Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats.

Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (Star, Cyp11a1, Cyp17a1) and genes involved in ovulation regulation (Adamts-1, Cox-2, Egr-1, Mt-1); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.

Aflibercept suppresses ovarian hyperstimulation syndrome: an experimental study in rats.

OBJECTIVE: In this study, we aimed to determine the impact of the antiangiogenic medications, namely, aflibercept and cabergoline in the prevention and treatment of ovarian hyperstimulation syndrome in a rat model. METHODS: A total of 36 female Wistar rats were randomly allocated to one of the five groups, including disease-free and ovarian hyperstimulation syndrome controls: Group no OHSS (control, n=6) received saline only intraperitoneally (i.p.); group just OHSS (ovarian hyperstimulation syndrome only, n=6) received 10 IU pregnant mare serum gonadotropin and 30 IU human chorionic gonadotropin subcutaneously to produce ovarian hyperstimulation syndrome; group cabergoline+OHSS (cabergoline+ovarian hyperstimulation syndrome, n=8) received 100 µg/kg oral cabergoline; group aflibercept (12.5 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 12.5 mg/kg i.p. aflibercept; and group aflibercept (25 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 25 mg/kg i.p. aflibercept. The groups were compared for ovarian weight, immunohistochemical vascular endothelial growth factor expression, spectrophotometric vascular permeability evaluated with methylene blue solution in peritoneal lavage, and body weight growth. RESULTS: Vascular endothelial growth factor immunoexpression was substantially greater in the just OHSS group (22.00±10.20%) than in the aflibercept (12.5 mg/kg)+OHSS (7.87±6.13%) and aflibercept (25 mg/kg)+OHSS (5.63±4.53%) groups (p=0.008 and p=0.005, respectively). Post-hoc tests indicated that cabergoline, 12.5 mg/kg aflibercept, and 25 mg/kg aflibercept decreased vascular permeability compared to the untreated ovarian hyperstimulation syndrome group (p=0.003, p=0.003, and p=0.001, respectively). JOH group had the heaviest ovaries, whereas aflibercept (25 mg/kg)+OHSS group had the lightest. In terms of body weight gain, cabergoline+OHSS group was substantially greater than the aflibercept (12.5 mg/kg)+OHSS and aflibercept (25 mg/kg)+OHSS groups (p=0.006 and p=0.007, respectively). CONCLUSION: Aflibercept, an antiangiogenic medication, decreased ovarian hyperstimulation syndrome by lowering the vascular permeability and vascular endothelial growth factor expression.

A promising treatment for spontaneous ovarian hyperstimulation syndrome due to familial partial lipodystrophy: GnRH analogs combined with cyst aspiration.

PURPOSE: To present a patient with familial partial lipodystrophy (FPLD) and polycystic ovary syndrome (PCOS) who was admitted with spontaneous ovarian hyperstimulation syndrome (OHSS)-like extremely enlarged ovaries, which was successfully treated using gonadotropin-releasing hormone analogs and abdominal cyst aspiration in combination. METHOD: This is a descriptive case report of a single patient with FPLD and PCOS. RESULTS: Clinical improvement was achieved 6 months after therapy besides progressive reduction in total testosterone and DHEAS. Furthermore, there was a significant improvement in hyperinsulinemia and hypertriglyceridemia. Additionally, reduction in the size of ovarian cysts, reduction in the size and number of localizations of acanthosis nigricans, reduction in scores of mFGS, and weight loss were also observed. CONCLUSION: Although there are few reports in the literature describing the association between PCOS with FPLD, management of this novel spontaneous OHSS-like condition has not yet been clearly defined. In the case of extremely enlarged multicystic ovaries and severe hyperandrogenemia, GnRH analogs may be considered to prevent ovarian enlargement and reduce hyperandrogenemia, especially when other treatment options are inappropriate.

Long-acting gonadotropin-releasing hormone agonist trigger in fertility preservation cycles before chemotherapy.

BACKGROUND: Oocytes/embryo cryopreservation and ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHas) are two established strategies for preserving fertility in patients with cancer, frequently both being offered to the same woman. As the first injection of GnRHa should be administered before chemotherapy, it is usually performed in the luteal phase of the urgent controlled ovarian stimulation (COS) cycle. The GnRHa flare-up effect on recently stimulated ovaries may cause ovarian hyperstimulation syndrome (OHSS) and this risk may discourage some oncologists to offer an ovarian function preservation method with proven efficacy. We suggest the long-acting GnRHa as an option to trigger ovulation for egg retrieval in oncological patients, whenever ovarian suppression during chemotherapy is planned. PATIENTS AND METHODS: We retrospectively analyzed prospectively collected data from all consecutive ovarian stimulation cases in oncological patients for oocyte cryopreservation from 2016 to 2021 in a single academic referral center. The COS was performed according to good clinical practice standards. Since 2020 long-acting GnRHa trigger was offered to all patients for whom ovarian suppression after cryopreservation was planned. All other patients served as controls, stratified for the triggering method used: highly purified chorionic gonadotrophin 10 000 UI or short-acting GnRHa 0.2 mg. RESULTS: Mature oocytes were collected, with the expected maturation rate, in all the 22 cycles triggered with GnRHa. The mean number of cryopreserved oocytes was 11.1 ± 4, with a maturation rate of 80% (57%-100%), versus 8.8 ± 5.8, 74% (33%-100%) with highly purified chorionic gonadotrophin and 14 ± 8.4, 80% (44%-100%) with short-acting GnRHa. No case of OHSS was observed after long-acting GnRHa triggering and by 5 days after egg retrieval most patients had reached luteinizing hormone levels showing suppression. CONCLUSIONS: Our preliminary data show that long-acting GnRHa is efficacious in inducing the final oocytes' maturation, reducing OHSS risk and suppressing ovarian function by the start of chemotherapy.

Introduce an optimal method of ovarian stimulation in the polycystic ovarian syndrome affected: a randomized controlled trial.

BACKGROUND: Currently, optimal method of ovarian stimulation (OS) to in-vitro fertilization (IVF) in the patients with polycystic ovarian syndrome (PCOS) is unknown. The present research aims to study the efficiency of minimal-OS method in treatment of infertile patients with PCOS and also the effect of gonadotropin type (recombinant FSH (r-FSH) vs. urinary Human menopausal gonadotropin (u-HMG)) on treatment cycles with GnRH-antagonist. METHODS: In this randomized controlled trial, a total of 120 eligible patients were randomly allocated into four groups of OS to IVF: minimal-OS with r-FSH, minimal-OS with u-HMG, mild-OS with r-FSH and mild-OS with u-HMG. IVF outcomes of groups were analyzed statically. RESULTS: The statistical analysis showed that there were significant differences among groups regarding stimulation duration (p < 0.0001), number of retrieved oocytes (p < 0.0001), number of obtained embryos (p < 0.0001). There were no statistically significant differences in fertilization rate (p = 0.289) and implantation rate (p = 0.757) among our participants. There were also significant differences among these four groups in terms of clinical pregnancy rate (/ET and /cycles) (p < 0.0001, p = 0.021, respectively) and live birth rate/cycles (p < 0.0001). Also cases of freeze all embryos due to prevention of ovarian hyper stimulation syndrome (OHSS) (p = 0.004). CONCLUSIONS: On the basis of present results the minimal-OS with u-HMG may be one of optimal methods of control OS in the patients with PCOS in respect to serum levels of estradiol on the day of triggering final oocyte maturation, total dose of prescribed gonadotropin, the optimal number of oocytes and embryos obtained, rate of clinical pregnancy and the incidence of OHSS risk. TRIAL REGISTRATION: NCT, NCT03876145. Registered 15/03/2019. Retrospectively registered, http://www. CLINICALTRIAL: gov/ NCT03876145.

Does cabergoline administration affect endometrial VEGFR-2 expression in a rat model of ovarian hyperstimulation syndrome?

OBJECTIVE: To assess the effect of cabergoline on endometrial vascular endothelial growth factor receptor-2 (VEGFR-2) immunoexpression in an ovarian hyperstimulation syndrome (OHSS) rat model. MATERIAL AND METHODS: Twenty-one immature female Wistar rats were assigned into three groups: group 1, the control group; group 2, stimulated with gonadotropins to mimic OHSS; and group 3, in which an OHSS protocol was induced and thereafter treated with cabergoline (100 µg/kg/day). Body weight, ovarian volume, corpora lutea numbers, and endometrial VEGFR-2 expression were compared between the groups. RESULTS: Weight gain and ovarian volume were highest in the OHSS-placebo group, while cabergoline administration significantly reversed those effects (p = 0.001 and p = 0.001, respectively). VEGFR-2 stained cells were significantly lower in groups 2 and 3 compared to group 1 (p = 0.002). Although VEGFR-2 expression was lowest in group 3, the difference was not statistically significant. Corpora lutea numbers were also similar (p = 0.465). CONCLUSION: While successful implantation requires a vascularized receptive endometrium, impaired expression of VEGFR-2 and disrupted endometrial angiogenesis due to cabergoline administration may be associated with IVF failure in fresh OHSS cycles. The insignificant decrease in endometrial VEGFR-2 expression observed in this research needs to be investigated by further studies involving additional techniques such as immunoblotting and/or RT-PCR analyses.

The impact of letrozole on oocyte quality in assisted reproductive technology (ART); a randomized double-blind clinical trial.

OBJECTIVE: To examine the effect of letrozole on oocyte quality and pregnancy outcome in assisted reproductive technology (ART). METHODS: This double blind placebo controlled clinical trial was conducted in Vali-Asr Infertility Center. Infertile women candidate for IVF that underwent antagonist protocol were selected. Eligible women randomly allocated into treatment (letrozole/Let group) and control (placebo) group. Participants received letrozole 5 mg/day or placebo at the time of gonadotropin start until trigger day in the same manner. Number of oocyte retrieved, metaphase II oocyte number, high grade oocyte number (G1), high quality embryo, Chemical and clinical pregnancy rate and OHSS (ovarian hyperstimulation syndrome) rate was recorded. 216 infertile women (104 in letrozole and 112 in the control group) were evaluated. RESULTS: In the Let group estradiol level was significantly lower (p_value < .001) and testosterone significantly higher than in the control group (p_value = .02). The number of retrieved oocytes, MII oocytes, G1 oocytes, and 2PN was significantly lower in the Let group (p < .05). No significant difference was found in the day of stimulation, total gonadotropin dose, OHSS rate, and clinical pregnancy rate between the two groups (p > 0.05). CONCLUSIONS: According to the results, letrozole may reduce oocyte quality and cause poor IVF outcomes as well.

Novel therapeutic avenues for kisspeptin.

Kisspeptin is a hypothalamic neuropeptide that acts via the hypothalamus to stimulate hypothalamic gonadotrophin-releasing hormone secretion and downstream gonadotrophin release. In health, kisspeptin induces normal puberty and modulates ovulation in healthy women. Hypothalamic kisspeptin expression is reduced in several functional reproductive disorders; thus, treating such conditions with kisspeptin is conceptually attractive. Recent studies have demonstrated that kisspeptin can induce a more physiological degree of oocyte maturation during in vitro fertilisation treatment that can reduce the risk of potentially life-threatening complications such as ovarian hyperstimulation syndrome seen with human chorionic gonadotrophin. Furthermore, chronic use of kisspeptin could potentially restore reproductive health in females with hypothalamic amenorrhoea, treat hyposexual drive disorder in otherwise healthy males and has potential indications in polycystic ovary syndrome, osteoporosis and metabolic dysfunction-associated fatty liver disease. Finally, kisspeptin analogues could potentially overcome some of the pharmacological challenges associated with the natural forms of kisspeptin such as short duration of action and development of tachyphylaxis.

Effects of intracerebroventricular and intravenous administration of Kisspeptin-54 and Gonadotropin-releasing hormone agonist in rats with ovarian hyperstimulation.

PURPOSE: We aim to determine the effect of local and systemic administration of kisspeptin-54 on ovarian hyperstimulation. METHODS: Immature female rats were used. In order to generate the ovarian hyperstimulation model, 50 IU PMSG was administered for 4 consecutive days and a single dose of 25 IU hCG was administered to all groups except for the sham group. To synchronize the sham group, a single dose of 10 IU PMSG followed by 10 IU hCG (48 h later) was applied. Kisspeptin-54 and gonadotropin-releasing hormone (GnRH) agonists were administered 48 h after hCG injection. While intracerebroventricular injection is performed with stereotaxic surgery, Intravenous administration was from the tail vein. Ovarian weights were measured. FSH, LH, estrogen and progesterone hormones were detected in serum by ELISA. VEGFa, IL-1ß, TNF-α, MCP-1 immunohistochemical staining was performed on the ovaries and hypothalamus and their optical densities were determined with Image J. Kiss1R mRNA expression was determined by qRT-PCR. RESULTS: Ovarian weights increased significantly in the OHSS group and the systemic GnRH agonist group. The optical densities of VEGFa, IL-1ß, TNF- α and MCP-1 immunoreactivity showed us that both local and systemic applied kisspeptin-54 attenuates the level of investigated inflammation parameters in the ovaries. Moreover, local administration of kisspeptin-54 has been shown to enhance the level of Kiss1R mRNA in both the ovaries and the hypothalamus. CONCLUSION(S): Local and systemic administration of Kisspeptin-54 as a post-treatment reduces inflammation parameters in the ovaries. These findings promote the potential use of kisspeptin-54 on OHSS.

Optimization of assisted reproductive technology outcomes in patients with polycystic ovarian syndrome: updates and unanswered questions.

PURPOSE OF REVIEW: Narrative review of recent literature on optimization of assisted reproduction technology outcomes in patients with polycystic ovarian syndrome (PCOS). RECENT FINDINGS: The key areas of focus include pre cycle treatment with the goal of cohort synchronization, methods of ovulation suppression and trigger medication. There is no definitive evidence that precycle treatment with combined oral contraceptives (COCs) or progestins improve or negatively impact in vitro fertilization outcomes in patients with PCOS. The reviewed evidence supports consideration of progestins as suppression of premature ovulation in patients with PCOS as an alternative to gonadotropin releasing hormone (GnRH) antagonist if a freeze all protocol is planned. There is limited prospective evidence in PCOS populations regarding use of a dual trigger using GnRH agonist and human chorionic gonadotropin (hCG). SUMMARY: This review has implications for clinical practice regarding ovarian stimulation protocols for patients with PCOS. We also identified areas of research need including the further exploration of the value of pre cycle COC or progestin use in a PCOS population, also the use of GnRH agonist in combination with hCG in a well defined PCOS population and using GnRH agonist trigger alone as a control.

Calcium gluconate infusion is not as effective as dopamine agonists in preventing ovarian hyperstimulation syndrome.

OBJECTIVE: The aim of the study was to compare the effectiveness of calcium gluconate and cabergoline therapy in the prevention of ovarian hyperstimulation syndrome (OHSS). PATIENTS AND METHODS: Eight hundred and forty-five women who underwent GnRH antagonist protocol and at high risk for developing OHSS were divided into two groups, those given cabergoline (n=435) or calcium gluconate (n=410). In cabergoline group, 0.5 mg of cabergoline was administered once daily p.o. starting on the day of ovulation trigger and continued until the following 8 days. In calcium gluconate group, intravenous calcium gluconate was administered daily for four days starting on the day of oocyte pickup (OPU). 10 ml of 10% calcium gluconate solution was dissolved in 200 ml of physiological saline and administered by intravenous route within 40 minutes. Infusion was started within the first 30 minutes following the OPU and continued on the 1st, 2nd and 3rd days after OPU. RESULTS: Mild OHSS was developed in 367 (89%) patients receiving calcium gluconate infusion, while 251 patients (57%) in the cabergoline group developed mild OHSS. The frequency of mild OHSS in the calcium group was significantly higher than the cabergoline group (p<.001). Moderate OHSS was observed in 32 people (7.8%) in the calcium gluconate group, while it was observed in 184 people in the cabergoline group (42.3%). Calcium gluconate infusion significantly reduced the development of moderate OHSS compared to cabergoline therapy (p<.001). Severe OHSS developed in 11 patients (2.7%) in the calcium gluconate group, while severe OHSS did not develop in those given cabergoline (0%, p<.001). Clinical pregnancy, live birth and abortion rates were similar in the two groups. When logistic regression analysis was performed, a significant correlation was found between age, BMI, AMH, the number of antral follicle count, OHSS history, paracentesis, progesterone on the day of hCG, 2 PN zygotes, and HbA1c levels and the development of OHSS. No correlation was found between the use of metformin or cetrotide and the development of OHSS. CONCLUSIONS: Calcium gluconate treatment is not effective in the prevention of OHSS.

Ginkgo biloba extract 761 reduces vascular permeability of the ovary and improves the symptom of ovarian hyperstimulation syndrome in a rat model.

AIMS: Ginkgo biloba extract (EGb) has been widely applied in the treatment of cerebrovascular and neurological diseases. However, the effect of EGb761 on ovarian hyperstimulation syndrome (OHSS), a vascular disorder and life-threatening complication of in vitro fertilization and intracytoplasmic sperm injection therapy (IVF/ICSI), has not been evaluated. MATERIALS AND METHODS: Forty female Wistar rats aged 22-days old (D22) were divided into eight groups: Control rats received intraperitoneal injection of saline for five consecutive days (D22-D26); OHSS model group received 10 IU equine chorionic gonadotropin (eCG) for four consecutive days (D22-D25) and 30 IU of human chorionic gonadotropin (hCG) on the 5th day (D26); Prophylactic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/day) 1 h before injection of eCG (hCG) for seven consecutive days; Therapeutic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/day) 48 h after injection of eCG (hCG) for seven consecutive days. RESULTS: All three doses of EGb761 therapeutic medication significantly reduced ovarian mass index of OHSS model rats (p ≤ .01). Furthermore, therapeutic treatment group exhibited improved vascular permeability, decreased estradiol and progesterone levels, lower corpus luteum, and higher follicle numbers compared with the OHSS model. Elevated protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in both ovary and kidney of the OHSS model was restrained by EGb761 therapeutic treatment. CONCLUSIONS: EGb761 therapeutic medication decreases vascular permeability in OHSS rat model by inhibiting VEGF and VEGFR expression, which may contribute to the treatment of OHSS.

Nintedanib Treatment After Ovulation is an Effective Therapeutic Strategy for the Alleviation of Ovarian Hyperstimulation Syndrome (OHSS) in a Mouse Model.

PURPOSE: Ovarian hyperstimulation syndrome (OHSS) is a serious complication of controlled ovarian hyperstimulation. In this study, we hope to explore whether nintedanib, a tyrosine kinase inhibitor, can inhibit OHSS by blocking signaling of vascular endothelial growth factor in a mouse model. Considering that nintedanib been approved for the treatment of some diseases. We believe that nintedanib has important potential in the treatment of OHSS. METHODS: Female ICR mice aged 6-8 weeks with similar initial weights were used to establish the OHSS model. At 12 and 24 hours after human chorionic gonadotropin (hCG) trigger, we administered nintedanib by subcutaneous injection and analyzed the OHSS-related physiological characteristics and biochemical indices of the model mice within 48 hours after hCG-trigger. RESULTS: Nintedanib significantly alleviated the symptoms of OHSS after hCG-trigger compared with those of OHSS group (weight change, P < 0.0001; ovarian weight, P < 0.0001, peritoneal exudation level, P < 0.01). Further investigation proved that the corpus luteum (number, P < 0.001; diameter, P < 0.0001) and luteal vessel (P < 0.0001) development were inhibited in the nintedanib administration group. Then, the vascular permeability test showed that the capillary bleeding points (P < 0.0001) were also significantly reduced in nintedanib administration group. Gene expression tests demonstrated that the intercellular connection-related genes expression in the nintedanib administration group was similar to that in the no-OHSS induced group. Further detection of coagulation and thrombosis indices indicated that the nintedanib administration in the OHSS model did not increase the risk of thrombosis or bleeding. CONCLUSION: Our study demonstrated that nintedanib can alleviate and manage the symptoms of OHSS in a mouse model. These findings identify a feasible scheme for the prevention and treatment of OHSS in clinical practice in the future. Moreover, since the scheme can be implemented after ovulation, it will not cause potential adverse effects on gametogenesis, fertilization or embryonic development.

Prevention of Premature Ovulation by Administration of Gonadotropin Releasing Hormone Antagonist the day After Ovulation Triggering in Diminished Ovarian Reserve Patients.

OBJECTIVE: The aim of the present retrospective study was to investigate the effectiveness of single-dose gonadotropin releasing hormone (GnRH) antagonist administration, the day after human chorionic gonadotropin (hCG) triggering for final oocyte maturation, on the prevention of premature luteinization in patients with diminished ovarian reserve in in-vitro fertilization (IVF) cycles. The secondary objective of the study was to search the effect of this protocol on pregnancy outcomes. METHODS: This is a retrospective study including 267 infertile patients who have single antral follicle seen with ultrasonography on the 2nd or 3rd day of the menstrual cycle before starting IVF treatment. We randomized patients into two groups. The case group comprised patients who had single-dose GnRH antagonist injection the day after hCG triggering formed, and the patients who had the standard treatment regime formed the control group. In both groups, the oocytes were collected 36 hours after hCG injection. RESULTS: The premature ovulation rate was significantly low in the case group compared with the control group (6.86 versus 20.6% per scheduled cycle) (p = 0.022). Also, the oocyte retrieval rate (93.14 versus 67.87% per scheduled cycle) (p = 0.013), the oocyte maturity rate (79.42 versus 47.87%) (p = 0.041), the fertilization rate (65.68 versus 34.54%) (p = 0.018), and the embryo transfer rate per scheduled cycle (44.11 versus 18.78%) (p = 0.003) were higher in the GnRH antagonist group than in the control group. CONCLUSION: The administration of GnRH antagonist the day after hCG trigger in IVF treatments of patients with diminished ovarian reserve enabled a significant decrease in the rate of premature ovulation but had no effect on live birth rate.

OBJETIVO: O objetivo do presente estudo retrospectivo foi investigar a eficácia da administração do antagonista do hormônio liberador da gonadotrofina (GnRH) em dose única no dia seguinte ao desencadeamento da gonadotrofina coriônica humana (hCG) para a maturação final do oócito, na prevenção da luteinização prematura em pacientes com diminuição do ovário reserva em ciclos de fertilização in vitro (FIV). O objetivo secundário do estudo foi pesquisar o efeito deste protocolo nos resultados da gravidez. MéTODOS: Trata-se de um estudo retrospectivo incluindo 267 pacientes inférteis que apresentam um único folículo antral visto por ultrassonografia no 2° ou 3° dia do ciclo menstrual antes de iniciar o tratamento de FIV. Nós randomizamos os pacientes em dois grupos. Os pacientes que receberam injeção de antagonista de GnRH em dose única no dia seguinte ao desencadeamento do hCG formaram o grupo caso, e os pacientes que receberam o regime de tratamento padrão formaram o grupo controle. Em ambos os grupos, os oócitos foram coletados 36 horas após a injeção de hCG. RESULTADOS: A taxa de ovulação prematura foi significativamente baixa no grupo caso em comparação com o grupo controle (6,86 versus 20,6% por ciclo programado) (p = 0,022). Além disso, a taxa de recuperação de oócitos (93,14 versus 67,87% por ciclo programado) (p = 0,013), a taxa de maturidade do oócito (79,42 versus 47,87%) (p = 0,041), a taxa de fertilização (65,68 versus 34,54%) (p = 0,018) e a taxa de transferência de embriões por ciclo programado (44,11 versus 18,78%) (p = 0,003) foram maiores no grupo antagonista de GnRH do que no grupo controle. CONCLUSãO: A administração de antagonista de GnRH, no dia seguinte ao desencadeamento de hCG em tratamentos de FIV de pacientes com reserva ovariana diminuída permitiu uma redução significativa na taxa de ovulação precoce, mas não teve efeito na taxa de nascidos vivos.

Treatment of Ovarian Hyperstimulation Syndrome in a Mouse Model by Cannabidiol, an Angiogenesis Pathway Inhibitor.

Studies suggest that ovarian hyperstimulation syndrome (OHSS) can be treated by reducing the level of vascular endothelial growth factor (VEGF). However, due to the side effects of commercially available VEGF-reducing drugs, they can be ruled out as a suitable treatment for OHSS; therefore, researchers are looking for new medications to treat OHSS. This study is aimed at investigating the effects of cannabidiol (CBD) in an OHSS model and to evaluate its efficacy in modulating the angiogenesis pathway and VEGF gene expression. For this purpose, 32 female mice were randomly divided into four groups (eight mice per group): control group, group 2 with OHSS induction, group 3 receiving 32 nmol of dimethyl sulfoxide after OHSS induction, and group 4 receiving 30 mg/kg of CBD after OHSS induction. The animals' body weight, ovarian weight, vascular permeability (VP), and ovarian follicle count were measured, and the levels of VEGF gene and protein expression in the peritoneal fluid were assessed. Based on the results, CBD decreased the body and ovarian weights, VP, and corpus luteum number compared to the OHSS group (p < 0.05). The peritoneal VEGF gene and protein expression levels reduced in the CBD group compared to the OHSS group (p < 0.05). Also, CBD caused OHSS alleviation by suppressing VEGF expression and VP. Overall, CBD downregulated VEGF gene expression and improved VP in OHSS.

Ginkgo biloba extract 761 reduces vascular permeability of the ovary and improves the symptom of ovarian hyperstimulation syndrome in a rat model.

AIMS: Ginkgo biloba extract (EGb) has been widely applied in the treatment of cerebrovascular and neurological diseases. However, the effect of EGb761 on ovarian hyperstimulation syndrome (OHSS), a vascular disorder and life-threatening complication of In Vitro Fertilization and Intracytoplasmic Sperm Injection therapy (IVF/ICSI), has not been evaluated. MATERIALS AND METHODS: Forty female Wistar rats aged 22-days old (D22) were divided into eight groups: Control rats received intraperitoneal injection of saline for 5 consecutive days (D22-D26); OHSS model group received 10 IU equine chorionic gonadotropin (eCG) for 4 consecutive days (D22-D25) and 30 IU of human chorionic gonadotropin (hCG) on the 5th day (D26); Prophylactic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/d) one hour before injection of eCG (hCG) for 7 consecutive days; Therapeutic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/d) 48 h after injection of eCG (hCG) for 7 consecutive days. RESULTS: All three doses of EGb761 therapeutic medication significantly reduced ovarian mass index in the OHSS model (p ≤ .01). Further, the therapeutic treatment group exhibited improved vascular permeability, decreased estradiol and progesterone levels, lower corpus luteum, and higher follicle numbers compared with the OHSS model. Elevated protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in both ovary and kidney of the OHSS model was restrained by EGb761 therapeutic treatment. CONCLUSIONS: EGb761 therapeutic medication decreases vascular permeability in OHSS rat model by inhibiting VEGF and VEGFR expression, which may contribute to the treatment of OHSS.

Study of clinical experience with different approaches to controlled ovarian hyperstimulation: a focus on safety and efficacy.

OBJECTIVES: Current retrospective cohort study analyses clinical database records of 4792 assisted reproduction procedures to assess the significance of target effectiveness endpoints from a safety perspective. METHODS: Stimulation protocols with urinary, recombinant or combination of both types gonadotrophin preparations are compared according to the following primary endpoints: incidence of ovarian hyperstimulation syndrome (OHSS), cycle cancellation, follicle count, induced estradiol values, clinical pregnancy achieved and cycles reached embryo transfer/freezing. We have investigated the incidence of cases evaluated as 'risky for OHSS' by secondary efficacy endpoints (exogenous gonadotrophin exposure, luteinising hormone and progesterone values, oocyte yield, eggs with normal maturation). The following statistical methods were applied: descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson chi-square test, Fisher's exact test, binary logistic regression. RESULTS: Only 16 cases (0.42%) of moderate and delayed OHSS were established. Three hundred and seven (8.6%) stimulation cycles have been cancelled, principally among urinary protocols. Although the clinical pregnancy rate does not differ significantly in compared groups, punctured follicle count, oocyte yield and progesterone level were higher for recombinant preparations, followed by combined and urinary protocols. Follicle count, mean estradiol and luteinising hormone levels are within the 'safe window' for all investigated groups, associated with minimised risk of stimulation cancellation. The mean follicle-stimulating hormone (FSH) dose was highest in urinary protocols at the same duration of stimulation compared with recombinant products. The younger age, bigger follicle count, oocytes yield, mature oocytes count, percentage of fertilised oocytes, more embryos transferred and the later day of embryo transfer are critical for both assisted reproduction techniques (ART) success rate and the safety profile of sterility treatment. CONCLUSIONS: Safety surveillance of ART exceeds the incidence of OHSS. Suboptimal effectiveness of stimulation protocols may also jeopardise the well-being of ART patients. Gonadotrophin exposure, induced values of sex hormones, and quantity and quality of extracted oocytes should be considered to minimise any unintended suffering of treated couples.

Oxytocin and cabergoline alleviate ovarian hyperstimulation syndrome (OHSS) by suppressing vascular endothelial growth factor (VEGF) in an experimental model.

PURPOSE: Ovarian hyperstimulation syndrome (OHSS) is a life-threatening complication of ovarian stimulation in reproductive medicine. Here, we aimed to investigate the role of oxytocin (OT) and cabergoline in the prevention and alleviation of the OHSS in an animal model. METHODS: Thirty-five female immature Wistar rats were randomly assigned to five groups. The control group (n = 7) received saline only for five consecutive days. Remaining twenty-eight rats received 10 IU of pregnant mare serum gonadotropin (PMSG) followed by 30 IU of human chorionic gonadotropin (hCG) to induce OHSS. Group 2 (n = 7) was managed with no additional intervention after the induction of OHSS. Group 3 (n = 7) received 100 µg/kg cabergoline 2 h before the PMSG injection for four consecutive days and 2 h before the hCG injection on the fifth day. Group 4 (n = 7) and group 5 (n = 7) received 80 µg/kg and 160 µg/kg OT after induction of OHSS, respectively. Oxytocin was administered 2 h before the PMSG injection for four consecutive days and 2 h before the hCG injection on the fifth day. Body and ovary weight, vascular permeability (VP), VEGF expression in the ovaries, and levels of VEGF in the peritoneal fluids were examined in all animals. RESULTS: Cabergoline and OT reduced body weight, ovary weight, and VP compared to that of the OHSS group (p < 0.05). VEGF expressions in ovaries and peritoneal VEGF levels were decreased in cabergoline and OT groups compared to that of the OHSS groups (p < 0.001 for cabergoline and OT-80 µg/kg; p < 0.00001 for OT-160 µg/kg). However, there was no statistically significant difference in these parameters between the OT and cabergoline groups. CONCLUSION: Both OT and cabergoline were active in the alleviation of OHSS through suppression of VEGF and VP. Overall, we conclude that OT is effective for downregulation for VEGF and improvement in vascular permeability in OHSS.

Melatonin stimulates VEGF expression in human granulosa-lutein cells: A potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome.

Melatonin can be synthesized and secreted not only by the pineal gland but also by many extra-pineal tissues. It has been shown that many ovarian functions are regulated by melatonin locally. Ovarian hyperstimulation syndrome (OHSS) is a serious complication during ovulation induction of the in vitro fertilization treatment. To date, the etiology of OHSS is not fully understood. However, vascular endothelial growth factor (VEGF) is recognized as a critical mediator for the pathogenesis of OHSS. High expression of melatonin has been detected in the follicular fluid of OHSS patients. However, whether VEGF expression can be regulated by melatonin in human granulosa cells and further contributes to the pathogenesis of OHSS remain unknown. In this study, we show that melatonin stimulates VEGF expression in human granulosa-lutein (hGL) cells. Our results reveal that the MT2 receptor and activation of AKT are involved in melatonin-induced VEGF expression. Using a rat OHSS model, we report that the VEGF levels are up-regulated in the ovaries of OHSS rats. Blocking the melatonin system by administrating MT2 receptor antagonist, 4-P-PDOT, alleviates OHSS symptoms by decreasing the expression of VEGF. In addition, the expression levels of melatonin and VEGF in the follicular fluid of OHSS patients are up-regulated and positively correlated. This study demonstrates an important role for melatonin in regulating the pathogenesis of OHSS.

GnRH triggering may improve euploidy and live birth rate in hyper-responders: a retrospective cohort study.

PURPOSE: Despite the increasing use of GnRHa to trigger final oocyte maturation in segmented IVF cycles, the effects of trigger modality on chromosomal competence and embryo quality remain controversial. Hence, the purpose of this study was to compare euploidy rates and pregnancy outcomes among hyper-responding women using hCG versus GnRHa trigger. METHODS: This retrospective study included 333 hyper-responders, defined as >15 oocytes retrieved, who underwent preimplantation genetic testing (PGT-A) in segmented IVF cycles using either GnRHa or urinary hCG trigger. Live birth rate (LBR) was the primary outcome of interest. Implantation rate (IR), clinical pregnancy rate (CPR), and euploidy rate were secondary outcomes. RESULTS: GnRH triggering was associated with improved IR (70.5 vs. 53.2%, p = 0.0475), LBR (51.3 vs. 33.8%, p = 0.0170) compared to hCG. A greater number of oocytes were retrieved (21.9 vs 18.4%, p < 0.001) and euploid embryos produced (2.8 vs. 2.1, p = 0.0109) after GnRHa triggering, while higher euploidy rates were only observed among women <35-years-old (62.0 vs. 51.7%, p = 0.0307) using GnRHa trigger. Higher OHSS rates were observed after hCG triggering (10.6 vs. 2.1%, p = 0.0009). CONCLUSION: Hyper-responders who received GnRHa trigger experienced improved pregnancy outcomes and lower rates of OHSS compared to hCG triggering. The higher number of oocytes retrieved and euploid embryos produced may reflect an improved developmental competence using GnRHa triggering due to physiologic induction of both LH and FSH surge or other undefined mechanisms that improve embryo development. However, higher overall euploid rates were only observed among women <35-years-old using the GnRHa trigger. Further prospective studies are required to validate this observation and evaluate the specific influence of different ovulation triggers on gamete developmental competence among hyper-responder women.