-
Chemistry & Biodiversity Jun 2024This study aims to combat breast cancer, which is a significant health concern for women worldwide. By targeting aromatase, an enzyme crucial in estrogen synthesis, the...
This study aims to combat breast cancer, which is a significant health concern for women worldwide. By targeting aromatase, an enzyme crucial in estrogen synthesis, the research focuses on breast cancer cases, emphasizing the importance of hormonal therapy. The innovative approach of this study involves the synthesis of novel bis-triazolopyridopyrimidines, designed to amplify the combined pharmacological advantages of the pyridopyrimidine and 1,2,4-triazole structures known for their aromatase inhibition and anti-cancer capabilities. Through the synthesis and characterization of these compounds using 1H-NMR, 13C-NMR, and MS spectral analyses, and evaluating their anticancer efficacy with MTT assays against MCF-7 breast cancer cell lines in vitro, the research endeavors to develop potent aromatase inhibitors as viable anti-breast cancer agents. Identifying compounds with strong binding energies to aromatase through molecular docking analyses further supports their potential effectiveness in inhibiting aromatase activity, a key mechanism in breast cancer progression. The findings, particularly regarding compounds 5b, 5c, 10a, and 10b, which exhibited the strongest binding energies with aromatase, highlight promising candidates for further development and testing as potential therapeutic agents against breast cancer. This approach showcases the potential of these synthesized compounds in combating breast cancer by inhibiting aromatase activity.
PubMed: 38829745
DOI: 10.1002/cbdv.202400701 -
Journal of Clinical Research in... May 2024A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside...
A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.
Topics: Humans; Male; Body Height; Child; Puberty; Growth Disorders; Adolescent; Female; Human Growth Hormone; Adult; Aromatase Inhibitors; Puberty, Precocious; Gonadotropin-Releasing Hormone; Testosterone
PubMed: 38828521
DOI: 10.4274/jcrpe.galenos.2024.2024-1-13 -
Cureus May 2024As estrogen-dependent breast cancer is more affected by the local production of estrogen via aromatase than serum estrogen, aromatase inhibitors for treating breast... (Review)
Review
As estrogen-dependent breast cancer is more affected by the local production of estrogen via aromatase than serum estrogen, aromatase inhibitors for treating breast carcinomas in postmenopausal women have been developed. As the aromatase enzyme converts endogenous androgen to estrogenic compounds, its blockade lowers the in situ production of estrogen, demonstrated to encourage tumor proliferation. Red wine, but not white wine, may have aromatase-inhibiting properties that are being elucidated, although the exact mechanisms of action are not known. Polyphenols, tannins, and resveratrol have all been implicated as aromatase blockers, and there may also be synergistic interplay among selected constituents. The role of red wine would be in chemoprevention, the use of natural or synthetic substances to retard, block, or reverse cancer. One gene encodes aromatase, so aromatase inhibition would stop endogenous estrogen production. The role of aromatase inhibition in breast cancer in premenopausal women is not clear. While animal studies have demonstrated that red wine contains constituents that could block aromatase in vivo, the benefits also exist with nonalcoholic grape seed extract. Further investigation is needed but there are challenges in designing appropriate clinical trials for a substance as variable as red wine. While there is insufficient evidence to advocate for red wine as an aromatase inhibitor, there is sufficient evidence to warrant further investigation.
PubMed: 38826984
DOI: 10.7759/cureus.59587 -
International Journal of Environmental... Jun 2024In our study, the protective role of synthetic aromatase inhibitors anastrozole (ANS), letrozole (LTZ) and exemestane (EXM) and natural aromatase inhibitors resveratrol...
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 ( < 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 ( < 0.05). These results show that ANS, LTZ and RSV treatments reduce the BPA-induced testicular damage.
PubMed: 38825800
DOI: 10.1080/09603123.2024.2362810 -
Angewandte Chemie (International Ed. in... May 2024Cytochrome P450 (P450, CYP) 19A1 is the steroid aromatase, the enzyme responsible for the 3-step conversion of androgens (androstenedione or testosterone) to estrogens....
Cytochrome P450 (P450, CYP) 19A1 is the steroid aromatase, the enzyme responsible for the 3-step conversion of androgens (androstenedione or testosterone) to estrogens. The final step is C-C bond scission (removing the 19-oxo group as formic acid) that proceeds via a historically controversial reaction mechanism. The two competing mechanistic possibilities involve a ferric peroxide anion (Fe3+O2-, Compound 0) and a perferryl oxy species (FeO3+, Compound I). One approach to discern the role of each species in the reaction is with the use of oxygen-18 labeling, i.e., from 18O2 and H218O of the reaction product formic acid. We applied this approach, using several technical improvements, to study the deformylation of 19-oxo-androstenedione by human P450 19A1 and of a model secosteroid, 3-oxodecaline-4-ene-10-carboxaldehyde (ODEC), by rabbit P450 2B4. Both aldehyde substrates were sensitive to non-enzymatic acid-catalyzed deformylation, yielding 19-norsteroids, and conditions were established to avoid issues with artifactual generation of formic acid. The Compound 0 reaction pathway predominated (i.e., Fe3+O2-) in both P450 19A1 oxidation of 19-oxo-androstenedione and P450 2B4 oxidation of ODEC. The P450 19A1 results contrast with our prior conclusions (J. Am. Chem. Soc. 2014, 136, 15016-16025), attributed to several technical modifications.
PubMed: 38820076
DOI: 10.1002/anie.202406542 -
NEJM Evidence May 2024In estrogen receptor-positive metastatic breast cancer, mutations (ESR1) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the...
BACKGROUND
In estrogen receptor-positive metastatic breast cancer, mutations (ESR1) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the impact alterations have on CDK4/6 inhibitor (CDK4/6i) sensitivity has not been established. Analyses of CDK4/6i trials suggest that the endocrine therapy partner and specific allele may affect susceptibility. We analyzed a real-world data set to investigate CDK4/6i efficacy in ESR1 metastatic breast cancer and associated clinical factors.
METHODS
ESR1 were identified by analysis of circulating-tumor deoxyribonucleic acid. The GuardantINFORM database contains genomic information from tumors linked with claims data. Patients who started a CDK4/6i within 30 days of sequencing were categorized as having ESR1 or non--mutant (non-ESR1) breast cancer. Data were analyzed to determine the real-world time-to-next-treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment.
RESULTS
One hundred forty-five patients with ESR1 and 612 with non-ESR1 metastatic breast cancer were analyzed. ESR1 and non-ESR1 tumors had similar real-world time-to-next-treatment on CDK4/6i regimens (hazard ratio, 1.02; 95% confidence interval, 0.82 to 1.23). Duration on therapy in the first-line and second-line plus treatment settings were comparable regardless of status. We stratified treatment duration by concurrent endocrine therapy, and patients with ESR1 had worse outcomes on ArIh but comparable real-world time-to-next-treatment on fulvestrant.
CONCLUSIONS
These data suggest variants are not associated with pan-CDK4/6i resistance and are consistent with the hypothesis that CDK4/6 blockade combined with a selective estrogen receptor degrader is potentially an effective option for ESR1 metastatic breast cancer.
Topics: Humans; Breast Neoplasms; Female; Estrogen Receptor alpha; Middle Aged; Cyclin-Dependent Kinase 4; Mutation; Cyclin-Dependent Kinase 6; Aged; Adult; Aromatase Inhibitors; Piperazines; Neoplasm Metastasis; Fulvestrant; Protein Kinase Inhibitors
PubMed: 38815172
DOI: 10.1056/EVIDoa2300231 -
Frontiers in Endocrinology 2024Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by... (Review)
Review
Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in , resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the ; copy number variants in , , , , , and , and sequence variants in , , , , , , and . Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.
Topics: Humans; Adrenal Hyperplasia, Congenital; 46, XX Disorders of Sex Development; Female; Male; Disorders of Sex Development
PubMed: 38812815
DOI: 10.3389/fendo.2024.1354759 -
Journal of Medicinal Chemistry Jun 2024Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial...
Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. , promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound demonstrates promising antiproliferative and ERα degradation activity against the ERα cells. These findings suggest that , being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.
Topics: Humans; Estrogen Receptor alpha; Breast Neoplasms; Female; Animals; Drug Resistance, Neoplasm; Cell Proliferation; Mice; Aromatase; Aromatase Inhibitors; Antineoplastic Agents; MCF-7 Cells; Proteolysis; Mice, Nude; Drug Discovery; Structure-Activity Relationship
PubMed: 38809993
DOI: 10.1021/acs.jmedchem.4c00196 -
Pediatric Blood & Cancer Aug 2024Aromatase inhibitors (AI) may improve height in short stature conditions; however, the effect in childhood cancer survivors (CCS) is unknown. We assessed final adult...
BACKGROUND
Aromatase inhibitors (AI) may improve height in short stature conditions; however, the effect in childhood cancer survivors (CCS) is unknown. We assessed final adult height (FAH) in CCS treated with AI and GH compared with those treated with GH alone.
METHODS
Retrospective cohort study of GH-deficient male CCS treated between 2007 and 2023. FAH was noted as the height at the fusion of growth plates or 18 years of age. Multivariable linear regression was used to examine treatment association with FAH, adjusting for other risk factors.
RESULTS
Ninety-two patients were included; 70 were treated with GH and 22 with combination AI/GH. The mean age at GH initiation did not differ between groups. The mean age at AI initiation was 13.7 ± 1.9 years. A greater proportion of patients in the AI/GH group were treated with stem cell transplantation, abdominal radiation, total body irradiation, and cis-retinoic acid (p < .01). Multivariable linear regression demonstrated no significant treatment association with FAH Z-score (β = 0.04, 95% CI: -0.9 to 0.9). History of spinal radiation (β = -0.93, 95% CI: -1.7 to -0.2), lower starting height Z-score (β = -0.8, 95% CI: -1.2 to -0.4), and greater difference between bone age and chronological age (β = -0.3, 95% CI: -0.5 to -0.07) were associated with lower FAH Z-score.
CONCLUSIONS
Adjuvant AI was not associated with increased FAH in male CCS compared with GH monotherapy. Future work is needed to determine the optimal adjunctive treatment to maximize FAH for this population.
Topics: Humans; Male; Aromatase Inhibitors; Retrospective Studies; Cancer Survivors; Body Height; Adolescent; Human Growth Hormone; Child; Neoplasms; Follow-Up Studies; Growth Disorders; Adult; Prognosis; Chemotherapy, Adjuvant
PubMed: 38804882
DOI: 10.1002/pbc.31117 -
Andrology May 2024Existing literature does not provide accurate epidemiological data regarding the true prevalence of men with non-obstructive azoospermia (NOA) who would be eligible for...
BACKGROUND
Existing literature does not provide accurate epidemiological data regarding the true prevalence of men with non-obstructive azoospermia (NOA) who would be eligible for hormonal optimization therapy, according to specific pre-treatment criteria.
OBJECTIVES
To investigate the characteristics of those men with NOA who would qualify for the medical therapy prior to any SR procedure in a large multi-centric cross-sectional study.
MATERIALS AND METHODS
Complete data from 1644 NOA patients seeking medical help for primary infertility at three tertiary referral centers from USA, Brazil, and Italy were analyzed. Baseline serum hormone levels were collected for all patients. NOA was confirmed after two consecutive semen analyses. Genetic tests, including karyotype analysis and Y microdeletions, were performed on all patients. Patients with secondary hypogonadism (total testosterone (T) levels less than 300 ng/dL and luteinizing hormone (LH) levels less than 8 mIU/mL) were earmarked as potential candidates for receiving clomiphene citrate (CC) and/or human chorionic gonadotropin (hCG). Patients with a T to 17β-estradiol (E2) ratio < 10 were classified as eligible for aromatase inhibitors (AIs) therapy (e.g., anastrazole). A third sub-cohort was created by combining the criteria of the first two sub-cohorts. Descriptive statistics was used to detail overall characteristics and differences between the different sub-cohorts.
RESULTS
Among the 1,644 men, 28% (n = 460) had T < 300 ng/dL and LH < 8 mIU/mL, thereby being potentially suitable for CC and/or hCG, while 37% (n = 607) had a T to E2 ratio < 10 thus potentially suitable for AIs. Lastly, 17.7% (n = 280) met the criteria for potential eligibility for both CC and/or hCG and AIs.
CONCLUSIONS
Findings from this multicentric cross-sectional study reveal that about 30% of men with NOA were eligible for hormonal treatment with CC and/or hCG while 37% were found to be potential candidates for AIs, and 17% for both therapies. Therefore, these findings show that a only a small subset of NOA patients can benefit from medical therapy prior to considering any SR procedures.
PubMed: 38804793
DOI: 10.1111/andr.13670