GnRH Agonist Research Articles

Relugolix prescribing practices and clinical experiences at an urban academic center.

e17008 Background: Relugolix is a novel oral GnRH antagonist that is now an alternative option for patients with prostate cancer (PC) who require androgen deprivation therapy (ADT). The potential benefits of relugolix include rapid testosterone decline and recovery, oral administration, and a possible cardiovascular (CV) benefit compared to traditional GnRH agonists. This study examines real-world data on relugolix prescribing practices and clinical experiences at a large, urban academic center. Methods: We conducted a retrospective, single-center cohort study of patients with PC prescribed relugolix from March 2021 through December 2023 at Beth Israel Deaconess Medical Center. We collected patient-related and clinical factors including demographics, comorbidities, CV risk factors, treatment history, reasons for relugolix prescription over GnRH agonists, medication compliance, adverse effects, and treatment outcomes. Descriptive statistics were used to characterize the cohort. Results: Among 267 patients who received a relugolix prescription, median age was 70 years old, 186 patients (69.6%) were Non-Hispanic White, 37 (13.9%) Non-Hispanic Black, 13 (4.9%) Asian, and 6 (2.2%) Hispanic of any race. Across all patients, 228 (85.3%) initiated relugolix with a median therapy duration of 181 days (range: 10 - 807). At the time of prescription, 88 patients (32.9%) were prescribed concurrent androgen receptor signal inhibitors (ARSI) and 186 (69.6%) had localized disease. Median CV risk factors per patient was 2 (range 0 - 7), and 4 patients (1.5%) developed major adverse CV events (MACE), including acute heart failure decompensation, sick sinus syndrome, ventricular tachycardia, and death during treatment. Among physician prescribers, the most common reasons for prescribing relugolix included concern for CV risk (90 prescriptions, 33.3%) and patient preference for oral administration (55 prescriptions, 20.4%). Forty-nine patients (18.3%) were switched from a GnRH agonist, mainly due to physician concern for CV risk (13, 4.9%) or patient preference (17, 6.4%). Conclusions: We describe real-world use of relugolix for PC in a large, diverse single center cohort. The most frequent reasons for choosing relugolix over a GnRH agonist were physician concern for CV risk and patient preference for a tablet over injection. Investigations of treatment initiation and adherence in relation to insurance coverage, adverse effects, and socioeconomic factors require further investigation.

Aggressive Angiomyxoma of the Female External Genitalia

Abstract Aggressive angiomyxoma (AAM) is a rare and benign mesenchymal tumor that localizes predominantly in the female pelvis. Its invasive growth and local recurrence are challenging for professionals. Histologically, AAM is a tumor with a myxoid stroma that is highly vascular and hypocellular. The diagnosis is made relatively late due to nonspecific symptoms. Treatment of AAM is extensive local surgical excision with intact resection lines. Gonadotropin-releasing hormone agonists are added postoperatively. The prognosis is good and metastasis is rare. We present a case of an aggressive angiomyxoma located in the left greater labial area in a 50-year-old woman. After discussion and informed consent signed by the patient, on 27.01.2023 at the University Hospital “St. Marina” Pleven, the patient was admitted to the hospital. The tumor was extirpated under epidural anaesthesia on the date of the patient's informed consent. The patient was prescribed postoperative therapy with Zoladex 3,6 mg implant according to the schedule.The patient was subjected to monthly gynecological check-ups for one year after the surgical intervention. To date, no recurrence of the underlying disease has been detected. Long-term results show a good trend. In conclusion, we can say that the optimal treatment of AAM is wide local excision. It is not recommended to aim for radicality because of the risk of postoperative complications. Postoperative administration of GnRH-a is advisable to avoid recurrences. All patients undergo regular follow-up examinations for long-term follow-up.

Fulvestrant with or without the cyclin-dependent kinase 7 (CDK7) inhibitor samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6 inhibition: Phase II SUMIT-BC study.

TPS1126 Background: CDK7 enhances oncogene transcription and upregulates anti-apoptotic genes, accelerates the cell cycle via CDK phosphorylation, and activates estrogen receptors (ERs) that can drive resistance to hormonal therapy in cancer. CDK7 inhibition therefore represents a potential anticancer strategy in cancer. Samuraciclib (CT7001) is a small molecule, ATP competitive, selective oral inhibitor of CDK7 that inhibits these key effects of CDK7. Samuraciclib had a favorable safety profile and showed clinical activity when combined with fulvestrant in a phase I study in patients with HR+/HER2− advanced breast cancer (BC) who had previously been treated with a CDK4/6 inhibitor. Patients with no detectable TP53 mutation in ctDNA at baseline and those without baseline liver metastases appeared to have better outcomes. The instant release capsule formulation of samuraciclib used in this study released large amounts of samuraciclib high in the gastrointestinal (GI) tract, which may have contributed to the observed low grade GI adverse events, which were managed with prophylaxis and counselling (1). Methods: A phase 2 open-label randomized study has been designed to evaluate the efficacy, safety, pharmacokinetics (PK), and quality of Life (QoL) of samuraciclib combined with fulvestrant compared to fulvestrant monotherapy (SUMIT-BC; NCT05963984). Eligible patients (n=60) are ≥18 years, have histologically or cytologically confirmed ER+/HER2− advanced or metastatic BC not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor combined with a CDK4/6 inhibitor in the adjuvant or advanced setting, are receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal, and have RECIST v1.1 evaluable disease. Prior SERD, mTOR inhibition, or chemotherapy for advanced BC are not permitted. All patients undergo baseline Guardant360 ctDNA analysis to establish TP53 and other mutation status. Patients are randomized 1:1:1 to fulvestrant alone (500 mg IM administered on days 1, 15 and 29 and then monthly), fulvestrant and samuraciclib 240 mg QD, or fulvestrant and samuraciclib 360 mg QD. In preparation for phase 3 development, a novel single tablet formulation of samuraciclib is used, which may enhance GI tolerability. Patients undergo RECIST v1.1 evaluation at baseline, every 8 weeks until week 48, and every 12 weeks thereafter. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and PK of fulvestrant and samuraciclib. QoL (Functional Assessment of Cancer Therapy - Breast questionnaire [FACT-B]) and correlations between TP53 mutation and efficacy/safety will be assessed. 1. Coombes et al. Nature Comms 2023. Clinical trial information: NCT05963984 .

H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive (ER+), HER2 negative (–) breast cancer (BC).

1015 Background: H3B-6545 is a novel selective ER covalent antagonist (SERCA) that inactivates wild-type and mutant ERα. This phase 1/2 study aimed to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and characterize safety and efficacy of H3B-6545 in women with advanced/metastatic ER+, HER2– BC. Methods: This multicenter, open-label study included dose-escalation [ph1] and -expansion [ph2] phases. Females (postmenopausal or concurrently receiving a luteinizing hormone-releasing hormone agonist) with ER+, HER2–BC who had disease progression on standard therapy were eligible. Prior therapy must have included a minimum of 2 hormonal therapies (HTs), or 1 HT + 1 chemotherapy, or 1 HT + a CDK4/6 inhibitor. H3B-6545 was administered orally QD at doses of 100-600 mg. The MTD was the highest dose at which ≤1 of 6 patients (pts) had a dose-limiting toxicity (DLT). In ph2, efficacy of the RP2D was examined. The primary endpoints were determination of RP2D (ph1) and efficacy (ph2; including objective response rate [ORR], duration of response [DOR], and progression-free survival [PFS] per RECIST v1.1 by investigator, and overall survival [OS]). Safety and PK were secondary endpoints. Results: At data cutoff (30 Nov 22), 151 pts received ≥1 dose of H3B-6545 during ph1 or ph2. Pts had a median (m [range]) of 2 (1-7) prior endocrine- and 1 (1-6) non-endocrine–containing therapies; 90.1% of pts received prior CDK4/6 inhibitors. During ph1, DLTs of grade (G) 3 rash (n=1) and G 3 fatigue (n=1) were observed at 600 mg; thus, 450 mg was determined to be the MTD/RP2D. In the full analysis set (N=151), 100% and 50.3% of pts had any grade and G ≥3 treatment-emergent adverse events (TEAEs), respectively. TEAEs leading to drug interruption, dose reduction, and withdrawal occurred in 38.4%, 20.5%, and 8.6% of pts, respectively. Nausea (45.7% [2.0% G ≥3]), sinus bradycardia (44.4% [0% G ≥3]), and diarrhea (41.1% [1.3% G ≥3]) were the most common TEAEs. QT prolongation occurred in 9.9% [3.3% G ≥3] of pts. Among 94 response-evaluable pts treated at 450 mg, ORR was 20.2% (95% CI 12.6–29.8) and clinical benefit rate (CBR) was 41.5% (95% CI 31.4–52.1); mPFS (95% CI) was 5.06 (3.15–7.26) months. Among all pts treated at 450 mg (n=115), mOS (95% CI) was 21.52 (16.56–25.46) months. Plasma concentration of H3B-6545 increased as dose increased. Additional results are shown (Table). Conclusions: H3B-6545 had a low rate of G ≥3 TEAEs and showed clinically meaningful antitumor activity in heavily pretreated female patients with ER+, HER2– BC. Clinical trial information: NCT03250676 . [Table: see text]

Neoadjuvant dalpiciclib combined with aromatase inhibitors in stage I-III HER2 negative luminal B breast cancer (DANCER): Preliminary findings from an ongoing phase II study.

e12622 Background: CDK4/6 inhibitors, in combination with endocrine therapy, have shown efficacy as neoadjuvant treatment in HR+/HER2- breast cancer (BC). This study investigates the efficacy and safety of dalpiciclib, a CDK4/6 inhibitor, combined with aromatase inhibitors (AI) as a neoadjuvant treatment for luminal B BC (defined as ER+/HER2- BC, with either Ki67≥20% and/or PR<20%). Methods: This single-arm, single-center, phase II study (NCT05640778) enrolled patients aged 18-75 with clinical stage I-III luminal B BC, primary tumor size ≥2 cm, and ECOG PS 0-1. Eligible patients, regardless of menopausal status, received AI therapy (either anastrozole 1 mg daily or letrozole 2.5 mg daily) combined with dalpiciclib (150 mg daily on days 1-21) starting from cycle 1 day 1 (C1D1), for four 28-day cycles, followed by surgery. Pre-/peri-menopausal patients received AI therapy 14 days prior to the first dose of dalpiciclib (C0D1-C0D14), concurrent with a GnRH agonist administered every 28 days from C0D1. Ki67 levels were assessed through serial biopsies at baseline, C1D15, and surgery. MRI assessments were performed at baseline, C2D28, and before surgery per RECIST v1.1. Serial plasma samples were collected for circulating tumor DNA (ctDNA) analysis. The primary endpoint was the complete cell cycle arrest (CCCA: Ki67≤2.7%) rate at 2 weeks (C1D15). Results: From Oct 2022 to Dec 2023, 23 patients with a median age of 52 years (range 38-73) were enrolled and received study treatment. Of these patients, 11 (47.8%) were pre-/peri-menopausal. Sixteen (69.6%) were diagnosed with stage II and the remaining had stage III disease. High Ki67 expression (≥20%) was observed in 21 patients (91.3%). As of Jan 7, 2024, all patients underwent the C1D15 Ki67 evaluation and the CCCA rate was 82.6% (95% CI: 60.5%-94.3%). The ctDNA concentration at C2D28 and post-surgery was significantly higher in patients who did not achieve CCCA compared to those who achieved CCCA ( P = 0.003 and 0.011, respectively). Ki67 expression decreased by a geometric mean of 93.1% (95% CI:76.0%-98.8%) from baseline to C1D15. Out of 20 patients who completed 2 cycles of treatment and received an MRI scan, 12 achieved a partial response, yielding an ORR of 60.0% at C2D28. Among 17 who completed all neoadjuvant therapy and underwent surgery, the ORR before surgery was 82.4% with 14 partial responses; none demonstrated residual cancer burden (RCB) 0/1, seven exhibited RCB 2, and 10 had RCB 3; one reached breast pathological complete response (ypTisN1). Grade ≥3 treatment-emergent adverse events included neutrophil count decreased (16, 69.6%), white blood cell decreased (9, 39.1%), and oral mucositis (1, 4.3%). Conclusions: Dalpiciclib plus anastrozole or letrozole exhibited biological and clinical activity with manageable toxicities in neoadjuvant treatment for stage I-III luminal B/HER2- BC. Clinical trial information: NCT05640778 .

Clinical Use of Long-Term GnRH Agonist in Prepubertal Bitches: Effect on P4, E2 and Melatonin Serum Concentration before and During First Estrus

Abstract The aim of this study was to determine the length of the contraceptive period after the application of deslorelin implant (4.7 mg) in juvenile, prepubertal bitches and assess the effects on the hormonal status (P4, E2 and melatonin), as well as on the occurrence of normal physiological estrus. Twelve crossbred prepubertal female dogs (4 months of age) were divided into the two groups, the treated group (DESLO) and control (placebo) group (C). Hormone assays, vaginal microbiological and cytological smears and the measurements of electrical resistance of cervical mucus were performed once in 3 weeks until the first signs of proestrus, and every day during estrus. GnRH implant significantly postponed time of onset of estrus (633 ± 30,38 days vs. 143.80 ± 52,30 days, P<0.001). In estrus, DESLO group showed statistically higher E2 (34.58 pg/mL vs. 20.59 pg/mL, P<0.001) and melatonin serum concentration (45.86 pg/mL vs. 18.85 pg/mL, P<0.001) compared to the control group. The average P4 serum concentration had no statistically significant differences between groups. In conclusion, deslorelin implants do not cause “flare up” effect in perpubertal bitches, however, increase of E2 and especially melatonin serum concentrations show the need to explore the consequences and mutual influence of melatonin and deslorelin implants in the future.

Real world data of leuprorelin castration efficacy in patients with prostate cancer: A comprehensive assessment of 1,744 tests.

e17000 Background: Androgen deprivation therapy (ADT) has been standing the cornerstone of systemic prostate cancer (PCa) treatment, since Huggins’ findings.Gonadotropin-releasing hormone (GnRH) agonists or antagonists has been used broadly as ADT. However, the majority of studies has focused on Gosserelin, leading to a lack of dedicated investigations into the efficacy of leuprorelin, despite its large use on practice. In this real-world study, we thoroughly analyzed data of testosterone tests in order to comprehensively assess the leuprorelin castration efficacy on the PCa management. Methods: We gathered data from patients diagnosed with PCa who were undergoing treatment with leuprorelin alone or in combination with a novel hormonal agent (NHA) in a single cancer center. The tests spanned a nine-year period from 2014 to 2023 and we assessed the testosterone levels in baseline and after leuprorelin administration, as well as their distribution according to clinicopathologic variables. Results: A total of 1,754 test reports were retrieved from 240 individual pts. The median baseline testosterone level was 317 ng/mL (range: 37-1,136) prior to leuprorelin initiation and the distribution across Gleason grades was: 20 pts had grade 1, 30 pts had grade 2, 61 pts had grade 3, 51 pts had grade 4, and 40 pts had grade 5. Testosterone levels < 50 ng/mL were achieved in 1,730 tests (98.7%) and testosterone levels < 20 ng/mL were found in 1,485 tests (84.7%). A total of 80 pts received combined treatment with leuprorelin + NHA, of which the majority received abiraterone/prednisone (n=52; 65%) or apalutamide (n=11; 13.8%). Following ADT discontinuation, 91 pts presented testosterone levels ≥ 50 ng/mL after a median interval of 258.5 days (range:82-710). Conclusions: In this comprehensive real world database analysis, leuprorelin is able to achieve suitable testosterone suppression levels in nearly the whole study population, such as are seen in others GnRH agonists pivotal trials. Deeper and maintained testosterone suppression levels is predictive of longer time to castration-resistant PCa and real life use of leuprorelin seems to meet this need.

Safety profiles of offspring born from early-follicular long-acting GnRH agonist protocol and daily mid-luteal GnRH agonist protocol: a retrospective study

BackgroundThe gonadotropin hormone-releasing hormone agonists (GnRH-a) have been widely used for controlled ovarian stimulation in assisted reproductive technology (ART). The early-follicular long-acting GnRH-a long protocol (EFL) and the luteal phase short-acting GnRH-a long protocol (LPS) are commonly used GnRH agonist protocols. We conducted a retrospective analysis to assess and compare the rates of congenital abnormalities and safety profiles in offspring born from the EFL and LPS protocols.MethodsWe conducted a retrospective cohort study to analyze and compare neonatal data from patients who using EFL or LPS protocols at our center between January 1, 2014, and June 30, 2017. The study ultimately included 1810 neonates from 1401 cycles using the EFL protocol and 2700 neonates from 2129 cycles using the LPS protocol.The main outcome measures are gestational age at delivery, birth weight, and congenital anomaly rate.To assess the influence of various factors on congenital abnormalities, a random-effects logistic regression model was employed.ResultsThe EFL and LPS protocols led to similar congenital anomaly rates (1.64% vs. 2.35%, P = 0.149). No significant differences were found between the two groups regarding birth weight and its categories, newborn gender and congenital anomaly rate. The results of the multivariate logistic regression model indicated no association between congenital anomaly and BMI, duration of infertility, treatment protocol, fertilization method, or embryo transfer stage. Compared with singleton pregnancies, the probability of congenital defects in multiple pregnancies was 2.64 times higher (OR: 2.64, 95% CI: 1.72–4.05, P < 0.0001). Newborns with congenital defects were born with a lower gestational age compared with full-term pregnancies.ConclusionIn conclusion, the EFL protocol is considered a safe option for ensuring offspring safety, comparable with the LPS protocol; however, multiple pregnancies represent an independent risk factor for congenital abnormalities. This approach can be widely adopted; however, prioritizing single embryo transfers is strongly recommended to minimize the potential risks associated with multiple pregnancies in offspring.

Outcomes of Vaginal Repair and Vaginal Repair Combined With GnRHa Administration in the Treatment of Cesarean Section Scar Defects: A Randomized Clinical Trial

Study ObjectiveTo prospectively investigate whether the application of vaginal repair (VR) of cesarean section scar defect (CSD) combined with a gonadotropin-releasing hormone agonist (GnRHa) achieve better clinical outcomes than VR alone. DesignA randomized clinical trial. SettingUniversity hospital. PatientsA total of 124 women with CSD were undergoing expectant management from December 2016 to September 2021. 61 were randomised to VR+ GnRHa and 63 to VR alone. InterventionVaginal repair combined with GnRHa and vaginal repair alone. Measures and Main ResultsThe primary outcome was the duration of menstruation and thickness of the remaining muscular layer (TRM) at 6 months after surgery. Secondary outcomes included the length, width and depth of the CSD; operation time; estimated blood loss; hospitalization time; and operative complications. Women were treated with either VR (n = 63) or VR + GnRHa (n = 61). Menstruation and TRM in patients pre. vs. post comparisons either with VR or VR + GnRHa are significant improved (P < .05). Significant differences in menstruation duration and TRM occurred in patients treated with VR + GnRHa compared with those treated with VR (P < .05). Moreover, the rate of CSD after surgery in the VR group was significantly higher than that in the VR + GnRHa group (P = .033), and CSD patients in the VR + GnRHa group achieved better therapeutic effects than those in the VR group (P = .017). Patients who received VR + GnRHa had a shorter menstruation duration and a greater increment of TRM postoperatively than did patients treated with VR alone (P = .021; P = .002, respectively). ConclusionVR + GnRHa therapy has a greater potential to improve scar healing and reduce the number of menstruation days than VR alone for symptomatic women with CSD. PrécisVaginal Repair Combined with GnRHa Creates Better Therapeutic Effects of CSD. Trial registrationDate of registration: October 13, 2016, Date of initial participant enrollment: December 20, 2016, Clinical trial identification number: NCT02932761, URL of the registration site: ClinicalTrials.gov, Figshare DOI: 10.6084/m9.figshare.24117114 Link to the clinical trial registrationhttps://clinicaltrials.gov/study/NCT02932761

The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males.

The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.

Modern issues of oncofertility and oncoreproduction

The problem of the occurrence of malignant neoplasms in women of reproductive age has not only medical, but also extremely important social significance, as it affects the demographic potential of the country as a whole.The article presents an analysis of the current state of the problem of fertility and preservation of reproductive function in cancer patients. Currently, there are a sufficient number of methods of assisted reproductive technologies aimed at preserving fertility in women with cancer. Among them are the following: cryopreservation of embryos and oocytes, ovarian tissue, in vitro maturation of eggs, obtaining oocytes obtained by removing the ovaries with their subsequent maturation. In addition, auxiliary methods are also distinguished, the main purpose of which is ovarian protection: the use of gonadotropin-releasing hormone agonists, ovarian transposition, gonadal screening. Each method has its advantages and disadvantages. It should be noted that the very fact of the presence of oncological pathology makes its own adjustments to the use of each specific technique. It has been shown that in vitro maturation technology is the most optimal for the preservation and realization of reproductive function in cancer patients. One of its few disadvantages is the high cost and complexity of laboratory control and cultivation of oocytes, which undoubtedly requires highly qualified specialists and relevant experience.

Identifying Suitable Patients for Overcoming Androgen Deprivation Monotherapy in De Novo Metastatic Hormone-Sensitive Prostate Cancer.

Although metastatic hormone-sensitive prostate cancer (mHSPC) treatments have evolved, androgen deprivation therapy (ADT) remains a widely used regimen. Therefore, this study sought patients who did not progress to castration-resistant prostate cancer (CRPC) but received ADT monotherapy and factors affecting overall survival (OS) in de novo mHSPC. De novo mHSPC patients who received ADT treatment were included. ADT included luteinizing hormone-releasing hormone agonists with or without anti-androgen. The total cohort was divided into two groups relative to CRPC progression within two years. Logistic analysis was used to identify factors that did not progress CRPC within two years. Cox regression was used to assess the independent predictors for OS. The total cohort was divided into the no-CRPC within two years group (n = 135) and the CRPC within two years group (n = 126). Through multivariate logistic analysis, the life expectancy (odds ratio [OR] 0.95, 95% CI 0.91-0.99, p = 0.014) and Gleason scores (≥9 vs. ≤8; OR 0.43, 95% CI 0.24-0.75, p = 0.003) were associated with the group without castration-resistant prostate cancer progression within two years. The multivariate Cox model revealed that life expectancy (hazard ratio [HR] 0.951, 95% CI 0.904-0.999, p = 0.0491), BMI (HR 0.870, 95% CI 0.783-0.967, p = 0.0101), and CCI (≥2 vs. <2; HR 2.018, 95% CI 1.103-3.693, p = 0.0227) were significant predictive factors for OS. Patients with long life expectancy and a Gleason score of 9 or more were more likely to develop mCRPC while alive. Patients with short life expectancy, low BMI, and worsening comorbidity were more likely to die before progressing to CRPC. Although intensified treatment is essential for oncologic outcomes in mHSPC, shared decision making is integral for patients who may not benefit from this treatment.

Research progress on the prevention and treatment of chemotherapy-induced ovarian damage.

Chemotherapy is a main treatment option for malignant tumors, but it may cause various adverse effects, including dysfunction of female endocrine system and fertility. Chemotherapy-induced ovarian damage has been concerned with ovarian preservation but also the prevention and treatment of ovarian dysfunction. In this article, the mechanisms of ovarian injury caused by chemotherapy, including apoptosis of the follicle and supporting cells, follicle "burn out", ovarian stromal and microvascular damage; and influencing factors, including age at diagnosis, initial low pre-treatment anti-Müllerian hormone levels, toxicity, dose and regimen of chemotherapy drugs are reviewed based on the latest research results and clinical practice. The article also discusses measures and frontier therapies for the prevention and treatment of ovarian injury, including the application of gonadotropin releasing hormone agonists or antagonists, tyrosine kinase inhibitors, antioxidants, sphingosine-1-phosphate, ceramide-1-phosphate, mammalian target of rapamycin inhibitors, granulocyte-colony stimulating factor, stem cell therapy and artificial ovaries.

Advancing Age May Decrease Mitochondrial Activity in Cumulus Cells.

Background: The goal of this study was to compare mitochondrial activity in cumulus cells (CCs) between young and advancing-aged women, the factors that affect mitochondrial activity, and their association with blastocyst quality. Materials and methods: This prospective study included 80 infertile women who underwent ICSI between May and October 2023. Participants were divided into two groups: older and younger than 38. The oocyte mitochondrial activity from CCs was evaluated using MitoTracker, and the mean fluorescence intensity (MFI) was also evaluated. Results: The univariate and multivariate analyses revealed a significant difference in the MFI between the woman ≥ 38 age group and the lower age group (162.68 ± 79.87 vs. 228.39 ± 121.38; p-value = 0.005; 95%CI 19.97, 111.45). The factors that affected the MFI were women ≥ 38 years of age (p-value = 0.005; 95%CI -111.45, -19.91), total gonadotropin dosages (p-value = 0.006; 95%CI -0.08, 0.01), and gonadotropin-releasing hormone agonist (GnRHa) triggering (p-value = 0.006; 95%CI 36.46, 210.06). However, only women aged ≥38 years remained statistically significant after a multivariable regression analysis (p-value = 0.014; 95%CI -121.00, -14.30). In addition, only male age (mean age ± SD = 38.26 ± 5.13) was associated with high blastocyst quality in univariate and mixed multivariate analyses (OR 0.91; 95%CI 0.56, 3.04). The chemical pregnancy rate was not significantly different between the two age groups (34.5% vs. 56.7%; p-value = 0.162; 95%CI 0.2, 1.30). Conclusion: Advancing age decreased mitochondrial activity in CCs but did not affect blastocyst quality. By contrast, male age may be a predictor of high-grade blastocyst quality.

BEYOND: a randomized controlled trial comparing efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus antagonist protocol during the first ovarian stimulation cycle.

BEYOND: a randomized controlled trial comparing efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus antagonist protocol during the first ovarian stimulation cycle.

Review of drug-drug interactions in patients with prostate cancer.

The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy. A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions. No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education. Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.

The comparision among euploidy of preimplantation blastocysts in different controlled ovary stimulation (COH) protocols.

To compare differences in euploidy rates for blastocysts in preimplantation genetic testing for aneuploidy (PGT-A) cycles after gonadotropin-releasing hormone agonist (GnRH-a) long and short protocols, GnRH-antagonist (GnRH-ant) protocol, progestin-primed ovarian stimulation and mild stimulation protocols, and other ovary stimulation protocols. This was a retrospective cohort study from the Assisted Reproductive Medicine Department of Shanghai First Maternity and Infant Hospital. A total of 1657 PGT-A cycles with intracytoplasmic sperm injection after different controlled ovary hyperstimulation protocols were analyzed, and a total of 3154 embryos were biopsied. Differences in euploidy rate per embryo biopsied, embryo euploidy rate per oocyte retrieved and cycle cancellation rate were compared. For the PGT-A cycles, the euploidy rate per embryo biopsied was lower in the GnRH-ant protocol than in the GnRH-a long protocol (53.26 vs. 58.68%, respectively). Multiple linear regression showed that the GnRH-ant protocol was associated with a lower euploidy rate per embryo biopsied (β = -0.079, p = 0.011). The euploidy rate per embryo biopsied was not affected by total gonadotropin dosage, duration of stimulation and number of oocytes retrieved. The embryo euploidy rate per oocyte retrieved was similar in all protocols and was negatively correlated with the total number of oocytes retrieved (β = -0.003, p = 0.003). Compared with the GnRH-a long protocol, the GnRH-ant protocol was associated with a lower euploidy rate per embryo biopsied. The total gonadotropin dosage, duration of stimulation and number of oocytes retrieved did not appear to significantly influence euploidy rates.

Effectiveness of gonadotropin-releasing hormone agonists for ovarian function suppression in premenopausal patients with hormone receptor-positive breast cancer: a retrospective single-center real-world study

PurposeThis study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed.Patients and methodsPremenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison.ResultsOf the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824–0.982), P = 0.018].ConclusionInsufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.

242 Comparison of GnRH administration day in the 7&amp;7 Synch versus 8&amp;6 Synch Protocol for fixed-timed artificial insemination in beef heifers

Abstract The research aimed to investigate the impact of reducing the time interval for progesterone exposure on the ovulatory follicle just before performing fixed-timed artificial insemination (FTAI). This was achieved by adjusting the timing of administering a gonadotropin-releasing hormone agonist (GnRH; specifically, 100 µg gonadorelin, known as Cystorelin). The study assessed the effectiveness of two estrous synchronization protocols, the “7 &amp; 7 Synch” and a modified protocol, by examining estrus expression (EE) and the resulting pregnancy rates (PR) following FTAI. The research utilized frozen conventional Angus semen from Select Sires, Inc. (Plain City, OH), and involved 66 Angus-cross heifers from the beef cattle research unit near Fayetteville at the University of Arkansas. To ensure consistency, the heifers were divided into two treatment groups based on their cyclicity status (CYC) and age. CYC status was determined by assessing a reproductive tract score (RTS) 1 wk before the synchronization process. RTS scores ranged from 1 to 5, with RTS 1-3 indicating pre- or peripubertal status and scores of 4 and 5 indicating cycling. Heifers with an RTS of 1 and 2 were excluded from the study before synchronization commenced. Both treatment groups involved the insertion of a controlled internal drug-releasing device (CIDR; specifically, Eazi-breed, containing 1.38 g of progesterone) into the vagina on d -14. Simultaneously, a prostaglandin F2α analogue (PGF; 500 µg cloprostenol sodium, known as Synchsure) was administered. In the first treatment group (7&amp;7), GnRH was administered on d -7, while in the second group (8&amp;6), GnRH was given on d -6. In both cases, PGF was administered on d 0 when the CIDR was removed, precisely 72 ± 1 h before FTAI, along with another dose of GnRH. Estrus expression (EE) was assessed during FTAI by examining Estrotect patches (Rockway Inc., Spring Valley, WI). EE was considered present when a patch had 50% or more of its color rubbed off, and it was deemed absent when less than 50% of the color had worn off. Pregnancy rates (PR) were determined through ultrasound examination on d 55. EE and PR were analyzed by treatment using the GLIMMIX procedure on SAS 9.4 (SAS Institute Inc., Cary, NC). Statistical differences were declared at α ≤ 0.05 and tendencies declared between 0.05 &amp;lt; P ≤ 0.1. Heifers on the 8&amp;6-d protocol had greater rectal temperatures at breeding compared with 7&amp;7-d heifers (P &amp;lt; 0.0001). AI pregnancy rates were greater in heifers on the 8&amp;6-d protocol compared with the heifers on 7&amp;7-d protocol (P = 0.625) with average pregnancy rates of 39.4% and 30.3%, respectively. Overall, pregnancy rate was greater as well for the 8&amp;6-d heifers compared with the 7&amp;7-d heifers (P = 0.044), with mean overall pregnancy rates of 78.8% and 54.5%, respectively.

Multicenter Study on the Frequency of Low Bone Mineral Density in Young Women With Breast Cancer and Associated Factors

IntroductionYoung women with breast cancer (BC) may experience bone mineral density (BMD) loss secondary to cancer treatment effects on estrogen levels. Studies assessing BMD in BC patients have had a limited representation of young women. This multicenter retrospective study analyzed the frequency of low BMD and associated factors in this age group. MethodsWomen diagnosed with stage 0-III BC at ≤40 years, treated with chemotherapy and/or endocrine therapy between 2010 and 2020 at 5 Mexican BC referral centers were eligible. Demographic, clinical and treatment data were collected, as well as bone dual-energy X-ray absorptiometry (DEXA) results. Low BMD was defined as lumbar or femoral neck T-score < -1.0 or Z-score ≤ -2.0. ResultsA total of 1259 patients were included; median age at diagnosis was 36 years (21-40). Overall, 93% received chemotherapy and 65% endocrine therapy (tamoxifen was received at some point by 61%, aromatase inhibitors by 17%, and GnRH agonists/bilateral oophorectomy by 21%). DEXA scans were documented in 254 (20%), of which 163 (64%; 95% confidence interval [CI] 58%-70%) had a low BMD report. Low BMD was associated with receiving aromatase inhibitors (Odds ratio [OR] 1.92; 95% CI 1.13-3.24), and GnRH agonists/bilateral oophorectomy (OR 2.25; 95% CI 1.21-4.21). ConclusionThe suboptimal frequency of BMD monitoring observed displays an alarming disregard for bone health in young patients. Thus, a high proportion of women with low BMD are potentially being missed and precluded from the opportunity to receive timely interventions. Particular focus should be put on BMD monitoring among patients treated with aromatase inhibitors, GnRH agonists or bilateral oophorectomy.