the occurrence of OHSS. Among various GnRH agonists, buserelin 0.5 mg, triptorelin 0.2 mg and leuprolide acetate (0.5-4 mg) have been mostly utilized. Although GnRH trigger is currently regarded as the best tool for OHSS prevention, intensive luteal support with exogenous administration of estradiol and progesterone or low-dose hCG on the day of oocyte retrieval or on the day of GnRH agonist trigger are required to achieve optimal conception rates due to early luteolysis. Among currently available dopamine agonists, cabergoline, quinagolide and bromocriptine are the most common drugs that should be used for prevention of both early and late OHSS. Mild stimulation protocols offer attractive option in OHSS prevention with satisfactory pregnancy rates.

Addition of low-dose hCG to rFSH during ovarian stimulation for IVF/ICSI: is it beneficial?

PURPOSE: The aim of the study was to assess the eftect ot the addition or iow-cose numan cnononic gonauoiropm (hCG) to ovarian stimulation with recombinant follicle stimulating hormone (rFSH) on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcome. MATERIALS AND METHODS: This retrospective clinical study was conducted on 141 women undergoing ICSI through a short GnRH-agonist protocol with rFSH and the addition of low-dose (100 IU/day) hCG. The control group consisted of 124 women undergoing ovarian stimulation with a similar protocol devoid of hCG. Statistical analysis in the study population along with a subgroup analysis for age 35 years and 36 years was performed. RESULTS: Women in hCG group were statistically significant older and with higher basal FSH compared to control group. This can be attributed to the Centre's latent tendency to add hCG in the stimulation protocol in poor prognosis patients. Despite this fact and the fact that several ovarian stimulation parameters, such as peak estradiol levels, number of oocytes retrieved, number of mature oocytes, and fertilization rates were in favor of the control group, the quality of transferred embryos and pregnancy rates were in favor of hCG group. Similar results were obtained in the subgroup analyses apart from peak estradiol levels, which did not differ among the study groups. CONCLUSIONS: The addition of hCG to rFSH may be associated with better quality embryos and higher pregnancy rates, even in women of advanced reproductive age with higher basal FSH levels, which are often considered to have poorer ovarian reserve.

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.

Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders.

All IVF-ICSI cycles carried out between October 2009 and October 2012 using GnRH agonist (GnRHa) ovulation trigger (n = 62) followed by a single dose of HCG plus progesterone and oestradiol in the luteal phase because of anticipated ovarian hypertsimulation were retrospectively compared with historic control cycles using HCG trigger (n = 29) and standard luteal phase support. Women's mean age, body mass index, anti-Müllerian hormone, FSH, LH, starting and total stimulation dose, number of follicles, oocytes, embryos, fertilization, implantation, polycystic ovary syndrome, ICSI, live birth and ongoing pregnancy rates per embryo transfer were similar (GnRHa 40.7% versus HCG 35.0%). For each started cycle, GnRHa resulted in 11.4% higher (statistically non-significant) live birth and ongoing pregnancy rate (OR 1.73, CI 0.64 to 4.69), with a similar difference for double-embryo transfers (OR 1.62, CI 0.44 to 6.38) and less need for freezing all embryos (9.7% versus 27.6%; P = 0.04). Incidence of mild-to-moderate OHSS was 16.2% with GnRHa trigger and 31.0% with HCG trigger) and no severe OHSS in the former. The addition of single low-dose HCG in the luteal phase after GnRHa trigger for suspected high-responders reduced the incidence of OHSS with good clinical outcomes, compared with HCG trigger.

Induction of an LH surge and ovulation by buserelin (as Receptal) allows breeding of weaned sows with a single fixed-time insemination.

The aim of this study was to demonstrate successful breeding of sows with a single fixed-time insemination following ovulation induction by buserelin, a GnRH analogue. In a first step, the optimal dose of buserelin (6, 10, or 16 µg) injected at 77 hours after weaning was determined in weaned sows (N = 15, 11, and 12, respectively) using its ability to induce an LH surge of similar magnitude as in control sows (N = 15) and induce ovulation. In 29/38 treated sows (76%), ovulation was induced and synchronized between 32 and 44 hours after injection, and the proportion of females ovulating during this time window was similar between groups at 73%, 73%, and 83% (6, 10, or 16 µg, respectively). Interestingly, whereas ovulation of 100% multiparous sows was induced and synchronized in the 32 to 44 hours posttreatment time window, successful induction was achieved in a lower proportion of primiparous sows (50%, 50%, and 67% following 6, 10, or 16 µg, respectively), the dose effect being nonsignificant. The magnitude of the LH surge was similar between control and treated sows, irrespective of the buserelin dose injected. Neither ovulation rate nor the number of good embryos on Day 5 postovulation differed between groups. Interestingly, the frequency of follicular cysts at slaughter was significantly affected by treatment (P < 0.05), being minimal and maximal in sows treated with 10 or 6 µg buserelin, respectively. In a second step, 419 sows from commercial herds in Spain, Germany, and France were randomly allocated to a control or treated group. The control sows were inseminated twice 12 ± 4 hours apart once estrus was detected. Treated sows received 10 µg buserelin at 86 ± 3 hours after weaning and were inseminated once 30 to 33 hours later. Farrowing rate of treated sows (87%, 166/192) was similar to that of control sows (84.5%, 169/200). Litter size was also similar between treated and control sows (13.6 ± 3.8 vs. 13.7 ± 3.2). In multiparous sows, neither duration of lactation nor magnitude of the fat loss during lactation significantly affected treatment effects. It is concluded that ovulation of weaned multiparous sows can be tightly synchronized by buserelin (10 µg) administration at 86 hours postweaning. This allows breeding once at a fixed time following buserelin injection while maintaining reproductive performance at a level similar to that of sows bred twice during estrus.

In vitro fertility rate of 129 strain is improved by buserelin (gonadotropin-releasing hormone) administration prior to superovulation.

The 129 mice are well recognized for their low fertility and it is speculated that this lack of fertility may be due to the oocyte condition. In this study we investigated superovulation regimens for the 129S1/SvImJ mouse strain to improve the oocyte quality and fertility rate of in vitro fertilization (IVF). Female mice were divided into four groups based on hormone and timing of injection. Group 1 received pregnant mare serum gonadotropin (PMSG) and 48 h later human chorionic gonadotropin (hCG); using the same dose, group 2 received hCG 52 h post-PMSG and group 3, 55 h post-PMSG. Group 4 received buserelin (gonadotropin-releasing hormone agonist [GnRH]) followed 24 h later by PMSG and then hCG 55 h post-PMSG. IVF was performed using 129S1/SvImJ oocytes and sperm; C57BL/6J sperm with 129S1/SvImJ oocytes was used as fertility control. The IVF fertility rate was 1% (Groups 1 and 2), 17% (Group 3) and 55% (Group 4) for 129 oocytes fertilized with 129 sperm. For 129 oocytes fertilized with C57BL/6J sperm, the fertility rate was 5% (Group 1), 10% (Group 2), 40% (Group 3) and 59% (Group 4). These results suggest that extending the interval time between PMSG and hCG and giving GnRH in addition to the standard PMSG and hCG treatments can improve IVF fertility rate of 129S1/SvImJ mouse strains significantly.

An investigational ovarian stimulation protocol increased significantly the psychological burden in women with premature ovarian failure.

OBJECTIVE: To assess the psychological impact (Hospital Anxiety and Depression Scale) of an investigational ovarian stimulation protocol in women with premature ovarian failure (POF). DESIGN: Prospective longitudinal study. POPULATION: Ten women with POF. METHODS: Women with idiopathic POF were placed on three consecutive treatment cycles consisting of gonadotropin ovarian stimulation after estrogen priming, gonadotropin-releasing hormone agonist pituitary desensitization, and corticosteroid immune suppression. RESULTS: Median anxiety and depression scores increased significantly from baseline following three consecutive treatment cycles from 4.0 (range 2.0-8.0) to 11.0 (range 10.0-14.0) (p-value 0.041) and from 1.5 (range 0-6.0) to 9.0 (range 7.0-10.0) (p-value 0.039), respectively. There were nine "probable" anxiety (90%) and three "probable" depression (30%) cases on the final treatment cycle compared with none (0%) on baseline (p-value 0.004 and 0.250, respectively). CONCLUSIONS: The use of investigational ovarian stimulation protocols in women with idiopathic POF was associated with excessive psychological strain. Women with POF should be cautioned against the potentially harmful aspect of similar treatments of unproven benefit.

Prediction of the shrinking rate of uterine leiomyoma nodules using needle biopsy specimens.

OBJECTIVE: To determine correlations between shrinkage of uterine leiomyomas after treatment with GnRH agonists (GnRH-a) or menopause and expression levels of estrogen receptors (ER), progesterone receptors (PR), and vascular endothelial growth factor (VEGF). DESIGN: Cohort study. SETTING: University teaching hospital. PATIENT(S): A total of 26 women with uterine leiomyoma. INTERVENTION(S): Ten women were treated with buserelin acetate injection (1.8 mg), four courses every 4 weeks, and 16 women went into menopause naturally. MAIN OUTCOME MEASURE(S): Tumor shrinkage rates determined from magnetic resonance images taken before and after GnRH-a therapy and before and after natural menopause; immunohistochemical analysis of ER, PR, and VEGF in uterine leiomyoma biopsy specimens taken before intervention or within 6 months before menopause. RESULT(S): Shrinkage rates of uterine leiomyomas were positively correlated with expression levels of ER in women treated with GnRH-a and in postmenopausal women managed conservatively, and with VEGF expression in women treated with GnRH-a. There were no significant correlations with PR expression levels in either group. CONCLUSION(S): Estrogen plays the predominant role in myoma shrinkage for women with GnRH-a therapy and naturally menopausal women.

Successful use of a gonadotropin-releasing hormone (GnRH) analog for the treatment of tertiary hypogonadism (GnRH deficiency) in a 5-year-old Belgian Blue bull.

A bull was referred for a progressive oligoasthenotheratozoospermia that resulted in a unsuitable seminal quality for the cryopreservation. Breeding soundness evaluation results suggested gonadal dysfunction. Because of the lack of normal ranges for these hormones in the bull, in this study, the hypogonadism and the site of the dysfunction (hypothalamus) were diagnosed by the gonadotropin-releasing hormone (GnRH) stimulation test. The evaluation of pituitary and testicular responsiveness by a GnRH stimulating test revealed a responsiveness of the pituitary and testis, thus a secondary hypogonadism (hypothalamic hypogonadism) was postulated and a therapeutic approach based on the subcutaneous administration of GnRH analog was attempted. An increase in semen volume, concentration and sperm characteristics were detected 9 weeks after the start of the treatment, corroborating the hypothalamic origin of the disease and the useful of the GnRH therapy.

Treatment of endometriosis in different ethnic populations: a meta-analysis of two clinical trials.

Approaches to the treatment of endometriosis vary worldwide, but studies comparing endometriosis medications in different ethnic groups are rare. A systematic literature search identified two studies directly comparing dienogest (DNG) versus gonadotropin-releasing hormone (GnRH) analogues in European and Japanese populations. Meta-analysis of visual analogue scale scores revealed no heterogeneity in response between the trials, indicating equivalent efficacy of DNG and GnRH analogues for endometriosis-related pain across populations. DNG was significantly superior to GnRH analogues for bone mineral density change in both trials, but significant heterogeneity between the studies may indicate ethnic differences in physiology.