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The Journal of Endocrinology Feb 2024Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect...
Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2-CREB signaling pathway in an AR-independent manner.
Topics: Animals; Male; Mice; Androgens; Extracellular Signal-Regulated MAP Kinases; Hippocampus; Memory Disorders; Receptors, Androgen; Testosterone
PubMed: 37991884
DOI: 10.1530/JOE-23-0114 -
Archives of Endocrinology and Metabolism Nov 2023This research aimed to evaluate retrospectively the effect of anastrozole on height gain and sex hormone levels in pubertal boys receiving growth hormone (GH).
OBJECTIVE
This research aimed to evaluate retrospectively the effect of anastrozole on height gain and sex hormone levels in pubertal boys receiving growth hormone (GH).
MATERIALS AND METHODS
Pubertal boys who received both GH and anastrozole (GH+A) were one-to-one matched with boys who received only GH (GH-Only) for chronological and bone age, pubertal stage and height before the GH initiation, treatment duration and midparental height. Anthropometric measurements throughout treatment and adult heights were compared between the groups. Sex hormone levels were evaluated longitudinally in the GH+A group.
RESULTS
Forty-eight cases (24 in each group) were included. There was no statistical difference in adult height between the GH+A and GH-Only (p = 0.071). However, when the analysis was limited to those receiving anastrozole for at least 2 years, mean adult height was higher in the GH+A than in the GH-Only group (173.1 ± 6.2/169.8 ± 5.6 cm, p = 0.044). Despite similar growth rates between the two groups, bone age advancement was slower in the GH+A than in the GH-Only in a mean anastrozole treatment period of 1.59 years (1.37 ± 0.80/1.81 ± 0.98 years, p = 0.001). The greatest increase for FSH, LH, total and free testosterone and decrease for estradiol levels were observed in the third month after anastrozole was started, albeit remaining within the normal ranges according to the actual pubertal stages.
CONCLUSION
Using anastrozole with GH for at least 2 years decelerates the bone age advancement resulting in adult height gain with no abnormality in sex hormone levels. These results suggest anastrozole can be used as an additional treatment to GH for further height gain in pubertal boys.
Topics: Male; Adult; Humans; Infant; Anastrozole; Growth Hormone; Retrospective Studies; Growth Disorders; Human Growth Hormone; Testosterone; Body Height; Puberty
PubMed: 37988665
DOI: 10.20945/2359-4292-2022-0524 -
American Journal of Cardiovascular... Jan 2024Pulmonary arterial hypertension (PAH) is a progressive, cureless disease, characterized by increased pulmonary vascular resistance and remodeling, with subsequent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pulmonary arterial hypertension (PAH) is a progressive, cureless disease, characterized by increased pulmonary vascular resistance and remodeling, with subsequent ventricular dilatation and failure. New therapeutic targets are being investigated for their potential roles in improving PAH patients' symptoms and reversing pulmonary vascular pathology.
METHOD
We aimed to address the available knowledge from the published randomized controlled trials (RCTs) regarding the role of Rho-kinase (ROCK) inhibitors, bone morphogenetic protein 2 (BMP2) inhibitors, estrogen inhibitors, and AMP-activated protein kinase (AMPK) activators on the PAH evaluation parameters. This systematic review (SR) was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CDR42022340658) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS
Overall, 5092 records were screened from different database and registries; 8 RCTs that met our inclusion criteria were included. The marked difference in the study designs and the variability of the selected outcome measurement tools among the studies made performing a meta-analysis impossible. However, the main findings of this SR relate to the powerful potential of the AMPK activator and the imminent antidiabetic drug metformin, and the BMP2 inhibitor sotatercept as promising PAH-modifying therapies. There is a need for long-term studies to evaluate the effect of the ROCK inhibitor fasudil and the estrogen aromatase inhibitor anastrozole in PAH patients. The role of tacrolimus in PAH is questionable. The discrepancy in the hemodynamic and clinical parameters necessitates defining cut values to predict improvement. The differences in the PAH etiologies render the judgment of the therapeutic potential of the tested drugs challenging.
CONCLUSION
Metformin and sotatercept appear as promising therapeutic drugs for PAH.
CLINICAL TRIALS REGISTRATION
This work was registered in PROSPERO (CDR42022340658).
Topics: Humans; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; AMP-Activated Protein Kinases; Familial Primary Pulmonary Hypertension; Estrogens; Metformin
PubMed: 37945977
DOI: 10.1007/s40256-023-00613-5 -
Frontiers in Pharmacology 2023The activation of the P2X7 receptor subtype (P2X7R) has a main role in orchestrating the cellular inflammatory response in many different tissues. Obesity is...
The activation of the P2X7 receptor subtype (P2X7R) has a main role in orchestrating the cellular inflammatory response in many different tissues. Obesity is characterized by dysfunctional fat deposition leading to a tissue-specific and systemic low-grade inflammation. Androgens and estrogens contribute to the whole adipose tissue inflammatory state, but the involvement of sex steroids in the purinergic signaling modulation in adipocytes is still unknown. We performed an study to evaluate the possible role of sex hormones on the P2X7R gene expression in human adipocytes, at baseline and after stimulation with bacterial lipopolysaccharide (LPS). We evaluated P2X7R gene expression during differentiation of human adipocytes, in the absence and presence of testosterone (T) and 17β-estradiol (E2) in the presence and absence of LPS. Furthermore, we analyzed the effects of incubation with dihydrotestosterone (DHT), a non-aromatizable androgen, using the co-incubation of isolated human adipocytes with T alone or in combination with anastrozole, an inhibitor of aromatase, the enzyme responsible of T conversion to E2. At baseline, incubation of adipocytes with T or E2 did not significantly affect P2X7R gene expression. On the contrary, the incubation with DHT was associated with a significant reduction of P2X7R gene expression. LPS incubation significantly increased gene expression of P2X7R with respect to baseline. Interestingly, after LPS stimulation, DHT exposure showed an additional effect, markedly increasing the P2X7R gene expression. This amplificatory effect was confirmed by the incubation of adipocytes to both anastrozole and testosterone. In these experimental conditions, while no effect was observed at baseline, an amplification of the expression of the P2X7R mRNA was observed after stimulation with LPS. The purinergic system is involved in the inflammatory response of adipocytes, and androgens may modulate its activity. In particular DHT, a non-aromatizable androgen, amplifies the LPS-induced P2X7R gene expression in human adipocytes thus showing a gender regulated response of the expression of this purinergic receptor strongly involved in the inflammatory response in adipose tissue.
PubMed: 37936906
DOI: 10.3389/fphar.2023.1251035 -
Frontiers in Pharmacology 2023Endocrine therapies (ETs) and inhibitors of cyclin-dependent kinases-4/6 (iCDK4/6s) are a standard treatment in breast cancer. However, data on potential neurocognitive...
Neurocognitive impairment in females with breast cancer treated with endocrine therapy and CDK4/6 inhibitors: a pharmacovigilance study using the World Health Organization's database.
Endocrine therapies (ETs) and inhibitors of cyclin-dependent kinases-4/6 (iCDK4/6s) are a standard treatment in breast cancer. However, data on potential neurocognitive impacts remain inconsistent for ET and are scarce for iCDK4/6s. To evaluate whether ET and iCDK4/6s are associated with neurocognitive impairment (NCI). We used observational, real-world cases of NCI from the World Health Organization's database VigiBase to perform disproportionality analysis. Cases were defined as any symptom of NCI in females treated with ETs or iCDK4/6s. The study period was from the date of the first adverse event reported in VigiBase with iCDK4/6s (1 January 2014) until the date of data extraction (16 March 2022). In our primary analysis, we calculated the reporting odds ratio (ROR) adjusted for age to identify a potential association between NCI and individual ETs in isolation or in combination with iCDK4/6s. We also performed subgroup analyses by the NCI class. We identified 2.582 and 1.943 reports of NCI associated with ETs and iCDK4/6s, respectively. NCI was significantly associated with each ET [anastrozole: = 405, aROR = 1.52 (95% CI: 1.37-1.67); letrozole: = 741, aROR = 1.37 (95% CI: 1.27-1.47); exemestane: = 316, aROR = 1.37 (95% CI: 1.22-1.53); tamoxifen: = 311, aROR = 1.25 (95% CI: 1.12-1.40); and fulvestrant: = 319, aROR = 1.19 (95% CI: 1.06-1.33)] and only with palbociclib for iCDK4/6s [ = 1,542, aROR = 1.41 (95% CI: 1.34-1.48)]. These findings suggest that in females treated for breast cancer, all ETs may be associated with NCI. However, amongst iCDK4/6s, NCI may be specific to palbociclib. NCI most frequently involved learning and memory as well as language. Neurocognitive impact of treatments requires better consideration and management.
PubMed: 37927591
DOI: 10.3389/fphar.2023.1278682 -
JCEM Case Reports May 2023An 8-year, 7-month-old male presented with puberty symptoms, including a 1.5-year history of facial hair with 9 months of phallic growth, body odor, and acne. Physical...
An 8-year, 7-month-old male presented with puberty symptoms, including a 1.5-year history of facial hair with 9 months of phallic growth, body odor, and acne. Physical examination revealed phallic enlargement but only 4 mL testes bilaterally. Laboratory evaluation revealed markedly elevated LH and testosterone, but a prepubertal FSH level and minimally elevated adrenal androgens. A magnetic resonance imaging scan of the head revealed an anterior pituitary adenoma, and after the patient failed to respond to leuprolide, he was initiated on spironolactone and anastrozole to minimize pubertal progression before transsphenoidal adenomectomy. Postoperatively, the patient had rapid reduction of LH and testosterone, with subsequent cessation of pubertal progression, confirming the diagnosis of an LH-secreting pituitary adenoma despite negative immunoreactivity for LH and FSH. Functioning gonadotroph adenomas are rare and have been documented only in small case series and case reports. When active, these most commonly secrete FSH or co-secrete FSH and LH, and only very rarely result in precocious puberty. Here, we describe a rare case of an isolated LH-secreting functioning gonadotroph adenoma resulting in precocious puberty. This case reinforces the need to critically analyze departures from the typical pubertal sequence and to expand one's differential to include etiologies that can cause unbalanced secretion of gonadotropins.
PubMed: 37908585
DOI: 10.1210/jcemcr/luad055 -
Pharmaceuticals (Basel, Switzerland) Oct 2023In the development of bioanalytical LC-MS methods for the determination of drugs in plasma samples in a clinical setting, adequate sample preparation is of utmost...
In the development of bioanalytical LC-MS methods for the determination of drugs in plasma samples in a clinical setting, adequate sample preparation is of utmost importance. The main goals are to achieve the selective extraction of the analytes of interest and attain thorough matrix removal while retaining acceptable ecological properties, cost-effectiveness, and high throughput. Solid-phase extraction (SPE) offers a versatile range of options, from the selection of an appropriate sorbent to the optimisation of the washing and elution conditions. In this work, the first SPE method for the simultaneous extraction of six anticancer drugs used in novel therapeutic combinations for advanced breast cancer treatment-palbociclib, ribociclib, abemaciclib, anastrozole, letrozole, and fulvestrant-was developed. The following sorbent chemistries were tested: octylsilyl (C8), octadecylsilyl (C18), hydrophilic-lipophilic balance (HLB), mixed-mode cation-exchange (MCX and X-C), and mixed-mode weak cation-exchange (WCX), with different corresponding elution solvents. The samples were analysed using LC-MS/MS, with a phenyl column (150 × 4.6 mm, 2.5 μm). The best extraction recoveries (≥92.3%) of all analytes were obtained with the C8 phase, using methanol as the elution solvent. The optimised method was validated in the clinically relevant ranges, showing adequate precision (inter-day RSD ≤ 14.3%) and accuracy (inter-day bias -12.7-13.5%). Finally, its applicability was successfully proven by the analysis of samples from breast cancer patients.
PubMed: 37895916
DOI: 10.3390/ph16101445 -
Pharmaceuticals (Basel, Switzerland) Sep 2023Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are a recent targeted therapy approved for patients with hormone receptor-positive (HR+), human epidermal growth...
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are a recent targeted therapy approved for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Abemaciclib, palbociclib and ribociclib demonstrated great efficacy and safety during clinical studies. However, differences in their adverse-event profiles have been observed. This work aims to describe the suspected adverse drug reactions (ADRs), such as leukopenia and thrombocytopenia, reported for each CDK4/6 inhibitor in the EudraVigilance (EV) database. Data on individual case safety reports (ICSRs) were obtained by accessing the European spontaneous reporting system via the EV website. Information on concomitant drug therapy, including fulvestrant, letrozole, anastrozole and exemestane, was also analyzed. A total of 1611 ICSRs were collected from the EV database. Most reports of palbociclib and ribociclib were classified as serious cases for both suspected leukopenia and thrombocytopenia ADRs. However, most patients had their leukopenia and thrombocytopenia recovered/resolved. On the contrary, reports of abemaciclib were mostly characterized as non-serious cases. Abemaciclib and palbociclib were often combined with fulvestrant, while ribociclib was generally associated with letrozole. Pharmacovigilance studies are crucial for the early identification of potential ADRs and to better differentiate the toxicity profile of the different CDK4/6 inhibitors, particularly in a real-world setting.
PubMed: 37895811
DOI: 10.3390/ph16101340 -
Cancer Biology & Therapy Dec 2023Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of...
PURPOSE
Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of apatinib combined with exemestane in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC).
METHODS
This single-center, single-arm phase II study enrolled patients with ER+/HER2- MBC progressed on previous letrozole or anastrozole. Stratified analysis was performed according to the number of chemotherapy regimens for metastatic disease. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and toxicity. Patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1-28 of each 4-week cycle.
RESULTS
Thirty patients were enrolled with median four prior anticancer therapies. Eighty percent of patients received chemotherapy for metastatic disease. The median PFS (mPFS) and OS were 5.6 (95%CI: 4.3-6.9) months and 15.7 (95% CI: 9.7-21.7) months, respectively. The ORR, DCR, and CBR were 21.4%, 71.4%, and 46.4%, respectively. Patients with 0-1 line chemotherapy for MBC showed a slightly longer mPFS compared to those with ≥2 lines chemotherapy (mPFS: 6.4 months vs 4.8 months, = .090). Most of the AEs were grade 1/2. One patient (3.3%) who suffered bone marrow metastases experienced grade 4 thrombocytopenia, and 14 experienced grade 3 AEs. Fifty percent of patients were given reduced dose for apatinib.
CONCLUSIONS
Apatinib plus exemestane exhibited objective efficacy in patients with ER+/HER2- MBC who have failed multiple lines of treatment. The AEs of apatinib required close monitoring and most of patients were well tolerated.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Receptors, Estrogen; Vascular Endothelial Growth Factor A
PubMed: 37831547
DOI: 10.1080/15384047.2023.2265055 -
Biomedicine & Pharmacotherapy =... Dec 2023Brain glucose hypometabolism is a significant manifestation of Alzheimer's disease (AD). 27-hydroxycholesterol (27-OHC) and the gut microbiota have been recognized as...
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-[ F] fluorodeoxyglucose (F-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.
Topics: Mice; Male; Animals; Gastrointestinal Microbiome; Mice, Inbred C57BL; Brain; Alzheimer Disease; Memory Disorders; Glucose; Anti-Bacterial Agents
PubMed: 37806088
DOI: 10.1016/j.biopha.2023.115649