Use Of Gonadotropin-releasing Hormone Agonists Research Articles

Reproductive Outcome After GnRH Agonist Triggering With Co-Administration of 1500 IU hCG on the Day of Oocyte Retrieval in High Responders: A Long-Term Retrospective Cohort Study

While triggering oocyte maturation with GnRH agonist (GnRHa) seems to be safe and effective in terms of the risk of developing OHSS and the number of metaphase II oocytes, it nevertheless results in luteal phase deficiency. To date, strategies have been developed in order to rescue defective luteal phase of GnRHa triggered cycles. Our study aimed to assess the reproductive outcome of GnRHa triggered cycles combined with modified luteal support (1500 IU hCG at the day of oocyte retrieval) in women with high ovarian response and to compare the outcome with hCG triggered cycles in GnRH antagonist IVF-ICSI procedures. A retrospective cohort database review of the results of GnRH antagonist IVF-ICSI cycles was conducted at a tertiary-care IVF center in Ljubljana, Slovenia. A total of 6126 cycles, performed from January 1, 2014, to December 31, 2020, were included in the final analysis. Final oocyte maturation was performed with either 5000, 6500, or 10,000 IU hCG (women with normal ovarian response) or 0.6 mg GnRHa (buserelin), supplemented with 1500 IU hCG on the day of oocyte retrieval (in women with high ovarian response). In cases of excessive ovarian response and/or high risk of OHSS luteal support was not introduced and all good quality blastocysts were frozen. According to significant differences in patients’ age and the number of oocytes in the two groups, matching by age and number of oocytes was performed. No significant differences were observed regarding pregnancy rate per embryo transfer, rate of early pregnancy loss, and livebirth rate per pregnancy between the GnRHa and hCG trigger groups, respectively. A significant difference in the number of developed embryos and blastocysts, as well as the number of frozen blastocysts, was seen in favor of the GnRHa trigger. However, the birth weight in the GnRHa trigger group was significantly lower.ConclusionThe results of our study support the use of GnRHa for final oocyte maturation in GnRH antagonist IVF cycles in women with high ovarian response. Luteal phase rescue was performed by co-administration of 1500 IU hCG on the day of oocyte retrieval and estradiol and progesterone supplementation. In our experience, such an approach results in a comparable reproductive outcome with hCG trigger group.

Correlation of LH level and steroid concentrations in GnRH antagonist protocol: A sub-analysis of Ganirelix phase III study of China

BackgroundBased on the data obtained from a phase III, multicenter, open-label, randomized clinical trial that compared the use of GnRH agonist vs. antagonist for LH-suppression in IVF cycles, the present study attempted to determine the effect of LH level on steroid concentrations and IVF outcomes in the GnRH antagonist protocol. MethodsA total of 109 patients with the GnRH antagonist protocol were stratified into three subgroups according to the stimulation day six LH levels (LH <25%, 25–75%, and >75%), and the effect of LH on steroid biosynthesis and the related IVF outcomes between subgroups was observed. ResultsIn comparing the three subgroups of GnRH antagonist, no difference in number of oocytes, top quality embryos and ongoing pregnancy was observed. The high LH group on day six was exposed to significantly lower concentrations of rFSH from day six onwards, and had significantly higher estradiol levels on the day of hCG. The progesterone levels did not differ between groups at the start of the stimulation, but patients with the highest LH on day six also had significantly (P < 0.0001) higher progesterone levels on day six (higher estradiol on day six and hCG, lower total rFSH dosage). Due to the significantly lower increase in progesterone in the high LH group between day six and the day of hCG, no difference in progesterone level was observed on the day of hCG. ConclusionsFor steroid biosynthesis, early follicular phase LH levels help pregnenolone metabolize primarily via the ∆5 pathway in the GnRH antagonist stimulation protocol, but not via the ∆4 pathway.

Effect of androgen receptor directed therapy in prostate cancer patients with COVID-19.

161 Background: TMPRSS2 is one of the two key enzymes that SARS-CoV-2 requires for its entry to the cell. TMPRSS2 is regulated by androgen receptor. It is well described Androgen Receptor Directed Therapy (ARDT) downregulates the expression of TMPRSS2. We hypothesized that the ARDT has a protective role in patients with prostate cancer (PCa) from poor outcome of COVID-19. Methods: A retrospective chart review of PCa patients with COVID-19 between March to October 2020 in the Yale-New Haven Health System was performed. Demographics, comorbidities, home medications, laboratory data, treatment, and clinical outcomes of COVID-19 were collected. ARDT was defined as the use of GnRH agonist, GnRH antagonist, or androgen receptor antagonist. This study was reviewed and approved by the Institutional Review Boards of Yale University. Results: A total of 146 (1.1%) prostate cancer cases were identified from the 13,642 cases of COVID-19. The clinical characteristics are summarized in the table. Twenty-five (17%) were on active ARDT and 121 (83%) not on ARDT (non-ARDT). The rates of hospitalization were the same: 52%, between the ARDT and non-ARDT group. Of those admitted, mean duration of hospitalization were 9.2 days (Range 1-25) and 14.9 days (Range: 2-47) in ARDT and non-ARDT groups, respectively (p=0.14). Rates of hospital stay &gt;30 days were 0% versus 14.3% (9/63) in ARDT and non-ARDT groups, respectively (p=0.15). Intubation rates were 0% versus 11% (7/63) for ARDT and non-ARDT groups, respectively (p=0.21). Mortality rates were 8% and 13.2%, in ARDT and non-ARDT groups, respectively (p=0.47). Conclusions: The prevalence of PCa was infrequent. Despite advanced stage of the cancer in ARDT group, there was a trend toward decreased severity of COVID-19 and mortality rates compared to non-ARDT group. Our data support further investigation on a protective role of hormone therapy in PCa patients with COVID-19.[Table: see text]

GnRH Analogues as a Co-Treatment to Therapy in Women of Reproductive Age with Cancer and Fertility Preservation.

In this review, we analyzed existing literature regarding the use of Gonadotropin-releasing Hormone (GnRH) analogues (agonists, antagonists) as a co-treatment to chemotherapy and radiotherapy. There is a growing interest in their application as a prophylaxis to gonadotoxicity caused by chemotherapy and/or radiotherapy due to their ovarian suppressive effects, making them a potential option to treat infertility caused by such chemotherapy and/or radiotherapy. They could be used in conjunction with other fertility preservation options to synergistically maximize their effects. GnRH analogues may be a valuable prophylactic agent against chemotherapeutic infertility by inhibiting rapid cellular turnover on growing follicles that contain types of cells unintentionally targeted during anti-cancer treatments. These could create a prepubertal-like effect in adult women, limiting the gonadotoxicity to the lower levels that young girls have. The use of GnRH agonists was found to be effective in hematological and breast cancer treatment whereas for ovarian endometrial and cervical cancers the evidence is still limited. Studies on GnRH antagonists, as well as the combination of both agonists and antagonists, were limited. GnRH antagonists have a similar protective effect to that of agonists as they preserve or at least alleviate the follicle degradation during chemo-radiation treatment. Their use may be preferred in cases where treatment is imminent (as their effects are almost immediate) and whenever the GnRH agonist-induced flare-up effect may be contra-indicated. The combination treatment of agonists and antagonists has primarily been studied in animal models so far, especially rats. Factors that may play a role in determining their efficacy as a chemoprotective agent that limits gonadal damage, include the type and stage of cancer, the use of alkylating agents, age of patient and prior ovarian reserve. The data for the use of GnRH antagonist alone or in combination with GnRH agonist is still very limited. Moreover, studies evaluating the impact of this treatment on the ovarian reserve as measured by Anti-Müllerian Hormone (AMH) levels are still sparse. Further studies with strict criteria regarding ovarian reserve and fertility outcomes are needed to confirm or reject their role as a gonadal protecting agent during chemo-radiation treatments.

Abstract P2-12-16: Use of ovarian function suppression to preserve fertility during neoadjuvant chemotherapy oncologically safe in women under age 40: An inverse probability weighting adjusted analysis

Abstract Backgrounds Ovarian function suppression by gonadotropin releasing hormone agonist (GnRHa) is used to preserve fertility during neoadjuvant chemotherapy (NCT) in breast cancer especially in young women. Some results showed that patients with hormone-receptor (HR) negative breast cancer treated with NCT concurrent with GnRHa to preserve fertility had better outcome than without GnRHa. Methods From 2011 to 2014, 296 women aged under 40 years old with stage I to IIIA breast cancer, treated with NCT before surgery were analyzed. Primary endpoint was rate of pathologic complete response (pCR). Secondary endpoint was disease free survival (DFS) and overall survival (OS) between two groups categorized by concurrent with GnRHa during NCT to preserve fertility. Subgroup analysis was done with different HR status. Results Ninety-eight patients (33.1%) received concurrent GnRHa with NCT. Baseline characteristic showed no different between two groups except younger age with GnRHa group (p&amp;lt;0.001) and more use of GnRHa in HR+/HER2- subtype (p=0.023). pCR rate was higher with GnRHa group (8.08% vs 20.41%, p=0.002). However there was no significant difference in 5yr DFS between without GnRHa and with GnRHa (HR 1.4 95% CI 0.60 2-3.582) in entire cohort. In HR positive subcohort, 5yr DFS was not different between without GnRHa and with GnRH a group (80.9% and 87.7% respectively,p=0.643). In HR negative subcohort, 5yr DFS was 71.6% vs 70.6% (p=0.931). There were no overall survival difference between two group in entire and subcohort (p&amp;gt;0.05). Multivariable analysis also did not show survival improvement after use of GnRHa in HR- subtype (hazard ratio 2.166, (95% CI 0.746-6.292), p=0.155) and HR+ subtype (hazard ratio 1.231, (95% CI 0.205-7.411), p=0.820). Conclusion Among young women with breast cancer with negative hormone receptor treated with concomitant GnRHa achieved more pCR com compared with no GnRHa during chemotherapy. This result did not reach out to better survival outcome at this point. Trend to better outcome seen in survival curve implies further evaluation in this particular population. Citation Format: Young Joo Lee, Seonok Kim, Hee J Kim. Use of ovarian function suppression to preserve fertility during neoadjuvant chemotherapy oncologically safe in women under age 40: An inverse probability weighting adjusted analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-16.

Abstract P4-11-08: Impact of ovarian stimulation for fertility preservation in young women with breast cancer: Updated survival and pregnancy outcomes

Abstract Background: Chemotherapy (CTx) and hormone therapy may impair fertility in women with breast cancer (BC) by direct gonadotoxicity or delayed childbearing. Inconsistent data regarding the safety and efficacy of ovarian stimulation for fertility preservation (FP) in BC may limit clinician referral and patient uptake of FP. We previously examined the effect of FP on BC recurrence and herein present updated survival and pregnancy outcomes in relation to FP from an expanded BC cohort. Methods: Women aged ≤ 40 years diagnosed with stage I-III BC between 2007-2018 referred to one of six cancer centres and to a reproductive endocrinologist in British Columbia, Canada were identified from a central database. Clinicopathologic, treatment and outcome characteristics were compared using uni/multivariate Cox and logistic regression analyses for survival and pregnancy outcomes, respectively, for patients who did and did not undergo FP prior to systemic cancer treatment. Results: 158 patients were identified. Sixty-four (41%) had lymph node involvement, 119 (75%) had ER-positive and 39 (25%) had HER2-positive BC. The 72 (46%) patients who underwent FP were more likely to be younger (mean age 33 vs 34 y, p=0.030), ECOG 0 (p=0.013), have CTx (p&amp;lt;0.001) and GnRH agonist during CTx (p=0.010) compared to patients with no FP. Tumor stage, ER/HER2/BRCA-positivity, BMI, radiation and number of existing children were not associated with decision to pursue FP (p&amp;gt;0.05). After a median follow-up of 4.7 years, BC recurrence occurred in 15 (17%) non-FP patients and 9 (13%) FP patients (Table 1). FP did not affect overall survival by univariate (HR 0.9; 95% CI 0.7-1.3) or multivariate analysis controlling for age, BMI, ECOG/ER/HER2 status, tumor stage and receipt of CTx or radiation (HR 1.0, 95% CI 0.7-1.4). Post-diagnosis, 22 (31%) FP patients and 11 (13%) non-FP patients had ≥ 1 pregnancy (Table 2). The use of assisted reproductive technology (ART) was similar in both groups. Patients who had FP were 2.8 times more likely (p=0.013) to conceive at least once. The results remained significant on multivariate analysis controlling for age, BMI, ECOG status and baseline parity (p=0.030). Non-FP patients had a 31% higher miscarriage rate than those who did (p=0.26). Conclusions: FP was not associated with an increased risk of locoregional recurrence, distant recurrence or death over a follow-up period of 3-11 years, supporting its safety in young women with BC. Despite more often receiving CTx, patients who underwent FP were significantly more likely to conceive after BC than those who did not, even when accounting for differences in patient profiles. This may relate to greater use of GnRH agonists during CTx, known to protect ovarian function, and stronger desires for future childbearing in patients who pursued FP. Although there was similar use of ART in both groups, the higher pregnancy rate and more successful reproductive outcomes in FP patients support the value and promotion of pre-oncologic treatment FP in young BC patients early in their disease trajectory, to enhance survivorship family planning. Table 1.Survival outcomes of patients.CharacteristicNo FP (n=86)FP (n=72)p-valueRecurred [n (%)]0.85Locoregional6 (7)4 (6)Distant9 (10)5 (7)Deceased [n (%)]8 (9)4 (6)0.38 Table 2.Characteristics of first pregnancies in patients conceiving after diagnosis.CharacteristicNo FP (n=11)FP (n=21)p-valuePregnancy outcome [n (%)]0.26Completed3 (27)11 (52)Miscarriage7 (64)7 (33)Ongoing1 (9)3 (14)Pregnancy interval from diagnosis [n (%)]0.29≤ 2 y04 (19)2-5 y8 (73)13 (62)&amp;gt; 5 y3 (27)4 (19)Type of conception [n (%)]0.52Natural9 (82)15 (71)Assisted2 (18)6 (29) Citation Format: Megan E Tesch, Ying Wang, Chloe Lim, Ying Hui Xu, Shaina Lee, Kirstin Perdrizet, Dan Yokom, Ellen Warner, Jeffrey Roberts, Caroline Lohrisch. Impact of ovarian stimulation for fertility preservation in young women with breast cancer: Updated survival and pregnancy outcomes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-08.

"Novel Use of GnRH agonist as Neoadjuvant Treatment for Giant Endometrial Polyps"

"Novel Use of GnRH agonist as Neoadjuvant Treatment for Giant Endometrial Polyps"

The Effect of Uterine Adenomyosis on IVF Outcomes: a Systematic Review and Meta-analysis.

To investigate the impact of uterine adenomyosis on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) clinical outcomes and also to evaluate the impact of gonadotropin-releasing hormone agonist (GnRHa) and surgical treatments. Infertile women with adenomyosis undergoing conventional IVF or ICSI were compared with women without adenomyosis. Fertility outcomes were evaluated in two patients with adenomyosis untreated and treated surgically or medically therapy. The review protocol was registered in PROSPERO (CRD42020214586). We consider the live birth rate (LBR) as the primary outcome. The analysis showed that women with adenomyosis had lower LBR (OR 0.59, 95% CI 0.37-0.92, p = 0.02), clinical pregnancy rate (OR 0.66, 95% CI 0.48-0.90), and ongoing pregnancy rate (OR 0.43, 95% CI 0.21-0.88) compared to those without adenomyosis, and miscarriage rate was higher in women with adenomyosis (OR 2.11, 95% CI 1.33-3.33). Surgical treatment increases natural conception in women with adenomyosis although the paucity of data (only two studies), and conversely, treatment with GnRHa does not increase the IVF outcomes. Women with adenomyosis have decreased IVF clinical outcomes. Pretreatment with the use of long-term GnRHa could not be beneficial, even though only three studies were included in the meta-analysis. The major part of the studies has not divided focal and diffuse adenomyosis, and this represents a relevant source of bias: studies conducted with standardized diagnostic criteria for adenomyosis are still needed to determine if the different clinical presentations of such condition could compromise IVF outcomes.

Ovarian hyperstimulation syndrome following the use of GnRH agonist trigger of final oocyte maturation and freeze-all strategy: A case report and review of the literature

Rationale: The current literature has a surprising controversy regarding the use of low-dose human chorionic gonadotropin (hCG) for luteal support as an explanation for the development of ovarian hyperstimulation syndrome, and this is because of the gap in the listing of the predisposing factors that put women at an increased risk of ovarian hyperstimulation syndrome.Patient concerns: A case of 25-year-old woman presented with abdominal pain, distention, dyspnea, and nausea with a 6.5 kg increase in weight from baseline. Ultrasonographic examination showed bilaterally enlarged multicystic ovaries after gonadotropin-releasing hormone (GnRH) agonist triggering and cycle segmentation with no hCG rescue administration.Diagnosis: Moderate/severe ovarian hyperstimulation syndrome. Interventions: The woman was admitted to the hospital for medical management of moderate/severe ovarian hyperstimulation syndrome, and pain management was advanced to patient-controlled anesthesia with the start of low molecular weight heparin. On day 2, albumin therapy followed by a furosemide chase was started due to an increase in abdominal girth. On day 1, Cabergoline was maintained, and on day 2 the GnRH antagonist Cetrorelix was started.Outcomes: The woman’s clinical condition improved, and a clinical pregnancy was eventually achieved during the first cryo-warmed blastocyst cycle.Lessons: Ovarian hyperstimulation syndrome can still happen even after the use of GnRH agonist and avoidance of hCG support. Segmentation of in vitro fertilization with complete avoidance of hCG for luteal support remains the best approach.

Ovarian Stimulation in Assisted Reproductive Technology Cycles for Varied Patient Profiles: An Indian Perspective.

ABSTRACTControlled ovarian stimulation has been an integral part of in vitro fertilisation (IVF) treatment cycles. Availability of different gonadotropins for ovarian stimulation and gonadotropin releasing hormone (GnRH) analogues for prevention of premature rise of leutinising hormone during follicular phase offer an opportunity to utilise them for a successful outcome in women with different subsets of ovarian response. Further, use of GnRH agonist as an alternative for human chorionic gonadotropin improves safety of ovarian stimulation in hyper-responders. Mild ovarian stimulation protocols have emerged as an alternative to conventional protocols in the recent years. Individualisation plays an important role in improving safety of IVF in hyper-responders while efforts continue to improve efficacy in poor responders. Some of the follicular and peri-ovulatory phase interventions may be associated with negative impact on the luteal phase and segmentalisation of the treatment with frozen embryo transfer may be an effective strategy in such a clinical scenario. This narrative review looks at the available evidence on various aspects of ovarian stimulation strategies and their consequences. In addition, it provides a concise summary of the evidence that has emerged from India on various aspects of ovarian stimulation.

Perioperative Serum Creatinine Change and Delayed Urologic Complications Following Total Laparoscopic Hysterectomy for Benign Indications.

Objectives:The objective of the study was to investigate the association between perioperative serum creatinine change and delayed urologic complications following total laparoscopic hysterectomy (TLH) for benign indications.Materials and Methods:A total of 510 cases (503 cases without delayed urologic injuries and 7 cases with delayed urologic injuries) in which TLH was performed for benign indications were retrospectively reviewed. The patient characteristics and surgical outcomes were compared between patients with and without delayed urologic injuries. Laboratory markers (serum creatinine level at the preoperative and postoperative periods, white blood cell [WBC] ratio, and C-reactive protein [CRP] ratio) were analyzed to evaluate the diagnostic value of these laboratory markers.Results:There were no statistically significant differences in age, parity, body mass index, the presence of diabetes mellitus, preoperative GnRH agonist use, previous history of abdominal surgery or the performance of adnexal surgery, ASRM score, the presence of cul-de-sac obliteration, operative time, blood loss or weight of the resected specimens between the two groups. The proportions of patients who showed an elevated creatinine level on postoperative day 1 was significantly higher in the delayed urologic injury group (9.9% vs. 57%, P < 0.001). The combination of the three laboratory markers yielded an area under the ROC curve value of 0.75 (95% confidence interval, 0.491–1) in the detection of delayed urologic injuries.Conclusion:A change in the serum creatine level over baseline after surgery may indicate the possibility of urologic injuries. The combination of creatinine change and other factors, such as WBC or CRP would be helpful for detecting urologic complications after TLH.

Impact of perioperative use of GnRH agonist or dienogest on ovarian reserve after cystectomy for endometriomas: a randomized controlled trial

BackgroundOvarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve.MethodsWe conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve.ResultsBefore and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy (P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment.ConclusionsOur data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions.Trial registrationThe registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021492, and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140. This randomized controlled trial was conducted in accordance with the CONSORT guidelines.

Long-Term Outcomes With Pharmacological Ovarian Suppression During Chemotherapy in Premenopausal Early Breast Cancer Patients.

Although use of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is an established strategy to protect ovarian function in premenopausal breast cancer patients, no long-term safety data are available, raising some concerns in women with hormone receptor-positive disease. There are controversial data on its fertility preservation potential. The Prevention of Menopause Induced by Chemotherapy: a Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6 (PROMISE-GIM6) trial is a multicenter, randomized, open-label, phase III superiority trial conducted at 16 Italian centers from October 2003 to January 2008. Eligible patients were randomly assigned to (neo)adjuvant chemotherapy alone (control arm) or combined with the GnRHa triptorelin (GnRHa arm). The primary planned endpoint was incidence of chemotherapy-induced premature ovarian insufficiency. Post hoc endpoints were disease-free survival (DFS), overall survival (OS), and post-treatment pregnancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Of 281 randomly assigned patients, 80.4% had hormone receptor-positive breast cancer. Median follow-up was 12.4 years (interquartile range = 11.3-13.2 years). No differences in 12-year DFS (65.7% [95% CI = 57.0% to 73.1%] in the GnRHa arm vs 69.2% [95% CI = 60.3% to 76.5%] in the control arm; HR = 1.16, 95% CI = 0.76 to 1.77) or in 12-year OS (81.2% [95% CI = 73.6% to 86.8%] in the GnRHa arm vs 81.3% [95% CI = 73.1% to 87.2%] in the control arm; HR = 1.17, 95% CI = 0.67 to 2.03) were observed. In patients with hormone receptor-positive disease, the hazard ratio was 1.02 (95% CI = 0.63 to 1.63) for DFS and 1.12 (95% CI = 0.59 to 2.11) for OS. In the GnRHa and control arms, 9 and 4 patients had a posttreatment pregnancy, respectively (HR = 2.14, 95% CI = 0.66 to 6.92). Final analysis of the PROMISE-GIM6 trial provides reassuring results on the safety of GnRHa use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer, including those with hormone receptor-positive disease.

Electrocardiogram Changes Following the Treatment with Gonadotropin-Releasing Hormone Agonists in Patients with Precocious Puberty

Background: GnRH agonists are the standard treatment for precocious puberty. Studies on the side effects of these drugs in adults have shown that these drugs may cause changes in ECG and some cardiovascular effects; however, few studies have evaluated these effects in children. This study aims to investigate the effect of these drugs on ECG intervals in children with precocious puberty.Methods: In this study with a pre-post design 50 children with precocious puberty referred to the endocrinology clinic of Tabriz Children's Hospital in 2019 for receiving GnRH agonists were included. From all patients, ECGs were obtained before starting the treatment and then 6, 12, and 18 weeks later and PR, QRS, and QTc intervals were extracted from ECG records.Results: The mean age of the participants was 91±9 months including 48 (96%) girls and 2 (4%) boys. Triptorelin (GnRH agonist) was administered for all patients with the standard protocol. Comparison of pre- and post-treatment ECG intervals showed that the drug did not cause a significant change in PR (p = 0.535) and QTc (p = 0.250) intervals, whilst there was a significant increase in QRS interval after the treatment (p = 0.001).Conclusion: The use of GnRH agonists in children can lead to some changes in ECG records by increasing in QRS intervals; and ECG could be used as a tool to detect these changes. Further studies are also needed to identify ECG changes in larger sample sizes and longer intervals.

Bone Mineral Density Changes Associated With Pregnancy, Lactation, and Medical Treatments in Premenopausal Women and Effects Later in Life.

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.

O-230 RCT comparing Recombinant-hcg trigger with Dual-trigger (GnRH-agonist and recombinant-hcg ) in improving clinical outcome in ICSI cycles in women with Diminished Ovarian Reserve

Abstract Study question Does use of Dual-trigger (GnRH-agonist with recombinant-hcg) improve the clinical outcome in women with diminished ovarian reserve as compared to Recombinant-hcg trigger? Summary answer Yes, the use of Dual-trigger (GnRH-agonist with recombinant-hcg) improve the clinical outcome in women with diminished ovarian reserve as compared to Recombinant-hcg trigger. What is known already The population of poor responders has grown exponentially over the years and their management of ovarian stimulation remains one of the most challenging aspects. In GnRH antagonist down-regulated IVF-ICSI cycles, dual triggering for the final oocyte maturation with GnRH-a and a reduced dose of hCG improves the rate of fertilization and clinical pregnancy in women with diminished ovarian reserve. Further more, the benefit of lowered cycle cancellation rate would also enable greater percentage of patients with diminished ovarian reserve to reach the final stage of their ART treatment, thereby enhancing their chances of achieving a successful pregnancy . Study design, size, duration This RCT included GnRH antagonist ICSI cycles from 2018-2019. 82 women with diminished ovarian reserve (AMH ≤ 1.1 ng/ml and AFC ≤5) were included. The primary outcome measured was the oocyte fertilization rate, implantation rate and clinical pregnancy rate per oocyte retrieval cycle. Secondary outcome measured was embryo transfer cancellation rate and abortion rate per oocyte retrieval cycle. Participants/materials, setting, methods 82 women with diminished ovarian reserve undergoing fresh embryo transfer were included and randomly divided in two groups - Group-A (hCG trigger/control group: n = 41); and Group-B (dual trigger/study group: n = 41). Both patient groups underwent controlled ovarian stimulation using antagonist. The final oocyte maturation was triggered either by recombinant hCG (Group-A) or by a combination of recombinant hCG and GnRH-agonist (Dual trigger) (Group-B). Main results and the role of chance The dual-trigger group had significantly higher fertilization rate (62.8 vs. 37.6%), higher clinical pregnancy rate (31.4% vs. 18.1%) as compared to the recombinant-hCG trigger group. In addition, the abortion rate(12.1% vs. 21.3%) and embryo transfer cancellation rate (8.3% vs. 16.1%) were both significantly lower in the dual trigger group. The baseline characteristics for the control and the study group were similar and there was no significant difference in the patient age, serum AMH level, and cause of infertility. The total r-FSH dose, duration of stimulation, endometrial thickness, and serum hormone profile on the day of trigger were also similar between the control and the study group. The main advantage of triggering with GnRH-a is that it induces a mid-cycle FSH surge which resembles the natural ovulatory cycle hormonal changes. Study shows that in GnRH antagonist ART cycles, dual triggering with GnRH-a and hCG could significantly improve the rate of fertilization and clinical pregnancy in diminished ovarian reserve women. Furthermore, the benefit of lowered cycle cancellation rate would also enable greater percentage of patients with diminished ovarian reserve to reach the final stage of their ART treatment thereby enhancing their chance of achieving a successful pregnancy as well as reducing their mental stress. Limitations, reasons for caution The main limitation of our study is the low patient number. Triggering with GnRH-a has become a significant part of contemporary ART practice, especially in high responders, oocytes donors and oncology patients. However, more RCTs are required in order to justify the use of GnRH-agonists in poor responders in ART cycles. Wider implications of the findings Results of our study concurred with other studies of dual triggering, calls for a possible paradigm shift in ovulation-triggering agent for GnRH-antagonist cycles. Diminished ovarian reserve patients are constituting a large part of clinical ART practice and for such patients, obtaining maximum mature oocytes and good embryos is vitally important. Trial registration number not applicable

P–671 Dual Trigger(low adjuvant HCG4h after GnRHagonist trigger)have positive impact of overall embryo’s quality, implantation ,clinical pregnancy and live birth rates in high-risk patients for OHSS

Abstract Study question Study aim is to compare implantation,clinical pregnancy and livebirth rates between giving1500IU of hCG4hours after GnRHagonist,on trigger day or GnRHagonist as alone trigger with luteal support withHCG1500IU.35h later on OPUday. Summary answer Adjuvant doze of1500IUhCG4h after bolus of GnRHagonist on trigger day significantly improve quality of blastocyst,implantation,clinical pregnancy and live birth rates without increasing the risk ofOHSS. What is known already The use of GnRHagonist for final oocyte maturation in antagonist cycle significantly decrease the incidence of OHSS,but there have been studies showing lower pregnancy rates in patients triggered with GnRHagonist compared with hCG in autologous cycles,attributed to a defective luteal phase, especially in high–risk patients despite intensive luteal phase support.To improve the results of IVF,an alternative approach is adding a small bolus dose of hCG(1500IU)35h later,on the OPU day after GnRHagonist trigger which provides more sustained support for the corpus luteum.The question is does low doses of hCGgiven on the same day with GnRHagonist trigger is making better quality oocytes. Study design, size, duration Single center prospective longitudinal cohort study fromJanuary2017 to Decembar2019.The initial inclusion criteria were:women age≥18and≤39years,AMH≥3,3ng/ml and ≥12 antral follicles on basal ultrasound.Patients with history of OHSS and PCO are also included in the study.Patients with applied “freeze-all” technique with peak estradiol≥4000pg/ml on trigger day&amp;gt;18oocytes on the OPU day,and recognized significant risk for developing OHSS were also included.The cumulative implantation,clinical pregnancy and live birth rates were analyzed,only in embryos from the same COS protocol in every patient. Participants/materials, setting, methods A total of 231 patients were entered for final analysis,who underwent a flexible antagonist protocol,ICSI and fresh or thawed ET on 3th(38.53%) or 5th( 61.47%)day in women’s autologous cycles.Patients were randomized in one of two groups: GroupA-Dual trigger group 1500IUof hCG 4h after GnRH agonist application on trigger day and GroupB –1500IU of HCG 35h later,on the OPU day.We used nonparametric and parametric statistical tests.Significant differences were considered all values ​​of p &amp;lt; 0.05 Main results and the role of chance Both groups are homogenous regarding several variables:age,BMI,type of sterility,smoking status,AMH,PCO, spermogram.There is no significant difference between the two(AvsB)groups according to average number of retrieved oocytes(13.6 vs 14.6 p &amp;gt; 0,05),M II oocytes(11.03 vs 11.99 p &amp;gt; 0.05).The dual trigger group(A)had a higher fertility rate(69.99% vs 64.11% p &amp;lt; 0,05)compared with GnRHagonist trigger group(B).There are no significant difference between groups(AvsB)according to cumulative average number of:transferred embryos(2.4vs2.5 p &amp;gt; 0.05)TQE transfered on 3th day(1.5.vs 1.3.p&amp;gt;0.05);transferred blastocyst(2.6 vs2.7 &amp;gt;0.05);cryo embryos(2.5vs1.9 p &amp;gt; 0.05),but there are significant difference according to cumulative implantation rate of transferred blastocyst in favor of group A(48.18% vs 33.89%p&amp;lt;0.05).Analyzes of morphological characteristics of transferred blastocyst depicted in the order of degree of blastocyst expansion,inner cellular mass(ICM)and trofoectoderm(TE) and ranking overall blastocysts quality from“excellent”,“good”,“average” and “pore” ,shows that there are significantly more percentage of patient with embryo transfer of “excellent” or even one “excellent” blastocyst in group A (30.56%,31.94% vs 21.54%,23.08% p &amp;lt; 0.05) in opposite of percentage of patients with embryo transfer with “poore “” blastocyst in group B (37.5% vs 46.15.%p&amp;lt;0.05). Clinical pregnanacy rate (71.68% vs 50.84% p &amp;lt; 0.05) , and live birth rate (60,18% vs 42,58% ), were significantly higher in group A. There were no cases of moderate or severe OHSS in both groups. Limitations, reasons for caution Dual trigger in GnRH antagonist protocols should be advocated as a safe approach but undetected high risk patients are reasons for caution for developing clinically significant OHSS. Wider implications of the findings: Adjuvant low dose of hCG on GnRHagonist trigger day improve clinical pregnancy and live birth rates without increasing the risk of clinically significant OHSS.Protocol of dual trigger and freezing all oocytes or embryos in patients with high risk of developing OHSS is promising technique in everyday practice. Trial registration number 8698

Final analysis of the PROMISE-GIM6 phase III trial assessing GnRH agonist use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer.

516 Background: Current guidelines recommend GnRH agonist (GnRHa) use during chemotherapy (CT) as a strategy to reduce the risk of premature ovarian insufficiency (POI) in premenopausal patients with early breast cancer (EBC). However, no long-term safety data are available raising some concerns on concurrent use of GnRHa during CT in patients with hormone receptor-positive disease. In addition, there is no evidence on the protective role of this strategy in patients with germline BRCA mutations ( mBRCA). Here, we report the final analysis of the PROMISE-GIM6 phase III randomized study, the largest trial addressing the role of GnRHa use during CT in premenopausal EBC patients (Del Mastro et al, JAMA 2011 &amp; Lambertini et al, JAMA 2015). Methods: From October 2003 to January 2008, 281 premenopausal patients aged 18 to 45 years with stage I-III EBC candidates for (neo)adjuvant CT were randomized to receive CT alone or combined with the GnRHa triptorelin. Primary endpoint was incidence of CT-induced POI (defined as amenorrhea and post-menopausal FSH/estradiol levels 1 year following CT). This final analysis reports on post-treatment pregnancies, disease-free survival (DFS) and overall survival (OS). An exploratory descriptive analysis in mBRCA patients is also reported. (ClinicalTrial.gov: NCT00311636) Results: Of the 281 randomized patients (CT+GnRHa arm = 148; CT alone arm = 133), 80% had hormone receptor-positive disease. At the time of this final analysis, 38 (13.5%) patients were lost to follow-up. Median follow-up was 12.4 years (IQR: 11.3-13.2 years). In the CT+GnRHa and CT alone arms, respectively, 9 (10-year cumulative incidence of pregnancy 6.5%, 95% CI 3.5%-12.3%) and 4 (10-year cumulative incidence of pregnancy 3.2%, 95% CI 1.2%-8.3%) patients had a post-treatment pregnancy (HR 2.14, 95% CI 0.66-6.92). No differences in 10-year DFS (72.4% in CT+GnRHa arm vs. 71.2% in CT alone arm: HR 1.16, 95% CI 0.76-1.77) nor in 10-year OS (82.0% in CT+GnRHa arm vs. 85.9% in CT alone arm: HR 1.17, 95% CI 0.67-2.03) were observed. There was no interaction between treatment effect and hormone receptor status. In patients with hormone receptor-positive disease, HR was 1.02 (95% CI 0.63-1.63) for DFS and 1.12 (95% CI 0.59-2.11) for OS. Out of 43 patients tested for BRCA, overall incidence of POI, irrespective of treatment arm, was 20% in mBRCA patients (n = 10) and 12% in patients without mBRCA (n = 33). In mBRCA patients, incidence of POI was 0% and 33% in the CT+GnRHa and CT alone arms, respectively. One post-treatment pregnancy was described in a patient with mBRCA1 in the CT alone arm. Conclusions: The final analysis of the PROMISE-GIM6 trial at a median follow-up of 12.4 years provides reassuring evidence on the safety of GnRHa use during CT as a strategy to preserve ovarian function in premenopausal patients with hormone receptor-positive EBC. Clinical trial information: NCT00311636.

Triggering change in stimulation protocols: a matter of oocyte maturation and beyond.

Since the birth of Louise Brown, in vitro fertilization (IVF) stimulation protocols have evolved significantly. One particular area of focus has been the process of final oocyte maturation, during which the oocyte gains competence to support fertilization and early embryonic development up to implantation. The field of human assisted reproductive technology (ART) is witnessing increased utilization of GnRH agonists (GnRHa) as trigger agents, in addition to or instead of the traditionally used human chorionic gonadotropin (hCG). Future translational studies will reveal whether oocyte developmental competence, as reflected in live birth outcomes, are not only non-inferior, but also superior with the use of GnRHa as a trigger for both nuclear and cytoplasmic oocyte maturation.

Gonadotropin-Releasing Hormone Agonist Induced Pituitary Apoplexy

Background: Gonadotropin-releasing hormone agonists (GnRHa), used in the treatment of prostate cancer (PC) and for reproductive purposes in women, have been implicated as the cause of pituitary apoplexy (PA), a potentially life-threatening condition. The pathophysiology of PA after GnRHa has not been completely elucidated. Proposed mechanisms include a stimulatory effect of GnRHa on pituitary adenoma cell metabolism, causing mismatched blood supply prompting hemorrhage or infarction. Prior documentation of PA associated with GnRHa has been scarce and limited to case reports. Methods: This is a detailed clinical case series of GnRH-induced PA from a single institution, obtained by a Research Patient Data Repository query. Clinical characteristics of the patients including demographics, detailed history, time interval between GnRHa and PA, physical exam, biochemical data, pituitary imaging and pathology were reviewed. Results: Seven cases were identified between 1990-2020; six men (aged 55 – 83 years) receiving treatment for PC and one woman (aged 22 years) receiving GnRHa for oocyte donation. All patients presented with headache; four within 48 hours of, one >1 month after, and one 5 months after, receiving GnRHa. One patient had insufficient data on time between GnRHa and PA. Most patients (86%) presented with nausea and vomiting. Other symptoms included ophthalmoplegia (43%), visual field defects (17%), and altered consciousness (29%). All patients had sellar masses and/or evidence of hemorrhage on MRI. Five patients underwent pituitary surgery while the others were managed medically. Of those who underwent surgical resection, 80% had positive histopathological staining for gonadotropins. Five patients with reliable hypothalamic-pituitary-adrenal (HPA) axis testing had impairment of this axis after PA; 40% recovered adrenal function. Central hypothyroidism occurred in 60% of whom 66% recovered. Hyponatremia occurred in 43%. Conclusions: Patients with gonadotrope-secreting adenomas may develop PA in response to GnRHa, more frequently in elderly men who are receiving GnRHa treatment for PC. This may be due to older age and higher prevalence of GnRHa use in this group. However, as demonstrated here and in prior case reports, women are not exonerated from this complication. Headache and adrenal insufficiency are typically present. HPA axis recovers in a subset. While most patients present <48 hours after GnRHa treatment, delayed presentations may occur. Therefore, a history of prior GnRHa exposure should be ascertained in patients presenting with PA. While the incidence of PA after GnRHa is low, this case series and prior case reports suggest that this serious potential complication should be recognized prior to treatment, especially in patients with known pituitary macroadenomas.