-
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 -
Frontiers in Physiology 2024In addition to loss of sensory and motor function below the level of the lesion, traumatic spinal cord injury (SCI) may reduce circulating steroid hormones that are...
In addition to loss of sensory and motor function below the level of the lesion, traumatic spinal cord injury (SCI) may reduce circulating steroid hormones that are necessary for maintaining normal physiological function for extended time periods. For men, who comprise nearly 80% of new SCI cases each year, testosterone is the most abundant circulating sex steroid. SCI often results in significantly reduced testosterone production and may result in chronic low testosterone levels. Testosterone plays a role in respiratory function and the expression of respiratory neuroplasticity. When testosterone levels are low, young adult male rats are unable to express phrenic long-term facilitation (pLTF), an inducible form of respiratory neuroplasticity invoked by acute, intermittent hypoxia (AIH). However, testosterone replacement can restore this respiratory neuroplasticity. Complicating the interpretation of this finding is that testosterone may exert its influence in three possible ways: 1) directly through androgen receptor (AR) activation, 2) through conversion to dihydrotestosterone (DHT) by way of the enzyme 5α-reductase, or 3) through conversion to 17β-estradiol (E2) by way of the enzyme aromatase. DHT signals via AR activation similar to testosterone, but with higher affinity, while E2 activates local estrogen receptors. Evidence to date supports the idea that exogenous testosterone supplementation exerts its influence through estrogen receptor signaling under conditions of low circulating testosterone. Here we explored both recovery of breathing function (measured with whole body barometric plethysmography) and the expression of AIH-induced pLTF in male rats following C2-hemisection SCI. One week post injury, rats were supplemented with either E2 or DHT for 7 days. We hypothesized that E2 would enhance ventilation and reveal pLTF following AIH in SCI rats. To our surprise, though E2 did beneficially impact overall breathing recovery following C2-hemisection, both E2 supplementation and DHT restored the expression of AIH-induced pLTF 2 weeks post-SCI.
PubMed: 38803364
DOI: 10.3389/fphys.2024.1390777 -
Frontiers in Oncology 2024Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular... (Review)
Review
Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular biomarkers that also serve as predictive indicators. More than two thirds of breast tumors are classified as luminal with positive hormone receptors (HR), indicating that cancer cells proliferation is promoted by hormones. Endocrine therapies play a vital role in the effective treatment of breast cancer by manipulating the signaling of estrogen receptors (ER), leading to a reduction in cell proliferation and growth rate. Selective estrogen receptor modulators (SERMs), such as tamoxifen and toremifene, function by blocking estrogen's effects. Aromatase inhibitors (AI), including anastrozole, letrozole and exemestane, suppress estrogen production. On the other hand, selective estrogen receptor degraders (SERDs), like fulvestrant, act by blocking and damaging estrogen receptors. Tamoxifen and AI are widely used both in early- and advanced-stage disease, while fulvestrant is used as a single agent or in combination with other agents like the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, ribociclib) or alpelisib for advanced-stage disease. Currently, SERDs are recognized as an effective therapeutic approach for the treatment of ER-positive breast cancer, showing proficiency in reducing and blocking ER signaling. This review aims to outline the ongoing development of novel oral SERDs from a practical therapeutic perspective, enhancing our understanding of the mechanisms of action underlying these compounds.
PubMed: 38800404
DOI: 10.3389/fonc.2024.1385577 -
General and Comparative Endocrinology Sep 2024The production of communication signals can be modulated by hormones acting on the brain regions that regulate these signals. However, less is known about how signal... (Review)
Review
The production of communication signals can be modulated by hormones acting on the brain regions that regulate these signals. However, less is known about how signal perception is regulated by hormones. The electrocommunication signals of weakly electric fishes are sexually dimorphic, sensitive to hormones, and vary across species. The neural circuits that regulate the production and perception of these signals are also well-characterized, and electric fishes are thus an excellent model to examine the neuroendocrine regulation of sensorimotor mechanisms of communication. We investigated (1) whether steroid-related genes are expressed in sensory brain regions that process communication signals; and (2) whether this expression differs across sexes and species that have different patterns of sexual dimorphism in their signals. Apteronotus leptorhynchus and Apteronotus albifrons produce continuous electric organ discharges (EODs) that are used for communication. Two brain regions, the electrosensory lateral line lobe (ELL) and the dorsal torus semicircularis (TSd), process inputs from electroreceptors to allow fish to detect and discriminate electrocommunication signals. We used qPCR to quantify the expression of genes for two androgen receptors (ar1, ar2), two estrogen receptors (esr1, esr2b), and aromatase (cyp19a1b). Four out of five steroid-related genes were expressed in both sensory brain regions, and their expression often varied between sexes and species. These results suggest that expression of steroid-related genes in the brain may differentially influence how EOD signals are encoded across species and sexes, and that gonadal steroids may coordinately regulate central circuits that control both the production and perception of EODs.
Topics: Animals; Female; Electric Fish; Male; Brain; Electric Organ; Sex Characteristics
PubMed: 38797340
DOI: 10.1016/j.ygcen.2024.114549 -
Cancers May 2024(1) Background: Abemaciclib combined with endocrine therapy is a standard first- or later-line of treatment for HR+/HER2- metastatic breast cancer (MBC). The aim of this...
(1) Background: Abemaciclib combined with endocrine therapy is a standard first- or later-line of treatment for HR+/HER2- metastatic breast cancer (MBC). The aim of this retrospective cohort study was to describe the outcomes of patients treated in a real-world setting, with particular focus on elderly patients. (2) Patients and methods: Patients treated with abemaciclib between November 2019 and February 2022 were included in the study. Data were collected from electronic medical records. The primary objective was to determine real-world progression-free survival (rwPFS), and secondary objectives included median overall survival (mOS) and safety. (3) Results: Analysis included 134 patients, with a median follow-up of 42 months. Median age was 62 years, with 29.9% aged 70+ years. A total of 51.5% of patients received abemaciclib in first-line, predominantly with aromatase inhibitor (68.1%). Median rwPFS was 21 in first-line and 20 months in the second-line, with no significant difference between treatment lines (HR 0.96; = 0.88). Patients treated in the third- or later-line had a significantly shorter rwPFS, at 7 months (HR 1.48, = 0.003). mOS was not reached in the first-line setting. For second- and third- or later-lines, mOS was 29 and 19 months, respectively. There was no significant difference in mOS between first- or second-line (HR 1.37, = 0.36). In the 70+ group, median rwPFS was 15 months and mOS was 25 months with no significant difference compared to younger patients (rwPFS HR 1.1; = 0.65; OS HR 1.4; = 0.21). Most common adverse events (AEs) were diarrhoea (68.7%), anaemia (64.9%), and increased serum creatinine (63.4%). Grade 3/4 AEs were reported in 21.6% of patients. Dose reductions occurred in 30.6% of patients and were more frequent in patients 70+ (40%) compared to younger patients (28%); the difference was not significant ( = 0.22). At study cut-off, 64.9% of patients discontinued abemaciclib, primarily due to disease progression (73.5%). (4) Conclusions: Our study provides valuable insights into the effectiveness and safety of abemaciclib for the treatment of MBC. We observed comparable outcomes in terms of rwPFS and OS between the first two lines, suggesting consistent effectiveness across treatment lines. In addition, our findings suggest that older age (70+) does not significantly impact the effectiveness and tolerability of abemaciclib, although the careful monitoring and management of AEs are warranted.
PubMed: 38791907
DOI: 10.3390/cancers16101828 -
Biomedicines Apr 2024Contamination by fungi and the toxins they secrete is a worldwide health concern. One such toxin is zearalenone (Zea), which is structurally similar to the hormone...
Contamination by fungi and the toxins they secrete is a worldwide health concern. One such toxin is zearalenone (Zea), which is structurally similar to the hormone estrogen, interferes with its action on the reproductive system, and is therefore classified as an endocrine disruptor. This study aims to determine the effectiveness of hispidin and magnesium nanoparticles (MgONPs) against zearalenone-induced myotoxicity, which causes polycystic ovary syndrome (PCOS) in rats. A three-month exposure study was performed using female Wistar rats ( = 42) with an average weight of 100-150 g. The animals were divided into six groups (I to VI) of seven rats each. Group I was administered distilled water as a negative control. Group II was exposed to Zea 0.1 mg/kg b.w. through gavage daily. Group III was treated with 0.1 mg/kg of hispidin through gavage daily. Group IV was given 150 µg/mL MgONPs orally each day. Group V was treated with Zea 0.1 mg/kg b.w. + 0.1 mg/kg hispidin orally each day. Group VI was treated with Zea 0.1 mg/kg b.w. and the combination treatment of 0.1 mg/kg hispidin + 150 µg/mL MgONPs through gavage every day. The effectiveness of hispidin and MgONPs against Zea toxicity was evaluated in terms of ovarian histological changes, gene expression, oxidative stress biomarkers, biochemical variables, and hormone levels. The findings showed that exposure to Zea promotes PCOS in rats, with Zea-treated rats displaying hyper-ovulation with large cysts; elevated testosterone, luteinizing hormone, insulin, and glucose; and reduced sex hormone-binding globulin. In addition, qRT-PCR for aromatase () showed it to be downregulated. Treatment with hispidin improved the histopathological and hormonal situation and rescued expression of . Our data indicate the potential therapeutic effects of hispidin against Zea-induced Fungal Toxicity.
PubMed: 38790905
DOI: 10.3390/biomedicines12050943 -
Genes May 2024The estrogen receptor signaling pathway plays an important role in vertebrate embryonic development and sexual differentiation. There are four major estrogen receptors...
The estrogen receptor signaling pathway plays an important role in vertebrate embryonic development and sexual differentiation. There are four major estrogen receptors in zebrafish: , , and . However, the specific role of different estrogen receptors in zebrafish is not clear. To investigate the role of in zebrafish development and reproduction, this study utilized TALENs technology to generate an knockout homozygous zebrafish line. The number of eggs laid by knockout female zebrafish did not differ significantly from that of wild zebrafish. The embryonic development process of wild-type and knockout zebrafish was observed, revealing a significant developmental delay in the knockout zebrafish. Additionally, mortality rates were significantly higher in knockout zebrafish than in their wild-type counterparts at 24 hpf. The reciprocal cross experiment between knockout zebrafish and wild-type zebrafish revealed that the absence of resulted in a decline in the quality of zebrafish oocytes, while having no impact on sperm cells. The knockout of also led to an abnormal sex ratio in the adult zebrafish population, with a female-to-male ratio of approximately 1:7. The quantitative PCR (qPCR) and in situ hybridization results demonstrated a significant downregulation of expression in knockout embryos compared to wild-type embryos throughout development (at 2 dpf, 3 dpf and 4 dpf). Additionally, the estrogen-mediated induction expression of was attenuated, while the estradiol-induced upregulated expression of was disrupted. These results suggest that is involved in regulating zebrafish oocyte development and sex differentiation.
Topics: Animals; Female; Male; Aromatase; Embryonic Development; Estrogen Receptor beta; Gene Expression Regulation, Developmental; Gene Knockout Techniques; Oocytes; Sex Differentiation; Sex Ratio; Zebrafish; Zebrafish Proteins
PubMed: 38790265
DOI: 10.3390/genes15050636 -
Clinical Breast Cancer May 2024Young women with breast cancer (BC) may experience bone mineral density (BMD) loss secondary to cancer treatment effects on estrogen levels. Studies assessing BMD in BC...
INTRODUCTION
Young women with breast cancer (BC) may experience bone mineral density (BMD) loss secondary to cancer treatment effects on estrogen levels. Studies assessing BMD in BC patients have had a limited representation of young women. This multicenter retrospective study analyzed the frequency of low BMD and associated factors in this age group.
METHODS
Women diagnosed with stage 0-III BC at ≤40 years, treated with chemotherapy and/or endocrine therapy between 2010 and 2020 at 5 Mexican BC referral centers were eligible. Demographic, clinical and treatment data were collected, as well as bone dual-energy X-ray absorptiometry (DEXA) results. Low BMD was defined as lumbar or femoral neck T-score < -1.0 or Z-score ≤ -2.0.
RESULTS
A total of 1259 patients were included; median age at diagnosis was 36 years (21-40). Overall, 93% received chemotherapy and 65% endocrine therapy (tamoxifen was received at some point by 61%, aromatase inhibitors by 17%, and GnRH agonists/bilateral oophorectomy by 21%). DEXA scans were documented in 254 (20%), of which 163 (64%; 95% confidence interval [CI] 58%-70%) had a low BMD report. Low BMD was associated with receiving aromatase inhibitors (Odds ratio [OR] 1.92; 95% CI 1.13-3.24), and GnRH agonists/bilateral oophorectomy (OR 2.25; 95% CI 1.21-4.21).
CONCLUSION
The suboptimal frequency of BMD monitoring observed displays an alarming disregard for bone health in young patients. Thus, a high proportion of women with low BMD are potentially being missed and precluded from the opportunity to receive timely interventions. Particular focus should be put on BMD monitoring among patients treated with aromatase inhibitors, GnRH agonists or bilateral oophorectomy.
PubMed: 38789360
DOI: 10.1016/j.clbc.2024.04.012