Laparoscopic ovarian drilling versus GnRH antagonist combined with cabergoline as a prophylaxis against the re-development of ovarian hyperstimulation syndrome

Objective: The aim of this work was to investigate the value of laparoscopic ovarian drilling (LOD) compared with GnRH antagonist flexible protocol combined with cabergoline (Cb), as a prophylaxis against the re-development of ovarian hyperstimulation syndrome (OHSS) in women with clomiphene citrate-resistant polycystic ovary disease (CCR-PCOD) who had severe OHSS before in a previous ICSI cycle.

Study design: It is a prospective controlled study, where 250 CCR-PCOD women (n?=?250) with a history of severe OHSS before, had been recruited for the study. LOD had been performed for 120 (n?=?120) of the recruited women before ovarian induction, and considered as group A. GnRH antagonist (Cetrotide 0.25?mg) was added when a leading follicle reaches 14–16?mm combined with oral Cb in a dose 0.5?mg a day before hCG, and for 8?d for another 130 (n?=?130) women, and considered as group B. Pregnancy was diagnosed with BhCG level ≥25?IU/L,?±?14?d after embryo transfer, followed with transvaginal ultrasound scanning (TVS) 2 weeks later to confirm intra-uterine pregnancy (IUP). Women were followed up weekly for 3?months for the possible development of any signs and symptoms of OHSS.

Results: None of the participants in group A developed severe OHSS, and only six women (5%) developed mild to moderate OHSS. The incidence of severe OHSS was significantly higher (n?=?3, 15%) in group B compared with group A (p?n?=?17, 13.3%) women in group B developed mild to moderate OHSS. The probability of developing severe OHSS was also significantly higher in group B as well (p?=?.031). Pregnancy rate (PR) was significantly higher in group A more than group B (67% versus 39%, respectively), and all were single intrauterine pregnancies (IUP) and all developed after fresh embryo transfer (ET), compared with frozen embryo transfer (FET) which was performed in 42 cases in group B after postponing ET due to significantly severe OHSS developed.

Conclusion: LOD could be considered a good prophylactic measure against OHSS, in addition to improving the total outcome of IVF cycles in women with CCR-PCOS.     

The effect of cabergoline on folicular microenviroment profile in patients with high risk of OHSS

Abstract

The aim of this study to evaluate the effect of cabergoline on follicular microenvironment by measuring follicular fluid (FF) insulin like growth hormone –I (IGF-I), antimullerian hormone (AMH), inhibin B and hepatocyte growth factor (HGF) levels in women with PCOS and high risk of ovarian hyperstimulation syndrome (OHSS). In this prospective cohort study, 41 women with PCOS undergoing controlled ovarian hyperstimulation for assisted reproduction and having the high risk factors for OHSS are included. The women in the study group (n?=?15) received cabergoline for OHSS prevention while the women in the control did not received any medications for OHSS prevention. FF samples were collected during oocyte pick-up procedure for all women were determined using commercially available ELISA kits. Concentrations of FF IGF-I, AMH, inhibin B and HGF were assessed. In the study group FF AMH (2.96?±?1.27 versus 1.91?±?0.64?ng/mL), Inhibin B (1339.47?±?198.56 versus 1200.09?±?133.64?pg/mL), HGF (5623.21?±?2411.09 versus 3787.42?±?2269.89?pg/mL) and IGF-I (298.60?±?37.80 versus 219.90?±?71.40?pg/mL) concentrations were significantly decreased compared with control group. Cabergolin prevents OHSS in high risk patients by disrupting FF hormone microenvironment.     

Lifesaving dose increment of cabergoline in life-threatening spontaneous ovarian hyperstimulation syndrome resistant to all interventions

Objective: Spontaneous ovarian hyperstimulation syndrome (SOHSS) is an extremely rare complication that deserves a multidisciplinary approach together with a thorough investigation for the correct diagnosis of the underlying pathology. The aim of this study was to present a case of severe SOHSS resistant to all interventions and to discuss the available interventions to overcome such a rare and serious clinical situation.

Case report: We report a case of severe, life-threatening spontaneous OHSS with a normal nine weeks singleton pregnancy in a 25-year-old nulliparous woman, which resulted with pregnancy termination and continuation of disease progression until the dose of cabergoline was increased to 1.5?mg/day.

Conclusion: This case report emphasizes that patients with life-threatening SOHSS resistant to all medical and surgical interventions may benefit from higher doses of cabergoline. Although spontaneous OHSS is extremely rare, it is potentially a life-threatening clinical entity in its severe form and needs time management and detailed examination of the underlying causes.     

Comparison of bevacizumab and cabergoline in the treatment of ovarian hyperstimulation syndrome in a rat model

Abstract

The aim of this study is to investigate the effects of bevacizumab in a rat model of ovarian hyperstimulation syndrome (OHSS) and compare with cabergoline. The study was performed with 24 rats in four main groups (one non-stimulated control and three OHSS treatment groups; bevacizumab, cabergoline and placebo). The rats were randomly assigned to four experimental groups (six rats per group). Efficacy of treatment was assessed on 29th day by measuring weight gain, number of eggs, presence of ascites and ovarian weight. Peritoneal fluid levels of vascular endothelial growth factor (VEGF) were measured using an enzyme-linked immunosorbent assay. Ovarian weights were significantly higher in the OHSS groups than the control group. Ovarian weights in OHSS placebo group were found to be higher than those in OHSS-treatment groups (p?=?0.002). VEGF levels were found increased in the OHSS-placebo group compared with the control group (p?<?0.05). This increase was not seen in the OHSS groups treated with either bevacizumab or cabergoline. We demonstrate in this study that bevacizumab can lower VEGF production and ovarian weight in rats treated with gonadotropins.     

Use of cabergoline and post-collection GnRH antagonist administration for prevention of ovarian hyperstimulation syndrome

Research questionDoes the addition of a gonadotrophin-releasing hormone (GnRH) antagonist to cabergoline treatment during the luteal phase in fresh IVF cycles triggered with a GnRH agonist, and planned for freeze-all, reduce the rate of mild and moderate ovarian hyperstimulation syndrome (OHSS)?DesignRetrospective cohort study of 480 IVF patients at risk for OHSS with GnRH agonist trigger from 2011 to 2018, stratified into three groups based on treatment received: GnRH agonist trigger alone (Group 1, n = 208), GnRH agonist trigger + cabergoline (Group 2, n = 167) or GnRH agonist trigger + cabergoline + GnRH antagonist (Group 3, n = 105). Data on patient demographics, incidence, severity and symptomatology of OHSS and laboratory findings were collected.ResultsGroup 1 had more free peritoneal fluid than Group 2 (28% versus 19%, P = 0.04) or Group 3 (28% versus 5%, P = 0.001). Group 1 reported abdominal discomfort and bloating more than Group 2 (33% versus 21%, P = 0.01) or Group 3 (33% versus 18%, P = 0.006). Group 1 had more electrolyte abnormalities than Group 2, who had more than Group 3. No patients developed severe OHSS. Mild and moderate OHSS rate was higher in Group 1 (38%) than Group 2 (29%, P = 0.048) or Group 3 (18%, P = 0.006) and in Group 2 than Group 3 (P = 0.046).ConclusionAddition of cabergoline to GnRH agonist triggering in high-risk OHSS patients, and subsequent addition of GnRH antagonist for 5 days in the luteal phase, sequentially reduces the risk of mild and moderate OHSS and improves patient comfort compared with GnRH agonist trigger alone.     

A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins

Objective: To study the benefits of a low-dose stimulation (LDS) protocol with purified urinary follicle-stimulating hormone in patients with polycystic ovaries who have presented previously with a very high ovarian response to a standard hMG stimulation.

Design: Cohort study.

Setting: Fertility center in a university hospital.

Patient(s): Sixty-one patients involved in an IVF/ICSI program from January 1995 to December 1996.

Intervention(s): The patients were first stimulated with a standard protocol using hMG and presented with a very high ovarian response. These patients were then stimulated a second time using a low-dose protocol. Cryopreserved embryos were transferred in later artificial or natural cycles until to December 1999.

Main Outcome Measure(s): Number of gonadotropin ampules; estradiol level on the day of ovulation induction; follicles, oocytes, and cryopreserved zygotes; fertilization, implantation, and pregnancy rates; and number of ovarian hyperstimulation syndromes (OHSS).

Result(s): The number of ampules used, the estradiol level reached, and the number of oocytes obtained were significantly lower under the LDS than the standard protocol. High implantation (21.8%) and clinical pregnancy (38.4%) rates were obtained after LDS. The cumulated deliveries per cycle started and per patient were, respectively, 41.6% and 52.5%. Five patients suffered OHSS with the standard protocol, and none with the LDS.

Conclusion(s): The LDS protocol offers a safe and efficient treatment for patients who present with echographic polycystic ovaries and are at risk of an excessive ovarian response to standard IVF stimulation protocols.     

Comparison of montelukast and cabergoline for prevention of ovarian hyperstimulation syndrome: in an experimental rat model

Abstract

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication that can occur during assisted reproductive techniques. The aim of this study is to investigate the effects of the leukotriene receptor antagonist (montelukast) treatment in prevention of OHSS and compare to cabergoline treatment. Twenty-four immature female Wistar rats were assigned to four groups. Group 1 was the control group. In the remaning three groups, OHSS was induced through ovarian stimulation with gonadotropins. No treatment was given to Group 2. Group 3 was administered a low-dose 100?mg/kg cabergoline treatment and Group 4 was received 20?mg/kg montelukast. Body weight, ovarian weight, vasculary permability (VP), peritoneal fluid vascular endothelial growth factor (VEGF) values and VEGF immune-expression were compared between the groups. Both cabergoline and montelukast prevented progression of OHSS compared to the OHSS group. Body weight, ovarian weight, VP, peritoneal fluid VEGF values and VEGF expression were significantly lower in both cabergoline- and montelukast-treated rats than in those not treated OHSS group. In conclusion, montelukast is an effective option for prevention of OHSS, as well as cabergoline. Montelukast may be a new treatment option to prevent and control the OHSS.     

Application of GnRH antagonist in combination with clomiphene citrate and hMG for patients with exaggerated ovarian response in previous IVF/ICSI cycles

Purpose To investigate if the combination of clomiphene citrate, hMG, and cetrorelix (CC/hMG/cetrorelix protocol) can be applied to patients who had excessive response to GnRHa long protocol. Methods Fifty patients who coasted and failed to conceive in their first cycles stimulated with GnRHa long protocol were stimulated with CC/hMG/cetrorelix protocol. The peak serum estradiol levels, the need of coasting and prolonged coasting (≥4 days), and the incidences of OHSS were compared. Results The peak estradiol level was significantly lower with CC/hMG/cetrorelix protocol compared to GnRHa long protocol. With CC/hMG/cetrorelix protocol, only four patients (8%) needed coasting and no one coasted ≥4 days. In contrast, in the first cycles, 11 patients (22%) needed coasting ≥4 days. The incidence of moderate OHSS was significantly lower with CC/hMG/cetrorelix protocol. Conclusions The CC/hMG/cetrorelix protocol is an acceptable alternative protocol for patients who had excessive response to GnRHa long protocol. Clomiphene citrate/hMG/cetrorelix protocol is a good alternative for patients who had excessive response to GnRHa long protocol.     

Repeated laparoscopic ovarian diathermy is effective in women with anovulatory infertility due to polycystic ovary syndrome

OBJECTIVE: To assess the effectiveness of a second laparoscopic ovarian diathermy (LOD) in women with polycystic ovary syndrome (PCOS). DESIGN: Retrospective study. SETTING: Tertiary infertility clinic. PATIENT(S): Twenty anovulatory infertile women with PCOS who underwent LOD 1-6 years previously. Twelve subjects had previously responded positively to the first LOD, but the anovulatory status recurred (Group I), whereas eight subjects had not responded at all (Group II). INTERVENTION(S): Laparoscopic ovarian diathermy. MAIN OUTCOME MEASURE(S): Rates of ovulation, pregnancy and resumption of menstrual regularity, and biochemical changes. RESULT(S): An overall ovulation rate of 12 out of 20 women (60%) and a pregnancy rate of 10 out of 19 (53%) were achieved after the second LOD. In women (n = 12) who previously responded positively to the first LOD (LOD-sensitive), the ovulation and pregnancy rates were 10 out of 12 (83%) and 8 out of 12 women (67%), respectively, which were significantly (P<.05) higher than 2 out of 8 (25%) and 2 out of 7 (29%) of the previous nonresponders (LOD-resistant). Statistically significant hormonal changes including reduction of luteinizing hormone (LH), testosterone (T), and free androgen index (FAI) after the repeat LOD were only observed in the LOD-sensitive group. CONCLUSION(S): Repeat LOD is highly effective in women who previously responded to the first procedure.     

Serum and follicular fluid levels of IGF-II,IGF-binding protein-4 and pregnancy-associated plasma protein-A in controlled ovarian hyperstimulation cycle between polycystic ovarian syndrome (PCOS) and non-PCOS women

Objective.?To investigate the difference of serum and follicular expression patterns for IGFα, IGFBP4 and PAPP-A in COH cycle between PCOS and non-PCOS women.

Methods.?COH was performed for total 30 sterile women (20 with PCOS and 10 with normal ovarian function). The serum and follicular fluid (FF)from dominant follicles levels of IGFα, IGFBP4 and PAPP-A before COH, day of hCG, and were measured using an ELISA.

Results.?The PCOS women had significantly higher day 3 serum PAPP-A, day of hCG serum IGFBP-4, and ff IGF-II levels compared to the normoovulatory subjects. Serum levels of IGF-II and IGFBP-4 in PCOS women had increased after gonadotropins stimulation, and yet PAPP-A was decreased. Within the PCOS women, day of hCG serum IGFBP-4 was strongly correlated with BMI (r?=?0.777; P?=?0.000), day of hCG IGF II (r?=??0.573, p?=?0.008), ff IGF II (r?=??0.573, p?=?0.008) and ff PAPP-A (r?=??0.461, p?=?0.041) was inversely related to diameter >16?mm follicle number and day 3 PAPP-A correlated to diameter?>16?mm follicle number (r?=?0.474; p?=?0.035).

Conclusions.?Ovarian IGF system on the gonadotropin response to differences in the PCOS and non-PCOS women in COH cycle, and may indicate a inordinate IGF system that might disturb folliculogenesis in PCOS women.     

Comparison of cabergoline versus calcium infusion in ovarian hyperstimulation syndrome prevention: A randomized clinical trial

Aim

To compare effectiveness of calcium infusion (CI) versus oral cabergoline (OC) in lowering the incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high risk women undergoing in vitro-fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles.

Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial

Sequential use of letrozole and human menopausal gonadotrophin (HMG) was compared with HMG only in poor ovarian responders undergoing IVF. Patients (n = 53) with less than four oocytes retrieved in previous IVF cycles or less than five antral follicles were randomized to either letrozole for 5 days followed by HMG or HMG alone. The letrozole group had lower dosage of HMG (P < 0.001), shorter duration of HMG (P < 0.001) and fewer oocytes (P = 0.001) when compared with controls. Live-birth rate was comparable with a lower miscarriage rate in the letrozole group (P = 0.038). Serum FSH concentrations were comparable in both groups except on day 8, while oestradiol concentrations were all lower in the letrozole group from day 4 (all P < 0.001). Follicular fluid concentrations of testosterone, androstenedione, FSH and anti-Müllerian hormone were higher in the letrozole group (P = 0.009, P = 0.001, P = 0.046 and P = 0.034, respectively). Compared with HMG alone, sequential use of letrozole and HMG in poor responders resulted in significantly lower total dosage and shorter duration of HMG, a comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment of follicular fluid.The management of poor ovarian responders or women with poor ovarian reserve in IVF is controversial. The use of letrozole has been studied; however, results are inconsistent. This randomized trial studied the sequential use of letrozole and gonadotrophin compared with gonadotrophin alone in poor responders undergoing IVF. The sequential use of letrozole and gonadotrophin led to a significantly lower dosage and shorter duration of gonadotrophin use, significantly fewer oocytes, comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment at a lower cost.