Anastrozole Research Articles

Improving the targeting and therapeutic efficacy of anastrazole for the control of breast cancer: In vitro and in vivo characterization

Anastrazole (ASZ) is an effective aromatase inhibitor that is used for breast cancer treatment. Nevertheless, ASZ’s effectiveness is diminished due to its low water solubility, unregulated release, absence of targeting, and inadequate patient compliance. The goal of the research was to create a hydrogel formulation of ASZ-loaded invasomes (ALI) to enhance the solubility, permeability, targeting, and efficacy of ASZ while also sustaining its release for treatment of breast cancer. The optimized ALI formulation was determined to be 3%w/v phospholipid, 0.15%w/v cholesterol, 3%v/v ethanol, and 1 %v/v cineole based on the results of the pre-formulation study. After conducting in vitro characterization of the optimum formulation, it was combined with carbopol for in vivo examination of its anti-tumor efficacy in a rat model of 7, 12-dimethylbenzanthracene. Compared to free ASZ, ALI hydrogel increased its penetration by 10.67 times and prolonged its release by 64.02%. Compared to the control positive group, ALI hydrogel reduced tumor volume by 99.19% and mortality by 10.93%. The anti-tumor effect of the ALI hydrogel was demonstrated by its ability to accumulate more ASZ in tumors and reduce hypercellular tumors. Overall, transdermal ALI hydrogel shows potential as a promising approach for treating breast cancer.

A Positive Feedback Loop Exists between Estradiol and IL-6 and Contributes to Dermal Fibrosis.

Systemic sclerosis (SSc) is characterized by dermal fibrosis with a female predominance, suggesting a hormonal influence. Patients with SSc have elevated interleukin (IL)-6 levels, and post-menopausal women and older men also have high estradiol (E2) levels. In the skin, IL-6 increases the enzymatic activity of aromatase, thereby amplifying the conversion of testosterone to E2. Therefore, we hypothesized that an interplay between E2 and IL-6 contributes to dermal fibrosis. We used primary dermal fibroblasts from healthy donors and patients with diffuse cutaneous (dc)SSc, and healthy donor skin tissues stimulated with recombinant IL-6 and its soluble receptor (sIL-6R) or E2. Primary human dermal fibroblasts and tissues from healthy donors stimulated with IL-6+sIL-6R produced E2, while E2-stimulated dermal tissues and fibroblasts produced IL-6. Primary dermal fibroblasts from healthy donors treated with IL-6+sIL-6R and the aromatase inhibitor anastrozole (ANA) and dcSSc fibroblasts treated with ANA produced less fibronectin (FN), type III collagen A1 (Col IIIA1), and type V collagen A1 (Col VA1). Finally, dcSSc dermal fibroblasts treated with the estrogen receptor inhibitor fulvestrant also generated less FN, Col IIIA1, and Col VA1. Our data show that IL-6 exerts its pro-fibrotic influence in human skin in part through E2 and establish a positive feedback loop between E2 and IL-6.

Protective roles of some natural and synthetic aromatase inhibitors in testicular insufficiency caused by Bisphenol A exposure

ABSTRACT In our study, the protective role of synthetic aromatase inhibitors anastrozole (ANS), letrozole (LTZ) and exemestane (EXM) and natural aromatase inhibitors resveratrol (RSV) and apigenin (APG) against testicular failure caused by exposure to Bisphenol A (BPA) was investigated. The epididymal sperm concentration, sperm motility and sperm morphology were determined. Oxidative stress and inflammatory response parameters were examined and histological examinations were performed in testicular tissues. Our results revealed that BPA exposure decreased serum testosterone and estrogen levels, increased FSH and LH levels (p < 0.05). BPA has been found to increase oxidative stress and inflammatory response and disrupt the histological structure. Also, BPA exposure decreased testicular weight, epididymal sperm concentration and motility, and increased abnormal sperm rate (p < 0.05). These results show that ANS, LTZ and RSV treatments reduce the BPA-induced testicular damage.

Aromatase Inhibitors and Plasma Lipid Changes in Postmenopausal Women with Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Women are typically diagnosed with estrogen receptor-positive breast cancer around the postmenopausal period when declining estrogen levels initiate changes in lipid profiles. Aromatase inhibitors (AI) are used to prevent the progression of cancer; however, a further reduction in estrogen levels may have detrimental effects on lipid levels, which was our working hypothesis. Methods: Our meta-analysis was conducted on the lipid profiles of postmenopausal breast cancer patients at baseline and at different treatment time points. Results: We identified 15 studies, including 1708 patients. Studies using anastrozole (ANA), exemestane (EXE), letrozole (LET), and tamoxifen (TMX) were involved. Subgroup analyses revealed that 3- and 12-month administrations of LET and EXE lead to negative changes in lipid profiles that tend to alter the lipid profile undesirably, unlike ANA and TMX. Conclusions: Our results suggest that, despite statistically significant results, EXE and LET may not be sufficient to cause severe dyslipidemia in patients without cardiovascular comorbidities according to the AHA/ACC Guideline on the Management of Blood Cholesterol. However, the results may raise the question of monitoring the effects of AIs in patients, especially those with pre-existing cardiovascular risk factors such as dyslipidemia.

Anastrozole Protects against Human Coronavirus Infection by Ameliorating the Reactive Oxygen Species-Mediated Inflammatory Response.

The common human coronavirus (HCoV) exhibits mild disease with upper respiratory infection and common cold symptoms. HCoV-OC43, one of the HCoVs, can be used to screen drug candidates against SARS-CoV-2. We determined the antiviral effects of FDA/EMA-approved drug anastrozole (AZ) on two human coronaviruses, HCoV-OC43 and HCoV-229E, using MRC-5 cells in vitro. The AZ exhibited antiviral effects against HCoV-OC43 and HCoV-229E infection. Subsequent studies focused on HCoV-OC43, which is related to the SARS-CoV-2 family. AZ exhibited anti-viral effects and reduced the secretion of inflammatory cytokines, TNF-α, IL-6, and IL-1β. It also inhibited NF-κB translocation to effectively suppress the inflammatory response. AZ reduced intracellular calcium and reactive oxygen species (ROS) levels, including mitochondrial ROS and Ca2+, induced by the virus. AZ inhibited the expression of NLRP3 inflammasome components and cleaved IL-1β, suggesting that it blocks NLRP3 inflammasome activation in HCoV-OC43-infected cells. Moreover, AZ enhanced cell viability and reduced the expression of cleaved gasdermin D (GSDMD), a marker of pyroptosis. Overall, we demonstrated that AZ exhibits antiviral activity against HCoV-OC43 and HCoV-229E. We specifically focused on its efficacy against HCoV-OC43 and showed its potential to reduce inflammation, inhibit NLRP3 inflammasome activation, mitigate mitochondrial dysfunction, and suppress pyroptosis in infected cells.

Lipid changes during endocrine therapy in early-stage breast cancer patients: A real-world study

BackgroundEndocrine drugs may affect lipid metabolism in breast cancer (BC) patients. This study explores lipid changes in early-stage BC patients taking different endocrine drugs.MethodsThe changing trend of blood lipid during endocrine therapy in 2756 BC patients from January 2013 to December 2021 was retrospectively analyzed. The changes in four lipid parameters were assessed by the Generalized Linear Mixed Model, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C). These parameters were quantified at baseline and at 6, 12, 18, 24, 36, 48, 60, and 72 months after endocrine therapy initiation. Furthermore, a subgroup analysis according to menopausal status or medication types was conducted.ResultsA total of 1201 patients taking aromatase inhibitors (AIs), including anastrozole (ANA), letrozole (LET), or exemestane (EXE), and 1555 patients taking toremifene (TOR) were enrolled. TC and TG levels showed a significantly elevated trend during 5 years of treatment (P < 0.05). HDL-C levels increased from baseline in the TOR group (P < 0.05). Compared with the postmenopausal AI group, the increasing trends of TC, TG, and LDL-C in the premenopausal AI group were more evident with the extension of time (β = 0.105, 0.027, 0.086, respectively). Within 3 years, TC, TG, and LDL-C levels in the ANA and LET groups were significantly higher than baseline (P < 0.05). Moreover, the levels of TG in the EXE group were significantly lower than that in the ANA or LET group (P < 0.05), but this significant difference disappeared after 3 years.ConclusionsAIs significantly influenced lipid profiles more than TOR. AIs had a greater effect on blood lipids in premenopausal patients. Steroidal AIs (EXE) may affect lipid levels less than nonsteroidal AIs (ANA and LET).

27-Hydroxycholesterol impairs learning and memory ability via decreasing brain glucose uptake mediated by the gut microbiota

Brain glucose hypometabolism is a significant manifestation of Alzheimer’s disease (AD). 27-hydroxycholesterol (27-OHC) and the gut microbiota have been recognized as factors possibly influencing the pathogenesis of AD. This study aimed to investigate the link between 27-OHC, the gut microbiota, and brain glucose uptake in AD. Here, 6-month-old male C57BL/6 J mice were treated with sterile water or antibiotic cocktails, with or without 27-OHC and/or 27-OHC synthetic enzyme CYP27A1 inhibitor anastrozole (ANS). The gut microbiota, brain glucose uptake levels, and memory ability were measured. We observed that 27-OHC altered microbiota composition, damaged brain tissue structures, decreased the 2-deoxy-2-[18 F] fluorodeoxyglucose (18F-FDG) uptake value, downregulated the gene expression of glucose transporter type 4 (GLUT4), reduced the colocalization of GLUT1/glial fibrillary acidic protein (GFAP) in the hippocampus, and impaired spatial memory. ANS reversed the effects of 27-OHC. The antibiotic-treated mice did not exhibit similar results after 27-OHC treatment. This study reveals a potential molecular mechanism wherein 27-OHC-induced memory impairment might be linked to reduced brain glucose uptake, mediated by the gut microbiota.

Prophylaxis for Treatment-Induced Gynecomastia in Prostate Cancer Patients: A Network Meta-Analysis.

Treatment-induced gynecomastia is a side-effect that can severely limit quality of life in prostate cancer patients. We performed a network meta-analysis (NMA) to comparing the effectiveness of multiple non-surgical prophylactic treatment for gynecomastia. A systematic review was performed through MEDLINE, Cochrane Central Register of Controlled Trials and meeting abstracts to identify randomized controlled trials comparing treatments for treatment-induced gynecomastia. Treatments included radiotherapy (RT), Anastrozole (ANZ), daily Tamoxifen (TMQD), and weekly Tamoxifen (TMQW), compared to no treatment/placebo (NoTx). The primary endpoint was events of gynecomastia development. Odds Ratio (OR) was the effect size of choice. An NMA was used to compare treatments with random-effects model was used. All tests were 2-sided with an alpha of 0.05. A total of 9 studies involving 1319 patients were identified with 5 distinct arms: RT (n = 358), ANZ (n = 90), TMQD (n = 321), TMQW (n = 39) and NoTx (n = 511). Gynecomastia occurred in 79.2% (405/511) of patients with NoTx, 65.5% (59/90) with ANZ, 37.7% (135/358) with RT, 19.6% (63/321) with TMQD and 74.4% (29/39) with TMQW. TMQD was significantly better than RT (OR 4.73 [1.53, 14.61]), ANZ (OR 7.21 [2.25,23.06]), TMQW (OR 6.25 [1.07, 36.43]) and NoTx (OR 26.30 [10.42,66.40]). RT were significantly better than NoTx (OR 5.56 [2.58,11.95]), but did not reach significance compared to ANZ (OR 1.52 [0.36, 6.43]) or TMQW (OR 1.32 [0.16, 10.70]). ANZ was significantly better than NoTx (OR 3.65 [1.03,12.93]). TMQW was not significantly better than NoTx. RT, TMQW and ANZ were significantly worse compared to TMQD in terms of preventing gynecomastia development. Daily Tamoxifen was the best prophylactic treatment choice, significantly better than RT, weekly Tamoxifen and Anastrozole. RT, weekly Tamoxifen and Anastrozole were significantly better than No Treatment/Placebo, but not daily Tamoxifen, in terms of prevention of treatment-induced gynecomastia in patients with prostate cancer.

OATH trial: A phase II clinical trial evaluating the combination of onapristone with anastrozole for women with hormone receptor positive endometrial cancer—Preliminary results.

5601 Background: Endometrial cancer is the most common gynecologic cancer and is primarily treated with chemotherapy. Many endometrial cancers though express hormone receptors and may respond to hormonal therapy, a potentially attractive non-chemotherapy alternative in such a population of women. The aim of OATH is to investigate the potential of dual hormonal blockade through the combination of antiprogesterone and anti-estrogen therapy via the administration of onapristone extended release (ONA) plus anastrozole (ANA), respectively. OATH is an open-label, multicenter, investigator-initiated, non-randomized, phase 2 study to evaluate the safety and efficacy of ONA + ANA in patients (pts) with endometrial cancer (EC). ClinicalTrials.gov Identifier: NCT04719273. Methods: Pts received ONA 50 mg twice daily plus ANA 1 mg once daily and were treated until progressive disease (PD) or unacceptable toxicity. Co-primary endpoints were 4-month progression-free survival (PFS) rate and overall response rate (ORR). A sample size of 25 pts will achieve 80% power to detect an improvement in 4-month PFS estimates from 25% (historical) to 52% and an improvement in response rate from 15% (historical) to 37%, using two-sided exact test at 5% significance level. Secondary endpoints include PFS, disease control rate (DCR), and safety. Results: As of January 20, 2023, 14 pts were enrolled. Median age was 67 years (44-80). ECOG performance status was 0 (36%), and 1 (64%). Number of prior chemotherapy regimens was 0 (1 pt,7%), 1 (9 pts, 64%) and 2 (4 pts, 29%). Seven (50%) pts received radiotherapy and 3 (21%) pts received prior checkpoint inhibitor therapy. Median treatment duration was 4.2 (1.0-19.9) months, and 8 pts remain on treatment. Adverse events were mainly grade 1 and 2. The most common treatment-related adverse events (AEs) and abnormal laboratory values were hot flashes (36%), alanine transferase (ALT) increased (29%), aspartate aminotransferase (AST) increased (29%), nausea (29%), and diarrhea (21%). No treatment-related serious AE, deaths on treatment, or treatment-related drug discontinuations were reported. The 4-month PFS Kaplan-Meier rate was 63.5%. Among 13 pts who had at least one tumor assessment after baseline, the best overall response was: 1 complete response, 1 partial response (response rate: 15.4%), 9 (69%) stable disease, and 2 (15.4%) progressions. Updated results will be presented. Conclusions: Preliminary results of dual hormonal blockade using ONA and ANA in heavily pretreated pts with EC suggest that this combination ONA + ANA has promising activity and is well tolerated. Clinical trial information: NCT04719273 .

A novel anastrozole intravaginal ring for endometriosis: Pharmacokinetic characteristics and mucosal irritation.

In order to achieve the long-term management of endometriosis, a more economical and environmentally friendly material, ethylene vinyl acetate (EVA), was used to prepare a intravaginal ring with anastrozole (ATZ). This paper has compared the pharmacokinetic parameters with oral tablets (Aida®) in mini pigs and evaluated the uterine targeted effect and mucosal irritation of the ring. A bioassay method was developed and validated for the determination of ATZ in mini pigs. The determination of ATZ was achieved by LC-MS/MS using terfenadine as the internal standard. Separation was achieved on a Kinetex-C18 110A chromatographic column (3 × 30 mm, 2.6μm; Phenomenex) with a gradient mobile phase consisting of methanol (0.1% formic acid) and water (0.1% formic acid). The method has been proved to be scientific and sensitive through methodological validation and can be easily and quickly applied to the determination of the content of anastrozole in mini pigs. The pharmacokinetic test results show that there was no significant difference in pharmacokinetic parameters between the two formulations. The intravaginal ring has a passive targeting effect on the uterus, and its mucosal irritation is acceptable. The intravaginal ring provides a new method for long-term management of endometriosis.

Use of multi-criteria ranking method for environmental risk assessment of antineoplastic agents and their transformation products

Among the various classes of pharmaceuticals, antineoplastic agents require particular attention. This work investigates the degradation of the anticancer drugs anastrozole (ANZ) and methotrexate (MTX) by the solar photo-Fenton (SPF) process under different experimental conditions and in different aqueous matrices. Tentative identification of the treatment transformation products (TPs) was performed by suspect screening, employing a purpose-built database containing thirty-three TPs from ANZ and MTX. The experimental condition that achieves the most favorable degradation of ANZ and MTX in real hospital wastewater was pH 5 and multiples additions of Fe2+. This condition provided a reduction of ANZ and MTX of 30 % and 70 %, respectively. Eighteen MTX TPs and five ANZ TPs were tentatively identified in the analyzed samples. After tentative identification, quantitative structure-activity relationship ((Q)SAR) in silico methods were used to predict eight endpoints of environmental risk of the selected analytes. When different possible structures could be proposed, all the possibilities were considered, resulting in fifty-nine structures evaluated. TOPSIS multicriteria decision-making method was used to rank the compounds according to their environmental concern, based on (Q)SAR predictions. As main results, TOPSIS ranking showed that all ANZ TPs and most MTX TPs showed higher environmental risk potential than the parent compounds. The findings highlighted the importance of qualitative tentative identification of TPs and their monitoring throughout treatments, as well as risk assessment using various endpoints simultaneously. The proposed approach can provide objective and holistic evaluation of treatment processes.

Validation of an MD simulation approach for electrical field responsive micelles and their application in drug delivery

In the current work, a new type of micelle is designed that has active connectivity in respond to exterior stimulus and the desired water solubility. Two end-ornamented homopolymers, polystyrene-beta-cyclodextrin (PS-β-CD) and polyethylene oxide-ferrocene (PE-FE), can aggregate as a supramolecular micelle (PS-β-CD/PE-FE) by the guest–host interactions. Our results showed that the Lennard–Jones and hydrophobic interactions are the main powerful forces for the micelle formation process. It was found that the electrical field plays a role as a driving force in the reversible assembly-disassembly of the micellar system. Moreover, for the first time, we examined the PS-β-CD/PE-FE micelle interaction as a drug delivery system with anastrozole (ANS) and mitomycin C (MIC) anti-cancer drugs. The investigation of the total energy between PS-β-CD/PE-FE micelle and drugs predicts the drug adsorption process as favorable (Etotal = − 638.67 and − 259.80 kJ/mol for the Micelle@ANS and Micelle@MIC complexes, respectively). Our results offer a deep understanding of the micelle formation process, the electrical field-respond, and drug adsorption behaviors of the micelle. This simulation study has been accomplished by employing classical molecular dynamics calculation.

Formulation and in-vitro Evaluation of Ethosomes using Anastrozole as a Modeling Drug

Anastrozole (ANZ) is a potent non-steroidal aromatase II inhibitor (AI) used to decrease or delay the progression of breast tumor growth in some women. Since ANZ could be delivered transdermally due to its physicochemical characteristics as (log p of 3.5, aqueous solubility of 0.5 mg /mL, low dosage and half-life of 46.8 hr.) so, it could be used as a modelling drug evaluation of ethosomes, the current study aimed to formulate ANZ loaded ethosomes and evaluate the formulated ethosomes for particle size and PDI, entrapment efficiency and in vitro release profile. Film hydration method was used to prepare ANZ-loaded ethosoms. using different ratios of phospholipid (Soy phosphatidyl choline) and ethanol at variables probe sonication energy and time ratios.&#x0D; polydispersity index and particle size were used to evaluate the prepared ANZ-loaded ethosoms. The optimized formula of ethosomes which contain (1% Soy phosphatidyl choline,20% ethanol subjected to 300watt sonication energy with 1/3 sonication on /off ratio) was studied for in vitro drug release. It had 127.75±0.36 nm particle diameter and 74.7136 ± 3.457 % entrapment efficiency, the release kinetics obey Korsmeyer-Peppas and non-Fickian release as R2=0.9779 and n=0.737.&#x0D; The ratios of Soy phosphatidyl choline, ethanol, sonication energy and duration had a significant impact on the particle size of ethosomes at (p0.05). The preformulating analysis of Powder X-ray diffraction (P-XRD) indicate amorphous ethosomes. Fourier transform infrared (FTIR) showed the inertness among components.

Analysis of enhancing drug bioavailability via nanomedicine production approach using green chemistry route: Systematic assessment of drug candidacy

Evaluation of drug candidacy for processing in nanonization is of great importance due to the importance of nanomedicine for enhanced bioavailability approach. Given that the majority of newly discovered drugs are poorly soluble in the body which makes also poor bioavailability of the drug substances, advanced techniques are required in order to enhance the drug efficacy and consequently its solubility. We employed three distinct machine learning models to make predictions in this work, including Multilayer Perceptron regressor (MLP), K-nearest Neighbors regressor (KNN), and Decision Tree Regressor (DT). The regression task has two input features: temperature (K) and pressure (MPa), and the only output is the solubility value of ANA (Anastrozole) drug in supercritical CO2 as the solvent. We tuned all three models using their important hyper-parameters and found the most appropriate combinations for each. Then, many standard measures are used to evaluate their performance. DT, KNN, and MLP models have R2-scores of 0.875, 0.992, and 0.9984, respectively, and have MSE errors of 1.5242, 1.0006 × 10−1, and 2.5688 × 10−2. Additionally, taking into account the MAE, 1.01, 2.62 × 10−1, and 1.17 × 10−1 values acquired. Finally, the multilayer perceptron (MLP) is selected as the most accurate model. Additionally, this model has a maximum error of 3.78 × 10−1 on the dataset.

Green processing based on supercritical carbon dioxide for preparation of nanomedicine: Model development using machine learning and experimental validation

Solubility data for ANA (Anastrozole) drug in supercritical solvent was investigated in this study, and models were developed to estimate the solubility values. The main aim was to provide a predictive methodology for determination of drug solubility in wide range of operational parameters for advanced green pharmaceutical manufacture. The properties used are temperature and pressure which were considered as the models’ inputs. Modeling has been done using three models based on the support vector regression. These models include support vector regression (with polynomial kernel), boosted support vector machine with AdaBoost, and improved support vector machine with bagging. These models were evaluated after optimization, and all three models have a coefficient of determination (R2) higher than 0.98. Also considering RMSE, AdaBoosted SVR, Bagging SVR, and SVR have error rates of 2.31E-01, 4.31E-01, and 5.01E-01.

Electrochemical Oxidation of Anastrozole over a BDD Electrode: Role of Operating Parameters and Water Matrix

The electrochemical oxidation (EO) of the breast-cancer drug anastrozole (ANZ) is studied in this work. The role of various operating parameters, such as current density (6.25 and 12.5 mA cm−2), pH (3–10), ANZ concentration (0.5–2 mg L−1), nature of supporting electrolytes, water composition, and water matrix, have been evaluated. ANZ removal of 82.4% was achieved at 1 mg L−1 initial concentration after 90 min of reaction at 6.25 mA cm−2 and 0.1 M Na2SO4. The degradation follows pseudo-first-order kinetics with the apparent rate constant, kapp, equal to 0.022 min−1. The kapp increases with increasing current density and decreasing solution pH. The addition of chloride in the range 0–250 mg L−1 positively affects the removal of ANZ. However, chloride concentrations above 250 mg L−1 have a detrimental effect. The presence of bicarbonate or organic matter has a slightly negative but not significant effect on the process. The EO of ANZ is compared to its degradation by solar photo-Fenton, and a preliminary economic analysis is also performed.

Impact of anastrozole use on the prediction of final height in male adolescents: a retrospective cohort

Introduction: The objective of this study was to evaluate the impact of the use of anastrozole (ANZ) in monotherapy or associated with growth hormone (GH) in the predicted of final height (PFH) and nearfinal height (NFH) of male adolescents with PEF below target familiar height (TH). Methods: This is a retrospective cohort. Data were obtained from medical records in a pediatric endocrinology service. Results: 75 patients between 11 and 14 years old participated in this cohort. Treatment with ANZ occurred for 1 year in 38.7%, 2 years in 40.0%, and 3 years in 21.3%. 76.0% used GH+ANZ, and 24.0% ANZ alone. TH and PFH at different treatment times showed a statistically significant difference, regardless of the use or not of GH. The ANZ group alone showed a mean increase of 5.73cm, 7.60cm, and 7.15cm in predicted height after 1, 2, and 3 years of ANZ. In the GH+ANZ group, this increase was 6.82cm, 10.27cm, and 7.44cm. Twenty-seven patients reached NFH, and in these, we observed a statistically significant increase concerning baseline PFH of 4.68 cm in the total group and 5.55 cm in the GH+ANZ group. Conclusions: The use of ANZ effectively increased PFH and NFH in adolescents with PFH below TH. However, the subgroup with concomitant use of GH had better outcomes.

Aromatase inhibition increases blood pressure and markers of renal injury in female rats.

Aromatase is a monooxygenase that catalyzes the rate-limiting step of estrogen biosynthesis from androgens. Aromatase inhibitors are widely used for the treatment of patients with hormone receptor-positive breast cancer. However, the effects of aromatase inhibitors on cardiovascular and renal health in females are understudied. Given that estrogen is protective against cardiovascular and kidney diseases, we hypothesized that aromatase inhibition elevates blood pressure and induces kidney injury in female Sprague-Dawley rats. Twelve-week-old female rats were implanted with radiotelemetry transmitters to continuously monitor blood pressure. After baseline blood pressure recording, rats were randomly assigned to treatment with the aromatase inhibitor anastrozole (ASZ) or vehicle (Veh) in drinking water. Twenty days after treatment initiation, rats were shifted from a normal-salt (NS) diet to a high-salt (HS) diet for an additional 40 days. Rats were euthanized 60 days after treatment initiation. Body weight increased in both groups over the study period, but the increase was greater in the ASZ-treated group than in the Veh-treated group. Mean arterial pressure increased in ASZ-treated rats during the NS and HS diet phases but remained unchanged in Veh-treated rats. In addition, urinary excretion of albumin and kidney injury marker-1 and plasma urea were increased in response to aromatase inhibition. Furthermore, histological assessment revealed that ASZ treatment increased morphological evidence of renal tubular injury and proximal tubular brush border loss. In conclusion, chronic aromatase inhibition in vivo with ASZ increases blood pressure and markers of renal proximal tubular injury in female Sprague-Dawley rats, suggesting an important role for aromatization in the maintenance cardiovascular and renal health in females.NEW & NOTEWORTHY Aromatase enzyme catalyzes the rate-limiting step in estrogen biosynthesis. Aromatase inhibitors are clinically used for the treatment of patients with breast cancer; however, the impact of inhibiting aromatization on blood pressure and renal function is incompletely understood. The present findings demonstrate that systemic anastrozole treatment increases blood pressure and renal tubular injury markers in female rats fed a high-salt diet, suggesting an important role for aromatization in preserving cardiovascular and renal health in females.

Efficacy and safety of initial five years of adjuvant endocrine therapy in postmenopausal hormone receptor-positive breast cancer: A systematic review and network meta-analysis.

535 Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.

Efficacy and safety of letrozole or anastrozole in the treatment of male infertility with low testosterone-estradiol ratio: A meta-analysis and systematic review.

Aromatase inhibitors (AIs) have been used to treat male infertility for decades. However, due to the lack of large-scale randomized controlled studies and basic research, the efficacy and safety of AIs in the treatment of male infertility remain controversial. Therefore, it is necessary to conduct an evidence-based preliminary evaluation of the existing clinical trials of AIs in the treatment of male infertility. A comprehensive literature search was performed in the PubMed, Embase, Cochrane, CNKI, VIP, CBM, and Wanfang databases through August 2021 for all studies. We conducted a systematic review with a meta-analysis of all available studies reporting sperm conventional parameters, gonadotropin and testosterone levels, and/or the pregnancy rate. A total of 10 studies involving 666 patients were included. Letrozole (LE) or anastrozole (AZ) administration significantly increased sperm concentration, total sperm count, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) levels, and the testosterone-to-estradiol ratio (T/E2), but E2 levels were significantly reduced compared with baseline values. Compared with the control group, which included selective estrogen receptor modulators (SEMRs) or human chorionic gonadotropin (HCG), LE, or AZ did not have any significant effect on sperm concentration, motility, and morphology, except that AIs had less effect on sperm motility than the control group (weighted mean difference [WMD]: -2.55; 95% CI: -4.11 to -1.00; p=0.001). AIs may be effective in the treatment of male infertility. For infertile male patients planning assisted reproduction, discontinuation of AIs for 2-7 days prior to sperm retrieval may increase the success rate of fertilization. Further studies with larger sample sizes are needed to validate these findings.