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Background: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer, yet its response to traditional chemotherapy remains limited, posing a challenge in achieving optimal therapeutic outcomes. In this study, we aimed to evaluate the clinical efficacy and safety of dalpiciclib, a novel CDK4/6 inhibitor, combined with letrozole as neoadjuvant therapy (NAT) in postmenopausal patients with HR+/HER2- stage II-III breast cancer. Additionally, we explored potential predictive biomarkers for treatment response using gene analysis., Methods: This single-arm, open-label, exploratory phase II trial involved 35 postmenopausal women with HR+/HER2- breast cancer (ClinicalTrials.gov identifier NCT05512780). Patients received four cycles of dalpiciclib (125 mg/day for 3 weeks, followed by 1 week off) plus continuous letrozole (2.5 mg/day). The primary endpoint was objective response rate (ORR), and secondary endpoints included changes in Ki-67 expression, complete cell cycle arrest (CCCA) rate, residual cancer burden (RCB), and safety profiles. Gene expression profiling and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify biomarkers predictive of response to NAT., Results: Among the 35 enrolled patients, 31 completed the full treatment course. Of the 29 patients with evaluable response data after 4 cycles, 16 achieved partial response (PR), resulting in an ORR of 55.2%. Following two weeks of treatment, the mean Ki-67 expression significantly decreased from a baseline of 17.5-1.8%, and CCCA was observed in 75% of patients. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were mainly decreased neutrophil count (45.7%), with a median duration of 3 days. The NAT predictive model, developed using gene expression analysis and clinicopathological factors, achieved an area under the curve (AUC) of 0.928, indicating that TFRC, SCUBE2, and MMP11A could serve as novel predictive biomarkers for response to NAT., Conclusions: Dalpiciclib combined with letrozole demonstrated promising antitumor activity and an acceptable safety profile in postmenopausal patients with HR+/HER2- breast cancer. The identification of TFRC, SCUBE2, and MMP11A as predictive biomarkers provides insights into the potential for personalized neoadjuvant treatment strategies., Competing Interests: Declarations. Ethics approval and consent to participate: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the institutional ethics committee at each site and informed consent was taken from all the patients. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) compared with an NSAI alone in a broad population of patients with hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS)., Patients and Methods: Premenopausal/postmenopausal women and men were randomized 1 : 1 to ribociclib (n = 2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n = 2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS, and overall survival. This final iDFS analysis was planned after ∼500 events., Results: At data cut-off (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI versus NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone [hazard ratio 0.749, 95% confidence interval (CI) 0.628-0.892; P = 0.0012]. The 3-year iDFS rates were 90.7% (95% CI 89.3% to 91.8%) versus 87.6% (95% CI 86.1% to 88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (positive/negative). Distant DFS and RFS favored ribociclib plus NSAI. Overall survival data were immature. No new safety signals were observed., Conclusions: With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: In boys during puberty who were undergoing recombinant human growth hormone (rhGH) treatment, we compared the therapeutic efficacy on growth, and any adverse reactions, of co-therapy with either letrozole or gonadotropin-releasing hormone analog (GnRHa)., Methods: Fifty-six pubertal growth hormone deficiency (GHD) boys were studied, they were treated with the combination of letrozole and rhGH (letrozole group, n = 28) or the combination of GnRHa and rhGH (GnRHa group, n = 28) for at least one year. Eighteen patients in the letrozole group and seventeen patients in the GnRHa group attained final adult height (FAH)., Results: The increase in height of the letrozole group was significantly more than the GnRHa group both in the first year [(10.37 ± 2.19) vs. (7.78 ± 1.55) cm] and at two years [(18.82 ± 2.49) vs. (13.84 ± 2.17) cm] (p < 0.05), however, there was no significant group difference in the advancement of bone age (BA) of in the first year or at two years (p > 0.05). The mean FAH in two groups were similar, but the treatment duration of the letrozole group was significantly less than GnRHa group. There was a significant body mass index (BMI) SDS increase in the letrozole vs. GnRHa groups. Of concern, bone mineral density (BMD) decreased in both groups after treatment, but more so in the letrozole cohort., Conclusion: The combination of letrozole/rhGH in pubertal GHD boys was similar to GnRHa/rhGH in terms of the progression of BA and FAH, but the former co-therapy was superior in the gain of height. Disconcertingly, however, this combination may adversely affect BMI and BMD., Clinical Trial Registration Number: ChiCTR2300068405., Competing Interests: Declarations. Ethics approval and consent to participate: This study was reviewed and approved by the Ethics Committee of Fuzhou Children’s Hospital of Fujian Medical University (2020-006), and was conducted in agreement with the Declaration of Helsinki Principles. Written informed consent was obtained from all individual participants’ parents included in the study. Consent for publication: Written informed consent was obtained from all individual participants’ parents included in the study. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: Multimodal anticancer therapies greatly damage the fertility of breast cancer patients, which raises urgent demand for fertility preservation. The standard options for fertility preservation are oocyte and embryo cryopreservation; both require controlled ovarian hyperstimulation (COH). However, there are safety concerns regarding breast cancer relapse due to the elevated serum estradiol levels during COH. Serum estradiol levels can be effectively decreased with the highly specific aromatase inhibitor letrozole. Letrozole is still uncommonly used during COH for fertility preservation, which has only been reported in a few studies, and the evidence of oocyte retrieval during ovarian stimulation and short-term safety from the perspective study is insufficient. As a result, this study will compare the efficacy of ovarian stimulation and the short-term safety of letrozole COH and non-letrozole COH protocols for preserving fertility in patients with breast cancer., Methods and Analysis: This is an open-label, multicentre RCT being conducted in five Chinese reproductive medical centres. 64 eligible patients diagnosed with breast cancer will be randomly assigned (1:1) to the letrozole or non-letrozole group during their COH cycles. The primary outcome is the number of mature oocytes. The secondary outcomes are the number of high-quality embryos, incidence of ovarian hyperstimulation syndrome(OHSS) and recurrence rate of breast cancer., Ethics and Dissemination: Ethical approval was obtained from the Ethics Review Committee of Guangdong Provincial People's Hospital (KY-Q-2023-840-02). Written informed consent will be obtained from each participant. Findings will be disseminated to patients, clinicians and commissioning groups through peer-reviewed publications., Trial Registration Number: ChiCTR2300078625., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Aromatase inhibitors, particularly letrozole (LZ), are now established as first-line ovulation induction agents, offering an effective ovarian stimulation strategy to enhance outcomes of intrauterine insemination. In recent years, they have also emerged as potentially valuable adjuvants to gonadotropin ovarian stimulation for in vitro fertilization, particularly in fertility preservation in women with estrogen-responsive cancers. Their primary mechanism of action is to reduce the circulating estrogen levels by inhibiting androgen aromatization. Recent studies have provided evidence that this property may confer therapeutic advantages in other patients undergoing in vitro fertilization. In this study, evidence supporting the role of adjuvant LZ in poor responders, as a moderator of ovarian hyperstimulation syndrome symptoms, and an agent for improving the luteal phase after ovarian stimulation is reviewed. The use of LZ for endometrial preparation in the frozen-thawed embryo transfer cycle is also considered., Competing Interests: Declaration of Interests N.B. has nothing to disclose. N.M. has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The CDK4/6 inhibitor palbociclib inhibits cyclin A, which is overexpressed in endometrial cancer. Combining palbociclib with endocrine therapy improves efficacy in hormone receptor-positive breast cancer. We investigated palbociclib combined with endocrine therapy for estrogen receptor-positive advanced/recurrent endometrial cancer., Patients and Methods: This placebo-controlled double-blind, randomized phase II screening trial (NCT02730429) enrolled women with measurable/evaluable estrogen receptor-positive endometrioid endometrial cancer that was primary metastatic or had relapsed after ≥1 prior systemic therapy. Patients were randomized in a 1:1 ratio, stratified by number of prior chemotherapy lines, measurable versus evaluable non-measurable disease, and prior medroxyprogesterone/megestrol acetate treatment, to receive oral letrozole 2.5 mg on days 1-28 plus either oral palbociclib 125 mg or placebo on days 1-21, repeated every 28 days until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS)., Results: Among 77 patients randomized between February 16, 2017, and December 21, 2018, 73 were treated (36 with palbociclib-letrozole, 37 with placebo-letrozole). Median follow-up was 21.9 (95 % CI, 16.7 to 22.3) months. Median PFS was 8.3 (95 % CI, 4.6 to 11.2) versus 3.1 (95 % CI, 2.7 to 6.8) months, respectively. In a landmark analysis at 12 months the PFS hazard ratio was 0.57 (95 % CI, 0.32 to 0.99; P = .044). Grade ≥ 3 adverse events were more common with palbociclib-letrozole (67 %) than placebo-letrozole (30 %), most commonly neutropenia (44 % v 0 %, respectively)., Conclusion: These results support a potential role of the palbociclib-letrozole combination as treatment for hormone receptor-positive advanced/recurrent endometrial cancer. Based on these encouraging results, phase III evaluation of letrozole combined with a CDK4/6 inhibitor is planned., Clinical Trial Information: NCT02730429., Competing Interests: Declaration of competing interest MRM reports leadership roles and stock for Karyopharm Therapeutics and Sera Prognostics; honoraria from Roche, AstraZeneca, Genmab/Seattle Genetics, GSK, Merck, Mersana, Takeda, Zai Lab, Geneos, and Allarity Therapeutics; consulting/advisory roles for AstraZeneca, Genmab, Karopharm Therapeutics, Pfizer, and GSK; research funding (to institution) from AstraZeneca, Boehringer Ingelheim, Pfizer, Tesaro, Clovis Oncology, Ultimovacs, Apexigen, and GSK; grants and personal fees from Tesaro, AstraZeneca, Pfizer, and Clovis Oncology; travel/accommodation/expenses from AstraZeneca, Karyopharm Therapeutics, Pfizer, Roche, Tesaro, and SeraCare; and other relationships with ENGOT, GCIG, and ESGO. LB reports speaker's bureau participation for GSK and MSD and research funding from AstraZeneca. FM reports honoraria from Roche/Genentech, Novartis, Pfizer, AstraZeneca, Clovis Oncology, Eisai, Genomic Health, PharmaMar, Amgen, MSD Oncology, Seagen, Myriad Genetics, Pierre Fabre, GSK, Agendia, Lilly, Gilead, Daiichi Sankyo, and Immunomedics; consulting/advisory roles for Pfizer, Genomic Health, CureVac, Amgen, Eisai, GSK, Gilead, Seagen, Clovis Oncology, AstraZeneca, Roche, Vaccibody, and Immunomedics; research funding from Roche/Genentech, Novartis, AstraZeneca, Tesaro, Clovis Oncology, MSD Oncology, Vaccibody, Gilead, and GSK; and travel/accommodation/expenses from Roche, Pfizer, AstraZeneca, and Gilead Sciences. RdPC reports employment and stock ownership from Y-mAbs Therapeutics and consulting/advisory role for Karyopharm. MGM reports consulting/advisory roles for AstraZeneca; speakers' bureau for GSK and MSD Oncology; and travel/accommodation/expenses from AstraZeneca, GSK, and MSD Oncology. AA reports consulting/advisory roles and travel/accommodation/expenses from GSK and MSD. BA reports honoraria from Roche, AstraZeneca, MSD, GSK, Eisai Europe, Novartis, Lilly, and Pfizer; consulting/advisory roles for Roche, MSD, Sanofi Aventis GmbH, GSK, and Eisai Europe; and travel/accommodation/expenses from Roche, AstraZeneca, GSK, Lilly, and Daiichi Sankyo/AstraZeneca. VS reports honoraria from AstraZeneca, MSD Oncology, GSK, PharmaMar, and Novocure; consulting/advisory roles for AstraZeneca and Novocure; and travel/accommodation/expenses from GSK and PharmaMar. AR reports consulting/advisory roles for AstraZeneca, GSK, Boehringer Ingelheim, MSD, and Pharma&; speakers' bureau for AstraZeneca, GSK, MSD, and Pharma&; and travel/accommodation/expenses from AstraZeneca. KL reports honoraria from AstraZeneca; consulting/advisory roles for Eisai, MSD, GSK, and Nycode; research funding (inst) from GSK; and is Deputy Medical Director of NSGO-CTU. FT reports research funding and personal fees from AstraZeneca, Clovis, Eisai, ImmunoGen, MSD, SAGA diagnostics, and Tesaro/GSK. MPBG reports consulting/advisory roles for AstraZeneca, GSK, MSD Oncology, Eisai Europe, Clovis Oncology, PharmaMar, and Pharma&; speakers' bureau for AstraZeneca Spain, GSK, Eisai Europe, and MSD Oncology; and travel/accommodation/expenses from AstraZeneca, GSK, and MSD Oncology. JEK reports employment (immediate family member) with MSD; consulting/advisory roles for AstraZeneca, MSD, and GSK; and travel/accommodation from AstraZeneca, Eisai, PharmaMar, and GSK. JS reports honoraria from AstraZeneca, Eisai, Clovis Oncology, Olympus Medical Systems, Johnson & Johnson, PharmaMar, Pfizer, Teva, Tesaro, MSD Oncology, GSK, and Bayer; consulting/advisory roles for AstraZeneca, Clovis Oncology, PharmaMar, Merck, Pfizer, Tesaro, MSD Oncology, Lilly, Novocure, Johnson & Johnson, Roche Diagnostics, NGRESS-Health, Riemser, Sobi, GSK, Novartis, and Alkermes; research funding (inst) from AstraZeneca, Clovis Oncology, Merck, Bayer, PharmaMar, Pfizer, Tesaro, MSD Oncology, and Roche; travel/accommodation/expenses from AstraZeneca, Clovis Oncology, PharmaMar, Roche Pharma AG, Tesaro, MSD Oncology, and Olympus. No other potential conflicts of interest were reported., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The INGE-B trial (NCT02894398) aimed to confirm the efficacy and safety data from the PALOMA trials for patients treated first line (1L) with palbociclib (PAL) and letrozole or 1L and later line with PAL and fulvestrant. In addition, so far lacking evidence for efficacy and safety on the combination of PAL with anastrozole, exemestane (1L), or letrozole (later line) was investigated., Methods: The prospective, multicenter, multicohort phase 2 trial INGE-B enrolled adult patients with locally advanced, inoperable, or metastatic HR+/HER2- breast cancer in Germany. The primary endpoint was the clinical benefit rate (CBR) in patients with measurable disease according to RECIST v1.1. Secondary endpoints were overall response rate, progression-free survival (PFS), overall survival (OS), safety, and quality of life. Data were analyzed with descriptive statistics., Results: Between 2016 and 2018, 388 patients were enrolled at 64 German sites. Among patients with measurable disease treated with PAL in 1L (n = 157), the CBR was 63.7% (100/157). Among all patients treated with PAL 1L (n = 219), PFS was 20.1 months (95% CI 14.6-24.0), and OS was 40.9 months (95% CI 35.1-49.2). The most common grade 3/4 adverse event was neutropenia (33.4% n = 77). There were no treatment-related deaths., Conclusion: The INGE-B trial demonstrated good efficacy and tolerability of PAL with letrozole (1L) or fulvestrant (first and later line) in accordance with the PALOMA trials. In addition, the so far lacking proof of efficacy and safety of PAL in combination with anastrozole or exemestane in 1L and with letrozole in later line was provided by INGE-B., Introduction: The INGE-B trial (NCT02894398) aimed to confirm the efficacy and safety data from the PALOMA trials for patients treated first line (1L) with palbociclib (PAL) and letrozole or 1L and later line with PAL and fulvestrant. In addition, so far lacking evidence for efficacy and safety on the combination of PAL with anastrozole, exemestane (1L), or letrozole (later line) was investigated., Methods: The prospective, multicenter, multicohort phase 2 trial INGE-B enrolled adult patients with locally advanced, inoperable, or metastatic HR+/HER2- breast cancer in Germany. The primary endpoint was the clinical benefit rate (CBR) in patients with measurable disease according to RECIST v1.1. Secondary endpoints were overall response rate, progression-free survival (PFS), overall survival (OS), safety, and quality of life. Data were analyzed with descriptive statistics., Results: Between 2016 and 2018, 388 patients were enrolled at 64 German sites. Among patients with measurable disease treated with PAL in 1L (n = 157), the CBR was 63.7% (100/157). Among all patients treated with PAL 1L (n = 219), PFS was 20.1 months (95% CI 14.6-24.0), and OS was 40.9 months (95% CI 35.1-49.2). The most common grade 3/4 adverse event was neutropenia (33.4% n = 77). There were no treatment-related deaths., Conclusion: The INGE-B trial demonstrated good efficacy and tolerability of PAL with letrozole (1L) or fulvestrant (first and later line) in accordance with the PALOMA trials. In addition, the so far lacking proof of efficacy and safety of PAL in combination with anastrozole or exemestane in 1L and with letrozole in later line was provided by INGE-B., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objectives: Inhibition of estradiol production by letrozole may interfere with physiological effects of progesterone necessary to maintain the pregnancy. Treatment of tubal pregnancy (TP) with letrozole would allow to avoid the disadvantages of methotrexate (MTX). The aim was to compare the effectiveness of letrozole with MTX in the management of TP., Material and Methods: A prospective open-label cohort study was conducted among women with TP and increasing B-human chorionic gonadotropin (B-hCG) concentrations. MTX was administered in a single dose of 100 mg intravenously, while letrozole in a dose of 5 mg orally for 10 days. Blood parameters (B-hCG, hemoglobin, creatinine, urea, transaminases, bilirubin) were tested on days 0, 4 and 7., Results: Out of 22 eligible women, 14 received MTX and received 8 letrozole. Mean age, lesion diameter, gestation age in the MTX vs letrozole arm were: 31 vs 32 years (p = 0.3), 13.2 vs 16.3 mm (p = 0.1), 7 + 1 vs 7 + 0 weeks (p = 0.6), respectively. In case of 4 women treated with letrozole and in 2 treated with MTX (4/8, 50% vs 2/14, 14.3%, p = 0.07) the treatment was unsuccessful. There were no significant differences in blood parameters on days 0, 4 and 7 between both arms, except for the increasing urea concentration in the letrozole arm (p = 0.01)., Conclusions: Even though the results did not reach statistical significance, it is likely that a larger study sample would confirm the trend of letrozole being less effective. The results did not support the use of letrozole in the studied regimen as an alternative to MTX.

Anxiety is among the most prevalent mental health issues in children. While it is well established that gonadal steroids influence anxiety-like behavior in adulthood, a potential role in prepubertal juveniles has been overlooked because it is commonly thought that the gonads are quiescent during the juvenile period. However, the juvenile gonads secrete measurable amounts of steroids, and we have recently found that prepubertal ovariectomy decreases anxiety-like behavior of juvenile Siberian hamsters in the light/dark box test. The present study tested whether an injection of estradiol benzoate (1 μg or 10 μg, SC) to gonadectomized hamsters (Exp. 1) or chronic suppression of endogenous estradiol with the aromatase inhibitor, letrozole (2 mg/kg, PO), to intact hamsters (Exp. 2) affects anxiety-like behavior in the light/dark box test during the juvenile phase. Estradiol benzoate altered anxiety-like behavior of both male and female juveniles in a dose-dependent manner, with anxiolytic actions at the low dose, but no effect at the high dose. Similar effects were seen for activity measures, albeit only in females. Letrozole suppressed uterine weights demonstrating an active role for endogenous estradiol during the juvenile phase. Anxiety-like behavior, however, was impacted by the administration procedure itself, preventing conclusions on letrozole's actions on behavior. While the role for endogenous estradiol in juvenile anxiety-like behavior remains unresolved, the present findings indicate that the neural centers regulating affective behavior are responsive to exogenous estradiol prior to puberty. These findings highlight the potential impact of exogenous estrogen exposures on juvenile affective behavior., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A 50's postmenopausal woman, she was diagnosed with breast cancer, cT2N3aM0, Stage ⅢC, invasive ductal carcinoma, estrogen-receptor(ER)-positive, progesterone-receptor(PgR)-negative, human epidermal growth factor 2(HER2)-negative. A combination therapy of palbociclib(PAL)and letrozole(LET)was administered to the patient. A method of administration was 125 mg of PAL per day(14 days of treatment followed by 14 days off, 2 courses and 18 days of treatment followed by 10 days off, 8 courses)and 2.5 mg of LET per day every day. This therapy was effective, and the clinical stage showed down staging, T2N1M0, Stage ⅡB. Left total mastectomy and sentinel lymph node biopsy and swelled axillar lymph node resection was performed. Postoperative pathological histology revealed ypT2N1a(1/9). Subsequently this medication (125 mg of PAL per day, 21 days of treatment followed by 14 days off and 2.5 mg of LET per day every day)was continued as an adjuvant therapy and postmastectomy radiation therapy(PMRT 50 Gy)was underwent for her. This patient has survived without recurrence 12 months after operation. PAL probably has a certain effect even if oral administration method were changed.

Objective: This research was conducted to assess the therapeutic advantage of combined letrozole and clomiphene citrate versus monotherapy for polycystic ovarian syndrome (PCOS) patients., Study Design: Five databases were searched using the search string: (letrozole and clomiphene) AND (clomiphene OR clomiphene citrate OR CC) AND (letrozole OR LE) AND (ovulation induc* OR fertility induc* OR fertility preserv*) AND (polycystic ovarian syndrome OR PCOS). All statistical analyses were conducted in Review Manager 5.4.1. Random effect-effect model was used to pool risk ratio (RR), mean difference (MD), and odds ratio (OR) and their corresponding 95% confidence interval (CI). Moreover, qualitative analysis was conducted to qualitatively analyze ovulation, secondary outcomes, and cycle characteristics., Results: One clinical trial and three randomized clinical trials (RCTs) were used in the study. Two studies were used in a quantitative analysis showing that combination was superior for ovulation induction (RR = 1.86 [1.37, 2.53]; p  < 0.0001; I 2  = 0%), but the number of follicles ≥15 mm was significantly associated with the combination (MD = 0.40[0.14, 0.66]; p  = 0.002; I 2  = 0%). On subgroup analysis, only hot flushes were significantly associated with the combination (RR = 2.67[1.12, 6.36]; p  = 0.03; I 2  = 0%). The meta-analysis of two studies reported a significantly higher ovulation rate and number of dominant follicles in the combination therapy group compared with the LE alone arm but no significant difference in pregnancy rate, endometrial thickness, and adverse events., Conclusion: Our study demonstrates a significant effect of the combination on ovulation induction. The combination yielded a better chance of conception and viable pregnancy. Further studies are needed to determine the live birth rate. HighlightsCombined Letrozole and Clomiphene is superior to either of these drugs alone for ovulation induction in PCOS.Our results conclude that the combination results in better ovulation, cycle characteristics, and secondary changes.Only the incidence of hot flushes as an adverse effect is increasingly reported in combination.

Excessive aromatase can reduce reproductive performance in aged roosters. Aromatase inhibitors (AI) can inhibit the aromatase activity and improve the semen quality of aged roosters. However, relevant molecular mechanism is still unclear. The purpose of this study was to explore the regulatory mechanism of AI letrozole improving semen quality in aged roosters by transcriptomic and proteomic sequencing. In this study, 56-week-old roosters were reared in separate cages on a standard basice diet and oral letrozole 42 days (D) at a daily dose 0.25 mg/kg. Semen quality and serum hormone were measured before (0 D) and after (42 D) letrozole administration. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected, respectively. The results indicated that semen volume, sperm motility, sperm density, MMP, testosterone (T) and gonadotropin releasing hormone (GnRH) in letrozole treatment group (LET) were significantly increased than those in control group (CN) (P<0.05); estradiol (E 2 ) and ROS in LET were significantly lower than those in CN (P<0.05). Through transcriptomic and proteomic analysis, we identified 189 differently expressed genes (DEGs) and 64 differentially expressed proteins (DEPs) in the comparison of LET and CN. DEGs and DEPs Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) items are mainly enriched in steroid biosynthetic process, cell differentiation and proliferation, lipid metabolic process, oxidation-reduction process and electron transfer activity. Furthermore, 8 genes including STAR, CYP17A1, NSDHL, SULT1E1, EHF, NRNPA1, PLIN2 and SDHA were identified as key genes for letrozole to regulate semen quality in aged roosters. These results indicate that letrozole can up-regulate the expression of genes related to steroid hormone synthesis, cell differentiation and proliferation, electron transfer activity, and enhance mitochondrial activity, increase testicular weight, and ultimately improve the semen quality of aged roosters., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To evaluate the disease course of patients with low grade endometrial stromal sarcoma (LG-ESS) and compare oncologic outcomes associated with hormonal therapy in primary and recurrent disease., Methods: This is a retrospective study of patients with LG-ESS who underwent active treatment between January 2000 and July 2023. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier product-limit estimator and modeled via Cox proportional hazards regression., Results: A total of 221 patients were included; 58 % of patients (91/157) were stage I, 12 % (19/157) stage II, 13 % (20/157) stage III, and 17 % (27/157) stage IV. Surgery was the primary treatment for 98 % (213/218). Only 79 patients received hormonal adjuvant therapy, 58 % (46/79) Megace, 24 % (19/79) Letrozole, and 18 % (14/79) received other hormonal therapy. There was no significant difference in RFS (p = 0.159) and OS (p = 0.167) between patients receiving Megace versus Letrozole as adjuvant therapy. At first recurrence, patients given Megace had a similar RFS to those on Letrozole (p = 0.302), but a better OS (27 vs 10 months, p = 0.018).  Negative status of estrogen, smooth muscle actin, and desmin were associated with lower RFS (p = 0.039, p = 0.002, and p = 0.015, respectively) and OS (p = 0.008, p = 0.012, and p = 0.013, respectively). Lymphovascular invasion was associated with lower RFS (p = 0.033), and negative status of progesterone was associated with lower OS (p = 0.003)., Conclusion: There was no difference in oncologic outcomes between Megace and Letrozole in patients who received adjuvant therapy for LG-ESS. Megace may have potential survival advantage in recurrent disease. Further study is warranted to determine the most effective agents and their sequence in the treatment of LG-ESS., Competing Interests: Declaration of competing interest Michael Frumovitz – Consulting/speaking Stryker; Consulting Astellas; Research funding AkesoBio. Pamela Soliman – Consulting GSK, Aadi Research funding Merck, GSK, Leap Therapeutics. All other authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To evaluate the effectiveness of Letrozole and Clomiphene (CC) combination versus Letrozole alone for ovulation induction in infertile women with PCOS. This was an open label randomized controlled trial conducted between September 2020 and March 2023 at a tertiary level hospital. Women with a diagnosis of infertility and PCOS were included. Participants were randomized in a 1:1 ratio, to either the combination of 2.5 mg letrozole and 50 mg Clomiphene Citrate (CC) daily or 2.5 mg letrozole alone from 2nd to 6 th day of menstrual cycle for up to three treatment cycles. The primary outcome was ovulation rate per cycle. The secondary outcomes included ovulation rate per woman randomised, cumulative pregnancy and live birth rates. A total of the 120 participants, 59 women in Letrozole and CC arm (intervention) and 61 women in the Letrozole alone arm (control) were recruited. The woman per cycle ovulation rate following Letrozole and CC combination versus Letrozole alone (71/92 (77.2%) vs. 52/83 (62.6%), RR 1.43, 95%CI 0.99 to 2.06) but was not statistically significant. A per ITT analysis, the clinical pregnancy rate per woman randomized (16/61(26.2%) vs. 13/59(22%), RR 1.12, 95%CI 0.76 to 1.64) and live birth rate per woman randomized (10/61(16.4%) vs 11/59(18.6%), RR 0.92, 095%CI 0.57 to 1.50) did not differ significantly between Letrozole and CC versus Letrozole group. There was no significant improvement in ovulation, clinical pregnancy, or live birth rates with a combination of letrozole and CC versus letrozole alone in per woman randomized with PCOS. Trial RegistrationThe trial was prospectively registered in the clinical trial registry of India (CTRI registration number CTRI/2020/07/026263), Registration dated: February 26, 2020., Competing Interests: Declarations. Ethics Approval: Ethics committee approval was obtained from the institutional review board (IRB Min. No. 12632 dated 26.02.2020). Consent to Participate: Written consent for the use of anonymized data was obtained from the participants. Consent for Publication: Not applicable. Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Letrozole (LTZ) is an aromatase inhibitor that limits estrogen (E2) production and increases testosterone (T) levels. This research aimed to examine the impact of a single dose of LTZ on testicular hemodynamics, ejaculation time, and semen quality in goats under heat stress (HS). Therefore, Doppler examination and semen evaluation were performed on twelve mature bucks for two weeks (W-1, W-2) as pre-heat stress control during winter. Then during summer HS bucks were subjected to Doppler examination, semen evaluation, and hormonal analysis (T, E2, and LH) at 0 h. Afterward, bucks were assigned into two groups and subcutaneously injected with physiological saline (n = 6; CON) or LTZ (0.25 mg/kg BW; n = 6; LTZ). Both groups were subjected to Doppler scanning and hormonal analysis at 2, 4, 24, 48, 72, 96,144, and 168 h. Semen evaluation was performed at 48 and 168 h. The LTZ group showed increasing (P < 0.05) in semen volume, sperm motility, and viability and decreasing (P < 0.05) in ejaculation time and sperm abnormalities compared to CON group at 48 h. Additionally, T concentrations increased (P < 0.01) at 2, 24, and 48 h, E2 decreased (P < 0.01) from 2 to 48 h, and LH raised (P < 0.01) at 2 and 72 h in LTZ group compared to CON one. Doppler indices reduced (P < 0.05) at 96 h in LTZ group. semen pH and scrotal circumference were not affected by LTZ. In conclusion, LTZ administration shortened ejaculation time and enhanced semen quality in bucks during HS., (© 2024. The Author(s).)

Purpose: To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA -mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172)., Methods: Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability., Results: Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response., Conclusion: Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

Background: Male breast cancer is a very rare disease and only accounts for around 1% of all breast cancers. The treatment strategies are based on those used for breast cancer in women. So far, there is a lack of randomized data to support specific treatment modalities in men. To our knowledge, a therapeutic approach with a combination of letrozole and abemaciclib has not yet been described for a male patient with metastatic breast cancer., Case Description: Here, we report a case of a male patient with advanced metastatic breast cancer treated with a combination of letrozole and abemaciclib. The therapy was well tolerated with no reported side effects. The follow-up CT showed regression of the primary tumor mass and the lymph nodes and soft tissue metastases., Conclusion: In summary, this case report clearly shows the effectiveness of the therapeutic approach and should be discussed for the treatment of future patients., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Treatment strategies for preventing liver fibrosis have not yet been established. Letrozole, widely used for breast cancer, has recently been reported to suppress liver fibrosis in murine models. Therefore, we aimed to validate the suppressive effects of letrozole on liver fibrosis in the clinical setting. From 2006 to 2020, 23 consecutive patients who received continuous letrozole treatment for 24 months or more and had a liver fibrosis marker FIB-4 index of ≥ 2.30, were included. Forty-three patients who underwent anastrozole treatment for 24 months or more and had a liver fibrosis marker FIB-4 index of ≥ 2.30, were also included as controls. The Fisher exact, chi-square, unpaired Student t, and paired Student t test were used to analyze the data. The patient characteristics were similar between the letrozole- and anastrozole-treated patient groups. Among the letrozole-treated patients, the mean FIB-4 index tended to decline during letrozole treatment; a significant decrease was observed at 18 and 24 months compared with the baseline values (p = 0.044 and p = 0.013). In addition, the mean aspartate aminotransferase-to-platelet ratio index (APRI) decreased during letrozole treatment; the values at 18 and 24 months were significantly lower than those at baseline (p = 0.024 and p = 0.026). In contrast, among anastrozole-treated patients, the mean FIB-4 index and APRI did not change during anastrozole treatment. When changes in the FIB-4 index were further examined in a limited number of patients with a FIB-4 index ≥ 2.67, a significant reduction in the FIB-4 index at 24 months compared with baseline was also observed in letrozole-treated patients (p = 0.023), but not in anastrozole-treated patients. In conclusion, our findings support a possible suppressive effect of letrozole on liver fibrosis in the clinical setting. Further studies are required to better understand the pharmacological effects of letrozole., Competing Interests: Authors Enomoto H and Tachiki H are employees of Towa Pharmaceutical Co., Ltd., the funder company of this study. They were merely involved in the review process in the writing of this study, as were the other authors. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Ohkawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial., Patients and Methods: MP was tested in 1,866 patients randomly assigned to receive ELT or placebo. The primary end point was distant recurrence (DR). Secondary end points were disease-free survival (DFS) and BC-free interval (BCFI). Tumors were classified as MP high risk (MP-HR) or low risk (MP-LR). MP-LR tumors were further classified as ultralow risk (MP-UL) or low non-ultralow risk (MP-LNUL)., Results: There was no statistically significant difference in ELT benefit on DR between MP-HR and MP-LR (interaction P = .38). MP-LR tumors (n = 1,160) exhibited a statistically significant 10-year benefit of 3.7% for DR (hazard ratio [HR], 0.43 [95% CI, 0.25 to 0.74]; P = .002), whereas MP-HR tumors (n = 706) exhibited a nonsignificant 2.4% benefit (HR, 0.65 [95% CI, 0.34 to 1.24]; P = .19). The 10-year ELT benefit was significant for DFS (7.8%) and BCFI (7.0%) for MP-LR tumors, whereas MP-HR tumors did not significantly benefit (interaction DFS: P = .015, BCFI: P = .006). In exploratory analysis, the 10-year ELT benefit was significant and more pronounced in MP-LNUL (n = 908) tumors: 4.0% for DR, 9.5% for DFS, and 7.9% for BCFI; the benefit in MP-UL (n = 252) tumors was not significant: 3% for DR, 1.8% for DFS, and 4.1% for BCFI., Conclusion: The primary hypothesis of predictive ability of MP on DR was not confirmed. However, the secondary outcomes demonstrated MP was predictive of ELT response and identified a subset of patients with early-stage hormone receptor-positive BC (MP-LR) with improved outcomes from ELT. These data could have important clinical implications in patient selection beyond clinical risk assessment for EET.

Objective: The present study aimed to investigate the impact of combined use of letrozole in an antagonist protocol during IVF on live birth outcomes and to assess the safety of letrozole in terms of maternal and neonatal complications., Methods: This retrospective cohort study included women undergoing IVF/ICSI and fresh embryo transfer (ET) treatment with and without letrozole co-treatment from 2007 to 2021 at Shanghai Ninth People's Hospital (Shanghai, China). The primary outcome was the live birth rate, while the incidences of maternal and neonatal complications were secondary outcomes. Logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the analyzed outcomes. Sensitivity analysis was performed using a propensity score-based patient-matching (PSM) model, an inverse probability weighting (IPW) model, logistic regression models with women undergoing their first IVF-ET cycle, and subgroup analysis., Results: Of the 4780 women enrolled in the study, 3887 underwent an antagonist protocol for ovarian stimulation, while 893 received letrozole co-treatment. In this cohort, letrozole co-treatment demonstrated comparable live birth rates to the use of antagonist protocol alone (logistic regression: aOR, 0.88; 95% CI, 0.71-1.08; PSM: aOR, 0.97; 95% CI, 0.77-1.22; IPW: aOR, 0.88; 95% CI, 0.71-1.10). Notably, individuals with a body mass index (BMI) exceeding 24 and those with high ovarian response experienced higher live birth rates under the letrozole co-treatment regimen (BMI ≥ 24: aOR, 1.85; 95% CI, 1.14-3.00; high response: aOR, 1.60; 95% CI, 1.02-2.50). Letrozole co-treatment was also associated with decreased risks of gestational diabetes (aOR, 0.34; 95% CI, 0.15-0.69) and small for gestational age (SGA) fetuses (aOR, 0.42; 95% CI, 0.22-0.75) in fresh ET cycles. These finding were robust in both PSM and IPW models., Conclusions: Our findings suggested that letrozole co-treatment in antagonist protocol for IVF/ICSI was associated with a comparable live birth rate following fresh ET. Further prospective randomized studies are needed to verify our results., (© 2024. The Author(s).)

Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in patients receiving chemotherapy, leading to the use of adjuvant analgesics such as tramadol. This work introduces the first analytical approach for the concurrent quantification of letrozole and tramadol, two co-administered drugs, employing a rapid, highly sensitive, eco-friendly, and cost-effective first derivative synchronous spectrofluorimetric technique. The fluorescence of tramadol and letrozole was measured at wavelengths of 235.9 nm and 241.9 nm, respectively using a wavelength difference (Δλ) of 60.0 nm. The developed approach demonstrated exceptional linearity (r ˃ 0.999) within the specified concentration ranges for tramadol (10.0-1200.0 ng/mL) and letrozole (1.0-140.0 ng/mL). The results demonstrated that the proposed technique exhibits a high level of sensitivity, with detection limits of 0.569 and 0.143 ng/mL for tramadol and letrozole, respectively, indicating the good bioanalytical applicability. The within-run precisions, both intra-day and inter-day, for both analytes, were less than 0.71 % RSD. The developed approach was effectively applied to simultaneously estimate the mentioned drugs in their tablets and human plasma samples, achieving high percentage recoveries and low % RSD values. In order to assess the environmental sustainability of the developed approach, Analytical GREEnnessNNESS (AGREE) and the Green Analytical Procedure Index (GAPI) metric tools were employed. Both tools revealed that the developed approach is excellent green, suggesting its usage as an environmentally-friendly alternative for the routine assayof the investigated pharmaceuticals. The developed approach was validated according to the ICHQ2 (R1) requirements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Research Question: Does luteal phase support (LPS) with oral progesterone improve the live birth rate (LBR) in patients undergoing intrauterine insemination (IUI) cycles with letrozole?, Design: This retrospective cohort study included 1199 IUI cycles with letrozole between January 2017 and December 2021. A nearest neighbour random matching approach was employed to pair the LPS group and the control group in a 1:2 ratio. Eight variables were chosen for matching in the propensity score matching (PSM) model: age; body mass index; duration of infertility; cause(s) of infertility; antral follicle count; basal concentration of FSH; rank of IUI attempts; and leading follicle size. LBR was selected as the primary outcome., Results: In total, 427 LPS cycles were matched with 772 non-LPS (control) cycles after PSM. The LBR was significantly higher in the LPS group compared with the control group (19.7% versus 14.5%; P = 0.0255). The clinical pregnancy rate (23.2% versus 17.6%; P = 0.0245) and ongoing pregnancy rate (20.6% versus 15.8%; P = 0.0437) were also significantly higher in the LPS group. The biochemical pregnancy rate, ectopic pregnancy rate and miscarriage rate were similar in the two groups (P > 0.05). The intergroup comparison revealed no significant variances in terms of gestational age, mode of delivery, ectopic pregnancy rate or abortion rate. Furthermore, there were no significant differences in birth weight or birth length between the two groups., Conclusions: Luteal support with oral progesterone significantly improved the LBR in IUI cycles with letrozole, but did not affect neonatal outcomes., (Copyright © 2024 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: To compare fertility outcomes of obese patients (body mass index [BMI] ≥ 30 kg/m 2 ) undergoing superovulation and intrauterine insemination (SO-IUI) using gonadotropins versus letrozole., Methods: A single centre retrospective cohort study of obese patients undergoing SO-IUI using gonadotropins or letrozole between January/2019 and June/2022. Primary outcome was clinical pregnancy rate (intrauterine pregnancy with positive fetal heart rate). Secondary outcomes included rates of multifollicular development, multiple pregnancy, spontaneous abortion and cycle cancellation. Subgroup analysis was done stratifying by obesity class. A multivariate logistic regression model was used for primary/secondary outcomes, adjusting for clinically determined covariates., Results: Out of 802 total identified SO-IUI cycles, 715 cycles were completed (518-gonadotropins and 197-letrozole cycles). The clinical pregnancy rates were not significantly different in obese patients undergoing SO-IUI with gonadotropins versus letrozole when adjusted for age, gravidity, parity, cause of infertility, IUI cycle number, endometrial thickness, sperm source and post-wash motile sperm count (adjusted odds ratio [aOR] 1.37, 95% confidence interval [CI] 0.72-2.59). Similarly, no significant associations were found in spontaneous abortion (aOR1.46, 95%CI 0.42-5.08), multiple pregnancy (aOR1.33, 95%CI 0.20-8.88) or cancellation rates (OR0.89, 95%CI 0.55-1.45) between the two groups. The rates of multifollicular development were also comparable between the two groups (aOR0.51, 95% CI 0.19-1.38). For cycles involving gonadotropins, higher BMI classes required higher total gonadotropin dose (p < 0.001)., Conclusion: After adjusting for patient and cycle factors, gonadotropins and letrozole led to comparable odds of achieving pregnancy in obese patients undergoing SO-IUI. Future research in the obese population will help to better understand how to optimize fertility treatments for this growing population., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Fertility issues are of great concern for young women undergoing treatment for breast cancer (BC). Fertility preservation (FP) protocols using controlled ovarian stimulation (COS) with letrozole have been widely used with overall good results. However, letrozole cannot be used in every country in this context. This study aimed to assess the efficacy of tamoxifen for COS in women with early BC undergoing FP., Methods: This multicentric prospective study included patients aged 18-40, diagnosed with stage I, II and III invasive BC, undergoing tamoxifen-COS before adjuvant or neoadjuvant chemotherapy (NAC). The primary endpoint was the efficacy of tamoxifen-COS protocol evaluated by the number of oocytes collected and vitrified. Secondary endpoints included the time interval before chemotherapy, breast cancer (BC) recurrence rates, and reproductive outcomes., Results: Ninety-five patients were included between 2014 and 2017, aged 31.5 ± 4 years on average. 37.9 % received NAC and 62.1 % received adjuvant chemotherapy. FP procedure was successful in 89.5 % of the cycles. The mean number of collected and vitrified oocytes was 12.8 ± 7.9 and 9.8 ± 6.2, respectively. The mean duration of COS was 10.4 ± 1.9 days. Median time before chemotherapy initiation was 3.6 weeks (IQR 3.1; 4.1) for women receiving NAC. Five-year relapse-free and overall survival rates were in-line with those expected in this population. Twenty-one women had spontaneous full-term pregnancies, while 5 underwent IVF cycles with frozen-thawed oocytes, without pregnancy., Conclusion: Tamoxifen-COS protocols appear to be feasible before adjuvant or NAC treatment in young BC patients and efficient in terms of oocyte yield., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:None of the authors have any conflicts of interest related to this study. Florence Leperlier reports honoraria for lectures and presentations from Ferring Pharmaceuticals, Gedeon Richter, and IBSA, unrelated to this work. Pierre-Emmanuel Bouet reports travel and meeting support from Merck, Gedeon-Richter, Theramex, Ferring, Organon and IBSA. P-E.B. have undertaken consultancy work for Merck and Gedeon-Richter and have received research grants from Theramex, Ferring, MSD, and Genevrier, not related to the present work. Thomas Freour has undertaken consultancy work for Vitrolife France and Gedeon-Richter. T.F. reports travel and meeting support from Gedeon-Richter, Theramex, Ferring and IBSA. T.F. reports honoraria for lectures and presentations from Ferring Pharmaceuticals, Theramex, Gedeon Richter and Merck Serono, unrelated to this work. Marie Robert reports travel fees and congress fees from AstraZeneca, Gilead and Creafirst, and has undertaken consultancy work for AstraZeneca and Lilly. Mario Campone is on the advisory board of AstraZeneca, Novartis, Sanofi, Lilly, Pfizer, Seagen, Gilead and Daiichi-Sankyo. M.C. has undertaken consultancy work for AstraZeneca, Novartis, Daiichi-Sankyo, PET-Therapy, Menarini and DIACCURATE, and he is a speaker for Novartis, Lilly and Amgen. He reports travel support from Pfizer, Novartis, Roche, AstraZeneca and Daiichi-Sankyo., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Aromatase inhibitors improve male fertility by modifying the hormonal control of spermatogenesis. The present study aimed to investigate the effects of oral administration of letrozole on testosterone and estradiol concentrations and their ratios in blood serum, seminal plasma, prostatic fluid, sperm quality in fresh semen, and prostate gland dimensions. Seven adult male intact mixed-breed dogs were selected. The animals received letrozole (72 µg/kg, PO) daily for four weeks. Blood samplings and semen collections were carried out on days 0 (control), 14 (treatment), 28 (treatment), and 42 (post-treatment)., Results: Our results showed that letrozole administration resulted in a 4.3 fold significant increase in serum, seminal plasma, and prostatic fluid testosterone levels after 14 days. This remained high until the end of the study. Serum and prostatic fluid estradiol levels did not change significantly over the study period. However, the seminal plasma estradiol level showed a significant increase on day 14. The estradiol: testosterone ratio was significantly reduced on day 14 in serum, seminal plasma, and prostatic fluid samples. Letrozole significantly improved the ejaculated spermatozoa viability and concentration after 28 days of oral administration. However, the sperm plasma membrane functional integrity and kinematic parameters were not significantly affected by the treatment. Transabdominal ultrasound examination revealed a significant increase in the height, width, and volume of the prostate gland after 28 days of treatment., Conclusions: According to the present research, oral administration of letrozole for 28 days affects local and systemic sex hormone balance leading to an improvement of the ejaculated canine spermatozoa viability and concentration concurrent with an increase in the prostate gland dimensions., (© 2024. The Author(s).)

Background: Around 4% of women receive an endometrial cancer diagnosis before turning 40, mainly those without prior childbirth experience and a strong desire to preserve their ability to conceive. Consequently, for young patients diagnosed with atypical endometrial hyperplasia (AEH) or early endometrial carcinoma (EC), a fertility-preserving approach employing high-dose oral progesterone has been adopted. However, previous research has shown a notable relapse rate. Furthermore, the extended use of substantial oral progesterone doses may hinder ovarian function and raise the risk of weight gain, liver issues, blood clotting, and breast cancer. We previously assessed the clinical effectiveness and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH-a) based re-treatment for women with EC and AEH who did not respond to oral progestin therapy but achieved favorable treatment results and reproductive outcomes., Methods: This study will be an open-label, two-armed, randomized, investigator-initiated multicenter trial evaluating the combination of GnRH-a with the levonorgestrel-releasing intrauterine system or the combination of GnRH-a with an aromatase inhibitor (comprising a subcutaneous GnRH-a injection every 4 weeks and daily oral letrozole 2.5 mg). A total of 226 participants will be randomly allocated to one of the two treatment groups in a 1:1 ratio. The primary objective is to determine the effectiveness of GnRH-a-based re-treatment in achieving a complete response (CR) at 24 weeks for patients with AEH or EC. Secondary objectives include assessing the pregnancy rate 12 weeks after treatment, as well as post-treatment pregnancy outcomes and the rate of recurrence., Ethics and Dissemination: The protocol received approval from the Institutional Review Board of Peking Union Medical College Hospital and from boards at five other institutions. The trial will adhere to the principles outlined in the World Medical Association's Declaration of Helsinki and follow Good Clinical Practice standards. The trial results will be disseminated through publication in a peer-reviewed journal., Conclusions: Prospective evidence supporting conservative treatment for EC and AEH is limited. There is a need for new approaches that can achieve higher CR rates with fewer side effects. This trial will assess the effectiveness of GnRH-a-based fertility-sparing treatment in obese women and recurrent patients, offering a promising alternative for patients with EC and AEH., Trial Registration Number: Chinese Clinical Trial Registry ChiCTR2200067099. Registered on December 27, 2022., (© 2024. The Author(s).)

Background: The monarchE and NATALEE trials demonstrated the benefit of CDK4/6 inhibitor (CDK4/6i) therapy in adjuvant breast cancer (BC) treatment. Patient selection, based on clinical characteristics, delineated those at high (monarchE) and high/intermediate recurrence risk (NATALEE). This study employed a historical patient cohort to describe the proportion and prognosis of patients eligible for adjuvant CDK4/6i trials., Methods: Between 2009 and 2011, 3529 patients were enrolled in the adjuvant PreFace clinical trial (NCT01908556). Eligibility criteria included postmenopausal patients with hormone receptor-positive (HRpos) BC for whom a five-year upfront therapy with letrozole was indicated. Patients were categorized into prognostic groups according to monarchE and NATALEE inclusion criteria, and their invasive disease-free survival (iDFS) and overall survival (OS) were assessed., Results: Among 2891 HRpos patients, 384 (13.3 %) met the primary monarchE inclusion criteria. The majority (n = 261) qualified due to having ≥ 4 positive lymph nodes. For NATALEE, 915 out of 2886 patients (31.7 %) met the eligibility criteria, with 126 patients (13.7 %) being node-negative. Patients from monarchE with ≥ 4 positive lymph nodes and NATALEE with stage III BC exhibited the poorest prognosis (3-year iDFS rate 0.87). Patients ineligible for the trials demonstrated prognoses similar to the most favorable patient groups within the eligibility criteria., Conclusion: Patient populations eligible for monarchE and NATALEE trials differed. Nearly a third of the postmenopausal HRpos population, previously under upfront letrozole treatment, met the NATALEE prognostic eligibility criteria. As certain eligible groups had a prognosis similar to non-eligible patients, it might be interesting to explore additional patient groups for CDK4/6i therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.A.F. reports grants from Biontech and Cepheid, personal fees from Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, MSD, Lilly, Pierre Fabre, SeaGen, Roche, Hexal, Agendia, Gilead. C.C.H. received honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Novartis, Pfizer, Roche, Gilead and MSD, and travel grants from Daiichi-Sankyo. N.N. is an employee of Novartis Pharma GmbH. B.A. received honoraria from AstraZeneca, Gilead, Genomic Health, Roche, Novartis, Celgene, Lilly, MSD, Eisai, Stemline, Teva, Tesaro, Daiichi Sankyo and Pfizer. Received travel grants from AstraZeneca, Roche, Novartis, Celgene, Lilly, Eisai, Stemline, Daiichi Sankyo and Pfizer. Participated in the data safety monitoring board or advisory boards for AstraZeneca, Gilead, Genomic Health, Roche, Novartis, Celgene, Lilly, MSD, Eisai, Tesaro, Daiichi Sankyo and Pfizer. S.K. received honoraria from Amgen, Celgene, Daiichi Sankyo, Novartis and Roche. C.T. received honoraria for advisory boards and lectures from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Mylan, Nanostring, Novartis, Pfizer, Pierre Fabre, Puma, Roche, Seagen, Vifor. H.-C.K. received honoraria from Pfizer, Novartis, Roche, Genomic Health/Exact Sciences, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, TEVA, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Lilly, Daiichi Sankyo, Gilead and Zuellig, travel support from Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo, Tesaro, Gilead, AstraZeneca, Zuellig, and Stemline, participated in data safety monitoring or advisory boards for Pfizer, Novartis, SurgVision, Carl Zeiss Meditec, Amgen, Onkowissen, MSD, Gilead, Daiichi Sankyo, Seagen, Genomic Health/Exact Sciences, Agendia, Lilly and owns stock of Theraclion SA. W.J. has received research grants and/or honoraria from Sanofi-Aventis, Daiichi Sankyo, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Chugai, GSK, Eisai, Celgene and Johnson&Johnson. A.S. reported grants from Celgene, Roche and AbbVie. Personal fees from Celgene, Roche, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen, and Pierre Fabre, and travel grants from Celgene, Roche, Pfizer and AstraZeneca. F.M. received honoraria from Amgen, AstraZeneca, Celgene, Clovis Oncology, CureVac, Eisai, Genomic Health, GSK, Immunomedics, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, PharmaMar, Roche, Seattle Genetics, Tesaro. M.W.S. received honoraria from AstraZeneca, Pfizer, Clovis, Mylan, Roche, Gedeon Richter, Carl Zeiss Meditec, travel support from Pfizer, Carl Zeiss Meditec. C.J. reports personal fees from AstraZeneca, Exact Sciences, Lilly, Novartis and Roche. V.M. received speaker honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre, iMED Institut. Consultancy honoraria: Roche, Pierre Fabre, PINK, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Seagen, Gilead, Stemline. Institutional research support from Novartis, Roche, Seagen, Genentech, AstraZeneca. Travel grants from AstraZeneca, Roche, Pfizer, Daiichi Sankyo, Gilead. C.R. received honoraria from MSD and AstraZeneca, travel expenses from the Swiss Society of Senology and the Swiss Society of Gynecology. P.D. received honoraria from MSD, Pierre Fabre, Novartis, AstraZeneca, Lilly, Gilead, Pfizer, Roche. E.B. received honoraria from Novartis, Hexal, BMS, Lilly, Pfizer, Roche, MSD, Bayer, Ipsen, Bluebird, B. Braun and onkowissen.de for consulting, clinical research management or medical education activities. S.Y.B. has received honoraria from Roche Pharma, Novartis, Pfizer, MSD, Teva, AstraZeneca. T.N.F. has received honoraria from Novartis, Roche, Pfizer, TEVA, Diachii Sankyo, AstraZeneca and MSD. All of the remaining authors have declared that they do not have any conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The gut microbiome is involved in the pathogenesis of many diseases including polycystic ovarian syndrome (PCOS). Modulating the gut microbiome can lead to eubiosis and treatment of various metabolic conditions. However, there is no proper study assessing the delivery of microbial technology for the treatment of such conditions. The present study involves the development of guar gum-pectin-based solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing curcumin (CCM) and fecal microbiota extract (FME) for the treatment of PCOS. The optimized S-SNEDDS containing FME and CCM was prepared by dissolving CCM (25 mg) in an isotropic mixture consisting of Labrafil M 1944 CS, Transcutol P, and Tween-80 and solidified using lactose monohydrate, aerosil-200, guar gum, and pectin (colon-targeted CCM solid self-nanoemulsifying drug delivery system [CCM-CT-S-SNEDDS]). Pharmacokinetic and pharmacodynamic evaluation was carried out on letrozole-induced female Wistar rats. The results of pharmacokinetic studies indicated about 13.11 and 23.48-fold increase in AUC of CCM-loaded colon-targeted S-SNEDDS without FME (CCM-CT-S-SNEDDS (WFME)) and CCM-loaded colon-targeted S-SNEDDS with FME [(CCM-CT-S-SNEDDS (FME)) as compared to unprocessed CCM. The pharmacodynamic study indicated excellent recovery/reversal in the rats treated with CCM-CT-S-SNEDDS low and high dose containing FME (group 13 and group 14) in a dose-dependent manner. The developed formulation showcasing its improved bioavailability, targeted action, and therapeutic activity in ameliorating PCOS can be utilized as an adjuvant therapy for developing a dosage form, scale-up, and technology transfer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The present study was conducted to evaluate the combination effect of apple cider vinegar (ACV) and metformin against letrozole-induced polycystic ovary syndrome (PCOS). Female Wistar rats were administered letrozole (1 mg/kg/day, p.o) for 21 days, except for the control group of animals. On the 22nd day, PCOS-induced animals were segregated into 4 groups and administered with CMC, ACV, metformin, and a combination of ACV and metformin, respectively. The treatments were continued for 15 days, and on the 36th day, all the animals were sacrificed for biochemical (blood glucose, lipid profile), hormonal (sex hormones and adiponectin), and pro-inflammatory mediator estimations in blood samples. The ovarian tissue samples were used for oxidative stress parameters and histological alterations. The PCOS control animals showed a significant alteration in the estrous cycle. The administration of letrozole resulted in the alteration of hormonal balance and elevation of body weights, glycemic state, lipid profile, pro-inflammatory mediators in serum, and oxidative stress in ovarian samples. Individual treatment groups and combination treatment groups reversed the letrozole-induced alterations in PCOS animals, and more promising results were observed with combination therapy than with individual treatment groups. Further, the therapeutic potential of the combination treatment group was also confirmed by the histological observations in the ovarian samples. The study showed that the combination of ACV and metformin significantly alleviated letrozole-induced PCOS complications in rats. This might have been achieved by mitigating the hormonal imbalance, pro-inflammatory, hyperglycemic, and hyperlipidemic states in serum, and oxidative stress in the ovary samples., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

A 74-year-old woman was diagnosed with invasive breast ductal carcinoma, cT2N0M1 (PUL), stage Ⅳ, and treated with abemaciclib and letrozole. The day after drug administration, the patient developed a fever of 38℃ and dyspnea upon exertion, and was diagnosed with drug-induced pneumonia. Steroid pulse therapy was administered during hospitalization, and the patient was discharged after the dose of prednisolone was gradually reduced. This case shows that, when abemaciclib is administered, drug-induced lung injury can occur within 1 week.

Letrozole (LTZ) is used as first-line treatment for hormone-positive breast cancer (BC) in postmenopausal women. However, its poor aqueous solubility and permeability have reduced its clinical efficacy. Herein, we developed LTZ-nanotransferosomes (LTZ-NT) to address above mentioned issues. The LTZ-NT were optimized statistically using Design Expert ® followed by their characterization via dynamic light scattering (DLS), Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and Differential scanning calorimetry (DSC). The optimized LTZ-NT was incorporated into 1% chitosan-gel to develop LTZ-NTG. Moreover, in vitro drug release and ex vivo permeation of LTZ-NTG were performed and compared with LTZ-dispersion and LTZ-NT. Additionally, skin irritability and histopathology of LTZ-NTG were investigated. Furthermore, in vitro antitumor study of LTZ-NTG was investigated in BC cell lines. The optimized LTZ-NT showed suitable zeta potential (30.4 mV), spherical size (162.5 nm), and excellent entrapment efficiency (88.04%). Moreover, LTZ-NT exhibited suitable thermal behavior and no interactions among its excipients. In addition, LTZ-NTG had an optimal pH (5.6) and a suitable viscosity. A meaningfully sustained release and improved permeation of LTZ was observed from LTZ-NTG. Additionally, LTZ-NTG showed significantly enhanced cell death of MCF-7 and MCC-7 cells. It can be concluded that LTZ-NTG has the potential to deliver chemotherapeutic agents for possible treatment of BC.

Objective: To compare letrozole in combination with gonadotropins versus letrozole monotherapy in ovulation induction and clinical pregnancy among infertile women with polycystic ovarian syndrome (PCOS)., Methods: Several databases were searched for available clinical trials from inception until March 2023. We selected randomized controlled trials (RCTs) that compared sequential letrozole/gonadotropin versus letrozole alone among infertile women who met the Rotterdam criteria for PCOS. RevMan software was used to perform our meta-analysis. Our primary outcomes were ovulation and clinical pregnancy rates. Our secondary outcomes were endometrial thickness, number of mature follicles (diameter ≥ 18 mm), and incidence of miscarriage and ovarian hyperstimulation syndrome (OHSS)., Results: Six RCTs were retrieved with a total number of 723 patients. The ovulation and clinical pregnancy rates were significantly higher among the letrozole/gonadotropin group versus the letrozole monotherapy group (p < 0.001). In addition, there were significant improvements in endometrial thickness and number of mature follicles in the letrozole/gonadotropin group. There were no significant differences between the two groups regarding incidence of miscarriage and ovarian hyperstimulation syndrome., Conclusion: Letrozole in combination with gonadotropin is superior to letrozole alone in improving ovulation induction and clinical pregnancy among PCOS patients. More trials are required to confirm our findings., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Background: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3., Patients and Methods: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint., Results: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed., Conclusions: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study., Methods: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive., Results: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1-2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0-1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002)., Conclusions: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC., Competing Interests: Declaration of competing interest SDC reports consulting for MEDSIR and IQVIA and honoraria from Pierre-Fabre, Novartis, and AstraZeneca. JMPG reports consulting for Roche, Eiasi, Daichii Sankyo, AstraZeneca, Gilead, MSD and Seagen and travel expenses from Roche. MB reports consulting fees from Pfizer, Novartis, Lilly, and Steamline-Menarini; honoraria from Pfizer, Novartis, and Lilly; and trave support from Pfizer. FD reports travel grants for Daichii, Novartis, and Pfizer, and participation in monitor/advisory boards for Daiichi, Seagen, Novartis, Gilead, Lilly, and MSD. MGG reports honoraria from Pfizer, Novartis, and AstraZeneca, travel grants from Lilly, Daiichi-Sankyo, and Pfizer, and participation in monitoring/advisory boards for AstraZeneca, Seagen, and Gilead. MRB reports honoraria from Pfizer, Novartis, AstraZenca, and Daiichi Sankyo. JG reports consulting fees from Novartis, Pfizer, AstraZeneca; honoraria from Novartis; and travel support from Roche and AstraZeneca. EAO reports consulting for AstraZeneca, Daichii, Gilead, MSD, and Seagen; honoraria from AstraZeneca, Daichii, Lilly, MSD, and Seagen; travel support from Daichii, Lilly, Gilead, and AstraZeneca; and participation in monitor/advisory boards for Gilead, AstraZeneca, Seagen, and Dachii. PS reports honoraria from Pfizer, AstraZeneca, Novartis, Roche, Merck, and Boehringer Ingelheim; a consulting role for Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; and institutional grants from Roche, Genentech, Oncogenex, and Novartis. FM reports grants from Roche, Novartis, AstraZeneca, GSK, MSD, Clovis, Vaccibody, Gilead Sciences, and Esai; consulting fees from AstraZeneca, GSK, and Roche; honoraria from AstraZeneca, MSD, Lilly, Pfizer, Novartis, GSK, Clovis, Myriad, Daiich Sankyo, Seagen, Pierre-Fabre, and Agendia; travel support from AstraZeneca, GSK, Pfizer, and Roche; and participation in advisory boards for Palleos and Amgen. JG reports grant/research support from Roche, Eiasi, and Exact Science; honoraria or consultation fees from AstraZeneca, Daiichi, Eisai, Exact Science, Evapharm, GE Healthcare, Gilead, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Sothema and participation in company sponsored speaker's bureaus for Exact Science, Lilly, and Novartis. AS reports grants from Celgene, Roche, Abbvie; travel grants from Celgene, Roche, Pfizer, AstraZeneca, and honoraria from Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen, Pierre Fabre. JA reports trial funding from MEDSIR and consulting for Pfizer, Lilly, and Novartis. PZ reports honoraria from Pfizer, Novartis, Roche, and Pierre Fabre; and travel support from Pfizer, Novartis, Roche, and Lilly. DW reports honoraria from Pfizer, Novartis, AstraZeneca and travel grants from Roche, and Novartis. JC reports consulting for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo.; research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; stock shares for MEDSIR, Nektar Pharmaceuticals, Leuko (relative); Travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead; and Patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/0338368 A1. LICENSED. ALC reports research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo; consulting for Lilly, Roche, Pfizer, and Novartis; participation in speakers' bureaus for Lilly, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, Pfizer, AstraZeneca; and stock or other ownership in MEDSIR and Initia-Research. The remaining authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Water-stable metal-organic frameworks based on UIO-66@NH 2 were synthesized to transport Letrozole into breast cancer cells. The UIO-66@NH 2 nanoparticles had a spherical shape and triangular base pyramid morphology, with a size range of 100-200 nm. Fourier transform infrared spectroscopy confirmed the efficient adsorption of Letrozole on UIO-66@NH 2 . The drug release profile showed a gradual, pH-dependent release of Letrozole from the nanoparticles, with a significant increase in acidic environments, indicating the adaptable release potential of UIO-66@NH 2 @Let in the breast cancer microenvironment. The size and entrapment efficiency were more stable at 4 °C than at 25 °C. To evaluate the cytotoxic effects of UIO-66@NH 2 @Let, MTT assay, gene expression analysis, flow cytometry, reactive oxygen species generation, migration assay, and DAPI staining were performed. Moreover, according to IC 50 results, the incorporation of Letrozole into UIO-66@NH 2 significantly improved its anticancer activity. The results also showed that the developed formulations induced apoptosis through both intrinsic and extrinsic pathways and inhibited cancer progression. The efficacy of the formulations in inducing apoptosis was validated by DAPI staining microscopy and flow cytometry analysis. Therefore, the Letrozole-loaded UIO-66@NH 2 MOFs developed in this study can be considered as a unique and sophisticated anticancer delivery nanosystem with promising in vitro anticancer properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Purpose: AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced/metastatic breast cancer (aBC)., Materials and Methods: In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2- aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety., Results: Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively., Conclusion: The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.

Background: Current standard treatment for metastatic breast cancer (MBC) involves cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy, showing potential in enhancing anti-tumor immune responses., Case Report: This report details a clinical case of MBC where palbociclib was co-administered with letrozole. The integration of allogeneic tumor vaccination to this treatment led to heightened interferon-γ production, expansion of CD8+ and NK cell populations, and positive delayed-type hypersensitivity reactions, indicating successful development of anti-tumor immunity. The induced production of interferon-γ by tumor vaccination was associated with manageable modulation of sensitivity to palbociclib-letrozole therapy. Administration of the BioNTech/Pfizer Covid-19 vaccine compromised the anti-tumor immune response by reducing cytotoxic cell populations and increasing immunosuppressive cytokine production. The patient undergoing combined treatment achieved a progressive-free survival of 42 months., Conclusion: Incorporating active tumor vaccination with CDK4/6 inhibitor therapy presents a feasible approach for metastatic breast cancer. The precise regulation of the microenvironment emerges as a crucial factor and warrants careful consideration., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To evaluate the efficacy of two different regimens of Letrozole, an aromatase inhibitor, in the management of ectopic pregnancy compared to methotrexate., Study Design: This randomized controlled trial was conducted on 88 women diagnosed with ectopic pregnancy with a baseline level of serum beta-human chorionic gonadotropin under 3000 mIU/mL between June 30, 2023, and December 30, 2023, at the Department of Obstetrics and Gynecology of the Vali-e-Asr Hospital affiliated with Tehran University of Medical Sciences. Participants were allocated into either methotrexate (n = 43), 5-day course Letrozole (n = 24), or 10-day course Letrozole (n = 21) treatments. The methotrexate group received a single dose of 50 mg/m 2 dosage intramuscular methotrexate. The 5-day Letrozole group received a 2.5 mg Letrozole tablet three times daily for 5 days, whereas the 10-day Letrozole group received a 2.5 mg Letrozole tablet twice daily for 10 days. The primary outcome was the treatment response, defined as the achievement of a negative serum beta-human chorionic level without the need for additional methotrexate treatment or surgery. The secondary outcomes were the need for additional methotrexate dose or laparoscopic surgery intervention. The trial protocol was prospectively registered in ClinicalTrials.gov with code NCT05918718., Results: The treatment response rates in methotrexate, 5-day Letrozole, and 10-day Letrozole groups were 76.7 %, 75.0 %, and 90.5 %, respectively, with no significant differences between the groups (P-value = 0.358). A total of 10 (23.3 %) patients from the methotrexate group, 3 (12.5 %) from the 5-day Letrozole group, and 2 (9.5 %) from the 10-day Letrozole group required an additional methotrexate dose, with no significant differences between the groups (P-value = 0.307). Furthermore, only 3 (12.5 %) patients, all from the 5-day Letrozole group, were suspected of tubal rupture and underwent surgery (P-value = 0.016)., Conclusion: Our findings suggest Letrozole as a safe alternative to methotrexate in treating stable ectopic pregnancies, with a favorable treatment response rate. However, there is still a need for future larger studies to determine the applicability of Letrozole in the EP management. Also, the non-significant higher effectiveness of the 10-day Letrozole regimen than the 5-day Letrozole group underscores the need for future research to determine the optimal Letrozole regimen for the management of ectopic pregnancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Letrozole, an aromatase inhibitor metabolised via CYP2A6 and CYP3A4/5 enzymes, is used as adjuvant therapy for women with hormone receptor (HR)-positive early breast cancer. The objective of this study was to quantify the impact of CYP2A6 genotype on letrozole pharmacokinetics (PK), to identify non-adherent patients using a population approach and explore the possibility of a relationship between non-adherence and early relapse., Methods: Breast cancer patients enrolled in the prospective PHACS study (ClinicalTrials.gov NCT01127295) and treated with adjuvant letrozole 2.5 mg/day were included. Trough letrozole concentrations (C ss,trough ) were measured every 6 months for 3 years by a validated LC-MS/MS method. Concentration-time data were analysed using non-linear mixed effects modelling. Three methods were evaluated for identification of non-adherent subjects using the base PK model., Results: 617 patients contributing 2534 plasma concentrations were included and led to a one-compartment PK model with linear absorption and elimination. Model-based methods identified 28 % of patients as non-adherent based on high fluctuations of their C ss,trough compared to 3 % based on patient declarations. The covariate analysis performed in adherent subjects revealed that CYP2A6 intermediate (IM) and slow metabolisers (SM) had 21 % (CI95 % = 12 - 30 %) and 46 % (CI95 % = 41 - 51 %) lower apparent clearance, respectively, compared to normal and ultrarapid metabolisers (NM+UM). Early relapse (19 patients) was not associated with model-estimated, concentration-based or declared adherence in the total population (p = 0.41, p = 0.37 and p = 0.45, respectively)., Conclusions: These findings will help future investigations focusing on the exposure-efficacy relationship for letrozole in adjuvant setting., Competing Interests: Declaration of competing interest The authors declare no competing interests to declare that are relevant to the content of this article., (Copyright © 2024. Published by Elsevier B.V.)

What is the effect of a single low-dose recombinant hCG injection after embryo transfer (ET) in letrozole-induced modified natural frozen embryo transfer cycles (mNC-FET)?. An observational study was conducted in the university-affiliated referral clinic between 2022 and 2024. Women aged 18-42 with at least one vitrified blastocyst obtained from the previous cycle(s) were included. Ovulation induction for endometrial preparation was initiated with oral letrozol (5 mg/day) for five days. Ovulation was triggered using 6500 IU rec hCG sc when the leading follicle > 17 mm, endometrial thickness > 7.5 mm, and serum progesterone (P) < 1.5 ng/ml. All women received 30 mg dydrogesterone/day po for additional five-day luteal support. On the 6th day, ET was performed. Based on a quasi-randomized design, a group of women additionally received a half single bolus of (3250 IU) rec hCG (sc) on the morning of 3rd day of ET (hCG group). Women who did not receive additional hCG were assigned as controls. One hundred fifty-four women were detected to be eligible for the study among 2150 initiated FET cycles during the period. Demographic data of the groups, including mean women's age, BMI, serum AMH, and infertility etiologies, were comparable in terms of variables. Mean serum progesterone values and the number of transferred embryos were also similar. A significantly higher ongoing pregnancy/started cycle was documented in the hCG group than in controls (46.7% vs 33.6% respectively, p = 0.03*). A single low-dose hCG injection after ET may improve the OPRs of women in letrozole mNC-FET cycles., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Purpose: To summarize the findings of relevant randomized controlled trials (RCTs) and conduct a meta-analysis to investigate the potential effect of aromatase inhibitors on preventing moderate to severe ovarian hyperstimulation syndrome (OHSS) in infertile women undergoing in vitro fertilization (IVF)., Methods: We searched for relevant RCTs in electronic databases, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (from inception to August 2023). In addition, we manually searched the related reviews and reference lists of included studies for further relevant studies. We included RCTs where aromatase inhibitors prescribed either during controlled ovarian stimulation (COS) or in early luteal phase. The meta-analysis was performed using RevMan 5.4.1 software. The primary outcome was the incidence of moderate to severe OHSS. A descriptive analysis was conducted in cases where a meta-analysis was not feasible due to heterogeneity or lack of comparable data., Results: 2858 records were retrieved and 12 RCTs were finally included. Letrozole was administered in the treatment group during COS in seven RCTs, whereas in the early luteal phase in five RCTs. Compared with the control group, the risk of moderate to severe OHSS significantly reduced by 55% in the letrozole group (RR 0.45, 95% CI 0.32 to 0.64, I 2  = 0%, 5 RCTs, 494 patients). Moreover, serum estradiol (E2) levels on hCG trigger day significantly decreased with the administration of letrozole during COS (MD -847.23, 95% CI -1398.00 to -296.47, I 2  = 93%, 5 RCTs, 374 patients). And serum E2 levels on the 4th, 5th and 7th to 10th day after hCG trigger were also significantly lower than those in the control group when letrozole was administered in the early luteal phase., Conclusions: Patients with high risk of OHSS probably benefit from letrozole, which has been revealed to reduce the incidence of moderate to severe OHSS by this systematic review. However, the very limited number of participants and the quality of the included studies does not allow to recommend letrozole for the prevention of severe OHSS., (© 2024. The Author(s).)

Background: In the progestin-primed ovarian stimulation protocol, the oral administration of medroxyprogesterone acetate has been observed to effectively inhibit the LH surge during ovarian stimulation in patients experiencing infertility. Nevertheless, the use of utilizing medroxyprogesterone acetate during ovarian stimulation can result in more pronounced pituitary suppression, potentially necessitating increased doses of gonadotropins and extended treatment durations. Therefore, it is necessary to determine the optimal dose of medroxyprogesterone acetate, aiming to use relatively lower concentrations of medroxyprogesterone acetate to effectively and safely suppress early LH surges., Method: This retrospective cohort study included 710 patients who underwent cycles of in vitro fertilization or intracytoplasmic sperm injection and were subjected the progestin-primed ovarian stimulation protocol utilizing letrozole between from 1st January 2021 to 31st December 2021. The study population was divided into low, medium, and high concentration groups based on the daily dosage of medroxyprogesterone acetate.The primary focus of this investigation was on the cumulative live birth rate. Secondary outcomes encompassed the occurrence of a premature surge in luteinizing hormone, the quantity of retrieved oocytes, viable embryos, and high-quality embryos, as well as clinical pregnancy rate, abortion rate, ectopic pregnancy rate, and multiple pregnancy rate., Results: In this study, significant differences were observed among three groups in various parameters including body mass index, baseline levels of Anti-Müllerian hormone and luteinizing hormone, antral follicle count, total dose of gonadotropin, and duration of gonadotropin administration (p<0.05). The number of oocytes and viable embryos were significantly higher in medium group and higher than those in the low dose group. Following adjustments for confounding factors related to medroxyprogesterone acetate for various outcome measures, we conducted multiple regression analysis to investigate the independent effects of daily medroxyprogesterone acetate dosage within the combined progestin-primed ovarian stimulation and letrozole protocol. Following multivariable regression analysis, no disparities were found in embryo characteristics (number of oocytes retrieved, number of available embryos, number of high-quality embryos) or pregnancy outcomes (clinical pregnancy rate, cumulative live birth rate) among the three groups., Conclusion: Progestin-primed ovarian stimulation with letrozole using different dose of medroxyprogesterone acetate per day was comparable in terms of the number of oocytes retrieved, the number of high-quality embryos, clinical pregnancy rate and cumulative live birth rate after frozen embryo transfer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Shen, He, Wang and Sun.)

Objective: Our objective was to investigate the efficacy of letrozole co-treatment in an antagonist protocol for infertile women with polycystic ovary syndrome (PCOS)., Patients and Methods: This retrospective cohort study included infertile women with PCOS undergoing IVF/ICSI with and without letrozole co-treatment in an antagonist protocol from 2007-2021 at Shanghai Ninth People's Hospital (Shanghai, China). A total of 1559 participants were enrolled, with 1227 women in the antagonist group and 332 women in the letrozole co-treatment group. Propensity score-based patient-matching model was conducted to balance covariates between the groups. The primary outcome was the number of retrieved oocytes, with secondary outcomes including endocrine parameters, ovarian stimulation outcomes, pregnancy outcomes, and obstetrical and neonatal complications., Results: Letrozole co-treatment induced significant changes in hormonal regulation, increased the percentage of large follicles, and resulted in fewer retrieved oocytes ( P < 0.05). However, there was no negative impact on the number of usable embryos or good-quality embryos ( P > 0.05). The live birth rates following fresh embryo transfer were comparable between the letrozole and control groups (single embryo transfer: 28.9% vs 29.7%, P > 0.05; double embryo transfer: 37.3% vs 45.6%, P > 0.05). Additionally, there were no significant differences between the two groups in the live birth rate per patient after frozen embryo transfer and the cumulative live birth rate ( P > 0.05). No significant differences in obstetrical and neonatal complications were observed between the groups ( P > 0.05)., Conclusion: The addition of letrozole to the antagonist protocol for women with PCOS undergoing IVF induces a higher percentage of large follicles during oocyte retrieval, while reducing the overall number of retrieved oocytes. Moreover, the use of letrozole demonstrates comparable clinical outcomes following embryo transfers. These findings highlight the potential application of letrozole in an antagonist protocol for women with PCOS., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Lin et al.)

Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility in women. Animal models are widely used to study the etiologic mechanisms of PCOS and for related drug development. Letrozole-induced mouse models replicate the metabolic and reproductive phenotypes of patients with PCOS. The traditional method of letrozole treatment in PCOS mice requires daily dosing over a certain period, which can be labor-intensive and cause significant stress to the mice. This study describes a simple and effective method for inducing PCOS in mice by implanting a controlled letrozole-releasing mini-pump. A mini-pump capable of stable, continuous release of a quantitative amount of letrozole was fabricated and implanted subcutaneously in mice under anesthesia. This study demonstrated that the mouse model successfully mimicked PCOS features after letrozole mini-pump implantation. The materials and equipment used in this study are readily available to most laboratories, requiring no special customization. Collectively, this article provides a unique, easy-to-perform method for inducing PCOS in mice.

Introduction: Palbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses., Materials and Methods: We conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70-74 and ≥ 75 years)., Results: Of the 90 participants (median age 74 years [70-87]) enrolled, 75.6% (95% confidence interval [CI], 65.4-84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70-74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%-22.5%])., Discussion: Palbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70-74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults., Clinicaltrials: gov:NCT03633331., (Published by Elsevier Ltd.)

Objective: There have been rare data on letrozole for height improvement in girls. This study aimed to clarify the efficacy and safety of combination therapy with recombinant human growth hormone (rhGH), GnRHa, and letrozole in improving the height of girls with short stature and advanced bone age., Methods: This was a hospital record-based retrospective study. Follow-up was conducted on girls with short stature who received treatment with rhGH, GnRHa, and letrozole in our hospital. The treatment group included a total of 29 participants. Before treatment, the mean age of the patients was 11.17 years, and the mean treatment duration was 17.31 months. The control group consisted of 29 short-statured girls who received rhGH/GnRHa treatment, with the mean age and treatment duration of 12.43 years and 16.59 months, respectively., Results: The predicted adult heights (PAHs) before and after treatment were 155.38 and 161.32 cm (P < .001). The ΔPAH in the treatment group was 4 cm higher than that in the control group (5.85 vs 1.82 cm, P < .001). Significant differences were noted in the height standard deviation scores of bone age (P < .001) and chronological age (P = .003) before and after treatment. There was an increasing body mass index during therapy (P = .039). The height gain was 8.71 ± 4.46 cm, and the growth rate was 6.78 ± 3.84 cm per year., Conclusion: Combined treatment with GH, GnRHa, and letrozole can enhance the adult height and PAH in short-statured girls, and no significant side effects have been reported., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Worldwide, infertility affects about 15% of reproductive-age couples. In many cases, infertility can't be treated, however new treatment options with promising value have been involved in recent clinical trials. The aim of this clinical trial was to evaluate the impacts of adding coenzyme Q10 (CoQ10) to letrozole on the results of spermiogram and sex hormone tests in men diagnosed with idiopathic oligoasthenoteratozoospermia (iOAT) syndrome, which is a type of male defective spermatogenesis of unknown etiology. Methods: This randomized, open-label, parallel two-arm interventional study included 67 adult male patients aged 18-60 years with a confirmed diagnosis of iOAT syndrome recruited from The High Institute for Infertility Diagnosis & Assisted Reproduction Technologies/Nahrain University. Patients were randomly separated into two groups, Group A included 29 patients treated with letrozole 2.5 mg tablet orally twice a week, Group B included 38 patients treated with a combination of letrozole 2.5 mg tablet orally twice a week plus CoQ10 400 mg per day. Both groups completed treatment for three months. Semen samples, serum follicle-stimulating hormone (FSH), estradiol (E 2 ), and testosterone (T) were analyzed at day one, and at the end of month one, two and three. Results: Both groups showed that sperm concentration, normal morphology, total sperm count and motility, serum testosterone and FSH levels, and T/E 2 ratio were significantly increased, while estradiol levels significantly decreased after three months of treatment. Seminal fluid volume changed significantly in group A only. In comparing between the two groups, all measured parameters, apart from sperm motility and FSH level, demonstrated a significant difference after three months of treatment, while sperm volume reached significant value after only two months of therapy. Conclusions: CoQ10 as adjuvant treatment to letrozole effectively improved most of the tested sperm parameters in Iraqi men with iOAT. Registration: ClinicalTrials.gov ( NCT05847257, May 6, 2023)., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Fadhil EB et al.)

Background: Women with polycystic ovary syndrome (PCOS) are usually selected to undergo an ovulation induction regimen or a programmed regimen for endometrial preparation in the frozen-thawed embryo transfer (FET) during their IVF/ICSI treatment. The programmed regimen permits flexible scheduling of embryo transfer but requires long-term usage of exogenous estrogen and higher dosages of luteal support while the letrozole ovulation regimen needs lower dosages of luteal support only. Recently, multiple studies have shown that the letrozole ovulation regimen can improve pregnancy outcomes of FET in women with PCOS compared with the programmed regimen. However, most of these studies are retrospective, and prospective studies are urgently needed the evidence from the perspective study is insufficient., Methods/design: We are undertaking a multicentre, randomized, controlled clinical trial of an endometrial preparation regimen for FET in women with PCOS. The eligible women are randomly assigned to either the letrozole ovulation regimen or the programmed regimen for endometrial preparation. The primary outcome is the clinical pregnancy rate., Discussion: The results of this study will provide evidence for whether the letrozole ovulation regimen for endometrial preparation could improve pregnancy outcomes in PCOS women undergoing FET., Trial Registration: Chinese Clinical Trial Registry ChiCTR2200062244. Registered on 31 July 2022., (© 2024. The Author(s).)