A comparison of letrozole regimens for ovulation induction in women with polycystic ovary syndrome.

Objective: To determine the optimal letrozole regimen for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS). Design: Retrospective cohort study. Setting: Single academic fertility clinic from 2015-2022. Patients: A total of 189 OI cycles in 52 patients with PCOS. Interventions: Patients were prescribed 1 of 4 letrozole regimens (group 1: 2.5 mg for 5 days, group 2: 2.5 mg for 10 days, group 3: 5 mg for 5 days, and group 4: 5 mg for 10 days). Main outcome measures: The primary outcome was ovulation, and secondary outcomes included multifollicular development, and clinical pregnancy rate, which were analyzed with binary logistic regression. Kaplan-Meier cumulative response curves and a Cox proportional hazard regression model were used for time-dependent analyses. Results: Mean age was 30.9 years (standard deviation [SD], 3.6) and body mass index was 32.1 kg/m2 (SD, 4.0). Group 2 (odds ratio [OR], 9.12; 95% confidence interval [CI], 1.92-43.25), group 3 (OR, 3.40; 95% CI, 1.57-7.37), and group 4 (OR, 5.94; 95% CI, 2.48-14.23) had improved ovulation rates after the starting regimen as compared with group 1. Cumulative ovulation rates exceeded 84% in all groups, yet those who received 5 mg and/or 10 days achieved ovulation significantly sooner. Multifollicular development was not increased in groups 2-4 as compared with group 1. Groups 2-4 also demonstrated improved time to pregnancy. Conclusions: Ovulation rates are improved when starting with letrozole at 5 mg and/or a 10-day extended course as compared with the frequently-used 2.5 mg for 5 days. This may shorten time to ovulation and pregnancy.

The Efficacy of Letrozole Co-Treatment in an Antagonist Protocol for Women with Polycystic Ovary Syndrome Undergoing IVF: A Retrospective Study.

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.

Efficacy of letrozole for the treatment of tubal ectopic pregnancy: A meta-analysis.

BACKGROUND: Tubal ectopic pregnancy (EP) is a life-threatening condition, especially if undiagnosed or misdiagnosed, tipically in low income countries and/or where women have limited access to health care. The current management protocol of tubal EP consists of either surgical management, or medical management with methotrexate. Recent studies, while few, have suggested that letrozole, an aromatase inhibitor, may play a role in the medical treatment of tubal EP. OBJECTIVES: To evaluate the effectiveness of letrozole alone in the medical treatment of tubal EP. SEARCH STRATEGY: Electronic databases were searched until 31 December 2023. SELECTION CRITERIA: Retrospective or prospective studies reporting the treatment of tubal EP with letrozole alone were considered eligible for inclusion. DATA COLLECTION AND ANALYSIS: Pooled results were expressed as OR with 95 %CI. Heterogeneity was assessed using Higgins I2. Subgroup analysis was performed to compare outcomes according to time after intervention. Subgroup differences were checked through χ2 test. RESULTS: A total of 152 patients were included. Seventy-nine patients (51.97 %) were treated with letrozole, 39 patients (16.54 %) with methotrexate, and 34 patients (31.49 %) underwent surgical treatment. Pooled data analysis supports the consistency of the effect of letrozole in reducing ß-hCG over time at a comparable rate among studies, and that treatment with letrozole is superior to surgery and has the same efficacy as methotrexate. However, all the included studies were judged at high risk of bias in terms of study design, sample representativeness, and sampling technique. Furthermore, short and long term side effects were not reported in any of the included studies. CONCLUSIONS: Letrozole is a promising alternative to methotrexate and surgical therapy in the treatment of tubal EP. Although this meta-analysis suggests efficacy and low hazard of the drug and encourages its application, the data available today remain extremely sparse, which weakens any claims that can be made, and is not sufficient to assert that letrozole is safe and effective in the treatment of EPs. There is an absolute need for randomized studies with accurate patient selection, fixed doses, large sample sizes, and reporting of short- and long-term side effects to refute or confirm this assumption.

Comparing the effectiveness of letrozole versus methotrexate for treatment of ectopic pregnancy: A randomized controlled trial.

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/m2 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.

Evaluation of birth outcomes, congenital anomalies and neonatal complications of singletons born to infertile women treated with letrozole: A retrospective cohort study.

At present, safety of letrozole administration as an ovulation-inducing drug still remains controversial. Investigation of the safety of letrozole use for the induction of ovulation in the Chinese population is scant. The present study aimed to fill this gap. Data concerning mothers using letrozole and birth outcomes of their singleton offspring were collected as the letrozole group (n=194), equivalent data from mothers using non-letrozole drugs and their singleton offspring were included as the non-letrozole group (control, n=154). Birth outcomes, congenital anomalies and neonatal complications were compared and analyzed between the two groups. Univariate analysis, Spearman's rank correlation analysis and the logistic regression model were utilized. For birth outcomes, the percentage of caesarean section deliveries in the letrozole group was lower than the non-letrozole group (43.8 vs. 56.4%, P=0.019). For congenital anomalies, no significant difference was found between the two groups (all P>0.05). The statistical P-value for the correlation between the maternal use of letrozole and neonatal complications was marginal (P=0.051). Results from the logistic regression analysis confirmed that maternal use of letrozole was not a significant contributor for neonatal complications, independent of statistical adjustment [crude odds ratio (OR), 1.436; 95% confidence interval (CI), 0.803-2.569; P=0.223 vs. adjusted OR, 1.406; 95% CI, 0.748-2.643; P=0.290). The results of the present study suggested that maternal use of letrozole for ovulation induction does not associate with poorer birth outcomes or increased risk of congenital anomalies and neonatal complications.

Bilateral tubal ectopic pregnancy following induction ovulation can be missed in emergent ultrasonography: Case report.

INTRODUCTION: Bilateral tubal ectopic pregnancy (BTP) is a rare and potentially life-threatening condition that is, often challenging to diagnose preoperatively. PRESENTATION OF CASE: We present a case of BTP in a 25-year-old primigravid woman with a history of infertility due to polycystic ovarian syndrome. She was receiving letrozole when she presented with severe abdominal pain and vaginal bleeding. Initial evaluation revealed a ruptured ectopic pregnancy in the right fallopian tube, prompting an emergency laparotomy. During surgery, a second intact ectopic mass was discovered in the left fallopian tube, highlighting the diagnostic complexity of BTP. Management involved a salpingectomy on the right side and salpingostomy on the left to preserve fertility. DISCUSSION: This case underscores the importance of considering BTP in the differential diagnosis of ectopic pregnancies and the necessity for thorough preoperative imaging studies, namely ultrasonography and surgical exploration, to prevent missed diagnoses. CONCLUSION: BTP is a rare and challenging clinical entity that requires a comprehensive approach to diagnosis and management. Early recognition, prompt intervention, and close surveillance are essential to mitigate the risk of maternal morbidity and mortality associated with this condition.

Characteristics of the Vasa Gene in Silurus asotus and Its Expression Response to Letrozole Treatment.

The identification and expression of germ cells are important for studying sex-related mechanisms in fish. The vasa gene, encoding an ATP-dependent RNA helicase, is recognized as a molecular marker of germ cells and plays a crucial role in germ cell development. Silurus asotus, an important freshwater economic fish species in China, shows significant sex dimorphism with the female growing faster than the male. However, the molecular mechanisms underlying these sex differences especially involving in the vasa gene in this fish remain poorly understood. In this work, the vasa gene sequence of S. asotus (named as Savasa) was obtained through RT-PCR and rapid amplification of cDNA end (RACE), and its expression in embryos and tissues was analyzed using qRT-PCR and an in situ hybridization method. Letrozole (LT) treatment on the larvae fish was also conducted to investigate its influence on the gene. The results revealed that the open reading frame (ORF) of Savasa was 1989 bp, encoding 662 amino acids. The SaVasa protein contains 10 conserved domains unique to the DEAD-box protein family, showing the highest sequence identity of 95.92% with that of Silurus meridionalis. In embryos, Savasa is highly expressed from the two-cell stage to the blastula stage in early embryos, with a gradually decreasing trend from the gastrula stage to the heart-beating stage. Furthermore, Savasa was initially detected at the end of the cleavage furrow during the two-cell stage, later condensing into four symmetrical cell clusters with embryonic development. At the gastrula stage, Savasa-positive cells increased and began to migrate towards the dorsal side of the embryo. In tissues, Savasa is predominantly expressed in the ovaries, with almost no or lower expression in other detected tissues. Moreover, Savasa was expressed in phase I-V oocytes in the ovaries, as well as in spermatogonia and spermatocytes in the testis, implying a specific expression pattern of germ cells. In addition, LT significantly upregulated the expression of Savasa in a concentration-dependent manner during the key gonadal differentiation period of the fish. Notably, at 120 dph after LT treatment, Savasa expression was the lowest in the testis and ovary of the high concentration group. Collectively, findings from gene structure, protein sequence, phylogenetic analysis, RNA expression patterns, and response to LT suggest that Savasa is maternally inherited with conserved features, serving as a potential marker gene for germ cells in S.asotus, and might participate in LT-induced early embryonic development and gonadal development processes of the fish. This would provide a basis for further research on the application of germ cell markers and the molecular mechanisms of sex differences in S. asotus.

Ameliorative potential of rosmarinic acid in a rat model of polycystic ovary syndrome: Targeting MCP-1 and VEGF: A histological, immunohistochemical, and biochemical study.

Polycystic ovary syndrome (PCOS) is a multidisciplinary endocrinopathy that affects women of reproductive age. It is characterized by menstrual complications, hyperandrogenism, insulin resistance, and cardiovascular issues. The current research investigated the efficacy of rosmarinic acid in letrozole-induced PCOS in adult female rats as well as the potential underlying molecular mechanisms. Forty female rats were divided into the control group, the rosmarinic acid group (50 mg/kg per orally, po) for 21 days, PCOS group; PCOS was induced by administration of letrozole (1 mg/kg po) for 21 days, and rosmarinic acid-PCOS group, received rosmarinic acid after PCOS induction. PCOS resulted in a marked elevation in both serum luteinizing hormone (LH) and testosterone levels and LH/follicle-stimulating hormone ratio with a marked reduction in serum estradiol and progesterone levels. A marked rise in tumor necrosis factor-α (TNF-α), interleukin-1ß, monocyte chemotactic protein-1, and vascular endothelial growth factor (messenger RNA) in the ovarian tissue was reported. The histological analysis displayed multiple cystic follicles in the ovarian cortex with markedly thin granulosa cell layer, vacuolated granulosa and theca cell layers, and desquamated granulosa cells. Upregulation in the immune expression of TNF-α and caspase-3 was demonstrated in the ovarian cortex. Interestingly, rosmarinic acid ameliorated the biochemical and histopathological changes. In conclusion, rosmarinic acid ameliorates letrozole-induced PCOS through its anti-inflammatory and antiangiogenesis effects.

Effective Ki-67 Reduction by Pre-Surgery Short-Term Administration of Letrozole in (Hormone-Positive) Breast Cancer.

Background & Objective: Antigen Ki-67 (histone-based nuclear protein) is a static marker of tumor cell proliferation and growth and is commonly measured to indicate the effect of treatment in breast cancer patients. This single-arm trial study aimed to evaluate the effect of short-term endocrine therapy (letrozole) on Ki-67 levels in menopausal women with early hormone-positive breast cancer who were referred to two university hospitals. Methods: Patients with a pre-treatment Ki67 of 5% or less were excluded from the study. Participants (n=25) received oral letrozole (2.5 mg daily) seven days before surgery. Ki-67% on both biopsies and the surgical specimens were measured and compared. Results and Conclusion: The mean age of patients was 62±9.4 (48-83 years). Our result indicated that pre-surgery consumption of letrozole for hormone-positive breast cancer can significantly decrease the of Ki-67 labeling index (23.24±9.74 vs. 16.92±9.55, P=0.001 by paired t-test), with no drug-related adverse events.

Lasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer.

BACKGROUND: Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as well as by ER-independent signaling pathways. The breast ER antagonist lasofoxifene, alone or combined with palbociclib, elicited antitumor activities in a xenograft model of ER + metastatic breast cancer (mBC) harboring ESR1 mutations. The current study investigated the activity of LAS in a letrozole-resistant breast tumor model that does not have ESR1 mutations. METHODS: Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary duct inguinal glands of NSG mice (MIND model; 6 mice/group). Mice were randomized to vehicle, lasofoxifene ± palbociclib, fulvestrant ± palbociclib, or palbociclib alone 2-3 weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. The experiment was repeated with the same design and 8-9 mice in each treatment group. RESULTS: Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene ± palbociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus palbociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene ± palbociclib. The lasofoxifene + palbociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment. CONCLUSIONS: In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus palbociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.

Story of 20 Years of Triumph: A Case Report of Two Patients With Stage IV Granulosa Cell Tumor of the Ovary.

Ovarian granulosa cell tumors (GCTs) are rare neoplasms with a unique incidence pattern peaking in postmenopausal women. This case report presents two instances of stage 4 recurrent adult GCTs with a prolonged 20-year follow-up. Patient 1, diagnosed at 54 years, experienced multiple recurrences managed through surgery, hormonal therapy, and chemotherapy, culminating in hepatocellular carcinoma. Patient 2, diagnosed at 67 years, underwent various treatments, including surgery, chemotherapy, and hormonal therapy, demonstrating disease stability. Despite the generally favorable prognosis, these cases highlight the challenges of managing recurrent GCTs, emphasizing the need for tailored therapeutic approaches.

Enhancing the efficacy of letrozole-loaded PEGylated nanoliposomes against breast cancer cells: In vitro study.

Considering its overall impact on human health, letrozole (Let) has been described as having significant efficacy that could be improved by developing drug delivery systems. Considering the side effects of Let, this study aims to encapsulate Let in liposomes and PEGylated liposome nanoparticles (Lipo-Let-PEG) and evaluate the cytotoxic effects on the MCF-7 breast cancer cell line. For this purpose, the Lipo-Let-PEG formulation was designed and characterized by SEM, DLS, and FTIR methods, and the drug release from the optimized formulation and the stability of the optimized Lipo-Let-PEG were measured. Furthermore, the cytotoxicity and apoptotic studies were performed using MTT assay and flow cytometric analysis. According to the experimental data, the vesicle size and EE% were 170.05 ± 4.15 nm and 87.21 ± 1.36 %, respectively. The cumulative release from Lipo-Let-PEG at pH 5.4 and 7.4 was also approximately 60 % and 50 %, respectively. MTT results showed that Lip-Let-PEG produced more drug cytotoxicity than Lip-Let against MCF-7 cancer cells and was more compatible with normal cells. The results of apoptosis and cell cycle arrest using flow cytometry show that Lipo-Let-PEG caused the most significant increase in apoptotic rates and cell cycle arrest in cancer cells compared to other treated groups. In conclusion, Lipo-Let-PEG can be used as an anticancer agent by arresting cell cycle progression and inducing apoptosis, which can be applied in future studies to prevent breast cancer development.

Identification of non-adherence to adjuvant letrozole using a population pharmacokinetics approach in hormone receptor-positive breast cancer patients.

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 (Css,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 Css,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.

Adding Letrozole to Growth Hormone and Gonadotropin-Releasing Hormone Analog Increases Height in Girls With Short Stature: A Hospital Record-Based Retrospective Study.

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.

A highly sensitive first derivative synchronous spectrofluorimetric approach for the simultaneous analysis of the anti-breast cancer co-administered drugs, letrozole and tramadol in dosage forms and human plasma at nanogram levels.

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.

Apelin receptor modulation mitigates letrozole-induced polycystic ovarian pathogenesis in mice.

AIMS: Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis. METHODS: The current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks. KEY FINDINGS: The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary. SIGNIFICANCE: Despite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.

Fisetin mitigates letrozole-induced polycystic ovarian syndrome in rats: crosstalk of AMPK/PI3K/AKT-mediated-Nrf2 antioxidant defense mechanism and the inflammasome NLRP3/NF-κB P65/IL-1ß signaling pathways.

Polycystic ovarian syndrome (PCOS) is a highly prevalent condition affecting reproductive-aged women, causing insulin resistance, hyperandrogenism, weight gain, and menstrual problems. The present study intended to investigate the potential role of fisetin (FT) in letrozole (LZ)-induced PCOS in adult female rats and the possible mechanism underlying its action. PCOS was induced by oral administration of LZ (1 mg/kg) for 21 days. Treated rats received FT (1.25 or 2.5 mg/kg) orally once daily for 14 consecutive days. Following the experimental duration, blood samples and ovary tissues were isolated and preserved for biochemical and histopathological examinations. The results revealed that LZ-induced PCOS led to significant abnormalities in sex hormones and metabolic parameters. Additionally, it initiated an inflammatory cascade, evidenced by activation of the NF-κB p65/IL-1ß and AMPK/PI3K/AKT pathways, alongside downregulation of Nrf2 ovarian gene expression and NLRP3 inflammasome activity, which enhanced the production of proinflammatory cytokines. FT demonstrated its beneficial impacts by restoring hormonal disturbance and reversing the imbalanced metabolic parameters. Moreover, FT increased the mRNA of ovarian Nrf2 levels and suppressed the up-regulated inflammatory IL-1ß/NF-κB p65 signaling pathway, consequently alleviating the elevated levels of ovarian NLRP3. The histopathological examination also confirmed that FT has a beneficial effect in ameliorating PCOS, consistent with the aforementioned parameters. Finally, the present results demonstrated that FT ameliorates LZ-induced PCOS through the intricate interplay between the AMPK/PI3K/AKT-mediated Nrf2 antioxidant defense mechanism and the regulation of the inflammasome NLRP3/NF-κB p65/IL-1ß signaling pathways.

Protective Potential of Methanol Extract of Drymaria cordata Willd. ex Schult (MEDC) on Letrozole-Induced Polycystic Ovary Syndrome Via Modulation of Apoptotic Markers, Sex Hormones and Antioxidant Status in Rat Model.

Polycystic ovary syndrome (PCOS) is a gynecological disorder among reproductive-aged women and a major cause of infertility. Different treatment options are being employed but with side effects. This has mandated alternative treatment options, especially complementary therapy. This study therefore investigated the possible protective effects of methanol extract of Drymaria cordata in Letrozole-induced PCOS. The plant is folklorically used in the treatment of diverse ailments including PCOS, fibroids, uterine/ovarian/breast tumors, and cancers. Forty-eight female Wistar rats were acclimatized and initially divided into two groups: group I(control group) and group II(PCOS group). PCOS was induced by the oral administration of letrozole/high-fat diet for 21 days. After the induction, the PCOS group was sub-divided into four groups (n = 4): group II (positive control with PCOS), group III (MET 2mg/kg), group IV (MEDC 200mg/kg), and group V (MEDC 400mg/kg). Rats were orally treated with MET and MEDC for six weeks after the PCOS induction. At the end of the experimental period, blood samples were collected, sera were separated, mitochondria were isolated, and the mPT, some apoptotic biomarkers, hormonal and lipid profiles, and oxidative stress markers were determined. Ovarian histological evaluation and GC-MS analysis of MEDC were carried out. There was no significant mPT pore opening in the PCOS (untreated) group. However, treatments with MEDC caused significant mPT pore opening, upraised caspase 9, caspase 3, and Bax, and decreased anti-apoptotic Bcl-2 levels. The MEDC treatments restored the hormonal and lipid profiles, increased the levels of GSH-Px and SOD and decreased TBARS. Histological examination revealed resolved ovarian cysts and improved follicular growth with MEDC treatments. Comparable results were observed for both MEDC and metformin. The GC-MS analysis revealed the presence of some major pharmacologically relevant compounds. These findings suggest that MEDC contains phytochemicals that can protect against letrozole-induced PCOS possibly by normalizing the impaired hormonal balance, restoring the lipid profile, and improving the antioxidant milieu of the system.

Case report: Response to everolimus in a patient with platinum resistant, high grade serous ovarian carcinoma with biallelic TSC2 inactivation.

Background: Patients with platinum-resistant recurrent high grade serous ovarian carcinoma have poor outcomes and limited treatment options. Case presentation: We present a case of a 48-year-old woman with platinum-resistant high grade serous ovarian carcinoma harboring the pathogenic TSC2 R611Q variant with concomitant single copy loss of TSC2 (suggesting biallelic TSC2 inactivation) identified in targeted tumor sequencing. The patient was treated with the mTOR inhibitor everolimus, with an excellent response by imaging and a marked decrease in CA125; she remained on everolimus for 19 months until she developed progressive disease. Conclusions: While mTOR inhibition is frequently used in tumors associated with tuberous sclerosis complex (TSC), such as lymphangioleiomyomatosis and malignant perivascular epithelioid cell tumors, this is the first case of a patient with ovarian cancer harboring TSC1/2 mutations who responded to mTOR inhibition. This case highlights the utility of targeted DNA sequencing in the management of ovarian carcinoma and demonstrates the value of tumor-agnostic targeted therapies.

Tumor lysis syndrome following letrozole for locally advanced breast cancer: a case report.

BACKGROUND: Letrozole, an aromatase inhibitor, is used to treat breast cancer in postmenopausal women. Tumor lysis syndrome (TLS) is a complication that can trigger multiple organ failure caused by the release of intracellular nucleic acids, phosphate, and potassium into the blood due to rapid tumor cell disintegration induced by drug therapy. TLS is uncommon in solid tumors and occurs primarily in patients receiving chemotherapy. Herein, we report a rare occurrence of TLS that developed in a patient with locally advanced breast cancer following treatment with letrozole. CASE PRESENTATION: An 80-year-old woman with increased bleeding from a fist-sized left-sided breast mass presented to our hospital. Histological examination led to a diagnosis of invasive ductal carcinoma of the luminal type. The patient refused chemotherapy and was administered hormonal therapy with letrozole. Seven days after letrozole initiation, she complained of anorexia and diarrhea. Blood test results revealed elevated blood urea nitrogen (BUN) and creatinine (Cr) levels, and she was admitted to our hospital for intravenous infusions. On the second day after admission, marked elevations of LDH, BUN, Cr, potassium, calcium, and uric acid levels were observed. Furthermore, metabolic acidosis and prolonged coagulation capacity were observed. We suspected TLS and discontinued letrozole, and the patient was treated with hydration, febuxostat, and maintenance hemodialysis. On the third day after admission, her respiratory status worsened because of acute respiratory distress syndrome associated with hypercytokinemia, and she was intubated. On the fourth day after admission, her general condition did not improve, and she died. CONCLUSIONS: Although TLS typically occurs after chemotherapy initiation, the findings from the present case confirm that this syndrome can also occur after hormonal therapy initiation and should be treated with caution.