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Life (Basel, Switzerland) Dec 2023Bisphenol A (BPA) is an endocrine-disruptive chemical that is widely utilized in the production of polycarbonate plastic and epoxy resin, which are used to make a wide...
Bisphenol A (BPA) is an endocrine-disruptive chemical that is widely utilized in the production of polycarbonate plastic and epoxy resin, which are used to make a wide range of consumer products, food and drink containers, and medical equipment. When the potential risk of BPA emerged, it was substituted by allegedly less harmful substitutes such as bisphenols S, F, B, and AF. However, evidence suggests that all bisphenols can have endocrine-disruptive effects, while the extent of these effects is unknown. This study aimed to determine effect of BPA, BPAF, BPB, BPF, and BPS on viability and steroidogenesis in human adrenocortical carcinoma cell line in vitro. The cytotoxicity of bisphenols was shown to be considerable at higher doses. However, at low concentrations, it improved viability as well as steroid hormone secretion, indicating that bisphenols have a biphasic, hormetic effect in biological systems. The results are consistent with the hypothesis that bisphenols selectively inhibit some steroidogenic enzymes. These findings suggest that bisphenols have the potential to disrupt cellular steroidogenesis in humans, but substantially more detailed and systematic research is needed to gain a better understanding of the risks associated with bisphenols and their endocrine-disrupting effect on humans and wildlife.
PubMed: 38276253
DOI: 10.3390/life14010003 -
Hypogonadism and sexual function in men affected by adrenocortical carcinoma under mitotane therapy.Frontiers in Endocrinology 2023Adrenocortical carcinoma (ACC) is a rare and aggressive tumor. ACC male patients under adjuvant mitotane therapy (AMT) frequently develop hypogonadism, however sexual...
PURPOSE
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor. ACC male patients under adjuvant mitotane therapy (AMT) frequently develop hypogonadism, however sexual function has never been assessed in this setting. The aim of this retrospective study was to evaluate in AMT treated ACC patients the changes in Luteinizing hormone (LH), Sex Hormone Binding Globulin (SHBG), total testosterone (TT) and calculated free testosterone (cFT), the prevalence and type of hypogonadism and sexual function, the latter before and after androgen replacement therapy (ART).
METHODS
LH, SHBG, TT and cFT were assessed in ten ACC patients at baseline (T0) and six (T1), twelve (T2), and eighteen (T3) months after AMT. At T3, ART was initiated in eight hypogonadal patients, and LH, SHBG, TT and cFT levels were evaluated after six months (T4). In six patients, sexual function was evaluated before (T3) and after (T4) ART using the International Index of Erectile Function-15 (IIEF-15) questionnaire.
RESULTS
Under AMT we observed higher SHBG and LH and lower cFT levels at T1-T3 compared to T0 (all p<0.05). At T3, hypergonadotropic hypogonadism and erectile dysfunction (ED) were detected in 80% and 83.3% of cases. At T4, we observed a significant cFT increase in men treated with T gel, and a significant improvement in IIEF-15 total and subdomains scores and ED prevalence (16.7%) in men under ART.
CONCLUSION
AMT was associated with hypergonatropic hypogonadism and ED, while ART led to a significant improvement of cFT levels and sexual function in the hypogonadal ACC patients. Therefore, we suggest to evaluate LH, SHBG, TT and cFT and sexual function during AMT, and start ART in the hypogonadal ACC patients with sexual dysfunction.
Topics: Humans; Male; Mitotane; Adrenocortical Carcinoma; Retrospective Studies; Testosterone; Erectile Dysfunction; Luteinizing Hormone; Adrenal Cortex Neoplasms; Hypogonadism
PubMed: 38269251
DOI: 10.3389/fendo.2023.1320722 -
Frontiers in Endocrinology 2023Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis.... (Review)
Review
Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.
Topics: United States; Humans; Adrenocortical Carcinoma; Wnt Signaling Pathway; beta Catenin; Neoplastic Processes; Adrenal Cortex Neoplasms
PubMed: 38269250
DOI: 10.3389/fendo.2023.1260701 -
Frontiers in Endocrinology 2023Adrenocortical carcinoma (ACC) is rare and have high rates of recurrence and mortality. The role of adjuvant radiation therapy (RT) in localized ACC was controversial.
CONTEXT
Adrenocortical carcinoma (ACC) is rare and have high rates of recurrence and mortality. The role of adjuvant radiation therapy (RT) in localized ACC was controversial.
METHODS
We conducted a retrospective study in our center between 2015 and 2021 to evaluate the efficacy and safety of adjuvant RT in localized ACC. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to estimate the independent risk factors. Adverse events associated with RT were documented according to the toxicity criteria of the radiation therapy oncology group (RTOG) and the common terminology criteria for adverse events (CTCAE v5.0).
RESULTS
Of 105 patients with localized ACC, 46 (43.8%) received adjuvant RT after surgery. The median radiation dose was 45.0Gy (range:30.0-50.4) and median follow up time was 36.5 (IQR: 19.7-51.8) months. In comparison to the no adjuvant RT group, patients with adjuvant RT had better 3-year OS (87.9% vs 79.5%, P=0.039), especially for patients with ENSAT I/II stage (P=0.004). Adjuvant RT also improved the median DFS time from 16.5months (95%CI, 12.0-20.9) to 34.6months (95%CI, 16.1-53.0). Toxicity of RT was generally mild and moderate with six grade 3 events.
CONCLUSIONS
Postoperative adjuvant RT significantly improved OS and DFS compared with the use of surgery alone in resected ACC patients. Although this retrospective study on RT in localized ACC indicates that RT is effective in ACC, its findings need to be prospectively confirmed.
Topics: Humans; Adrenocortical Carcinoma; Radiotherapy, Adjuvant; Retrospective Studies; Disease-Free Survival; Adrenal Cortex Neoplasms
PubMed: 38260140
DOI: 10.3389/fendo.2023.1308231 -
Pharmaceuticals (Basel, Switzerland) Dec 2023Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As... (Review)
Review
Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.
PubMed: 38256859
DOI: 10.3390/ph17010025 -
International Journal of Molecular... Jan 2024The discovery of mitochondria-derived peptides (MDPs) has provided a new perspective on mitochondrial function. MDPs encoded by mitochondrial DNA (mtDNA) can act as...
The discovery of mitochondria-derived peptides (MDPs) has provided a new perspective on mitochondrial function. MDPs encoded by mitochondrial DNA (mtDNA) can act as hormone-like peptides, influencing cell survival and proliferation. Among these peptides, humanin has been identified as a crucial factor for maintaining cell survival and preventing cell death under various conditions. Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy that results from adrenal hormone dysfunction. This study aimed to investigate humanin expression in the adrenal tissue and serum of patients with ACC. For the first time, our study revealed significant reduction in the mRNA expression of humanin in patients with ACC compared to healthy controls. However, no significant changes were observed in the serum humanin levels. Interestingly, we identified a positive correlation between patient age and serum humanin levels and a negative correlation between tumor size and LDL levels. While the impaired expression of humanin in patients with ACC may be attributed to mitochondrial dysfunction, an alternative explanation could be related to diminished mitochondrial copy number. Further investigations are warranted to elucidate the intricate relationship among humanin, mitochondrial function, and ACC pathology.
Topics: Humans; Adrenocortical Carcinoma; Intracellular Signaling Peptides and Proteins; DNA, Mitochondrial; Adrenal Cortex Neoplasms; Hormones
PubMed: 38256114
DOI: 10.3390/ijms25021038 -
International Journal of Molecular... Jan 2024Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the... (Review)
Review
Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the severity of the hypertension. The principal aetiologies of PA include bilateral idiopathic hypertrophy (BIH) and aldosterone-producing adenomas (APAs), while the less frequent causes include unilateral hyperplasia, familial hyperaldosteronism (FH) types I-IV, aldosterone-producing carcinoma, and ectopic aldosterone synthesis. This condition, characterised by excessive aldosterone secretion, leads to augmented sodium and water reabsorption alongside potassium loss, culminating in distinct clinical hallmarks: elevated aldosterone levels, suppressed renin levels, and hypertension. Notably, hypokalaemia is present in only 28% of patients with PA and is not a primary indicator. The association of PA with an escalated cardiovascular risk profile, independent of blood pressure levels, is notable. Patients with PA exhibit a heightened incidence of cardiovascular events compared to counterparts with essential hypertension, matched for age, sex, and blood pressure levels. Despite its prevalence, PA remains frequently undiagnosed, underscoring the imperative for enhanced screening protocols. The diagnostic process for PA entails a tripartite assessment: the aldosterone/renin ratio (ARR) as the initial screening tool, followed by confirmatory and subtyping tests. A positive ARR necessitates confirmatory testing to rule out false positives. Subtyping, achieved through computed tomography and adrenal vein sampling, aims to distinguish between unilateral and bilateral PA forms, guiding targeted therapeutic strategies. New radionuclide imaging may facilitate and accelerate such subtyping and localisation. For unilateral adrenal adenoma or hyperplasia, surgical intervention is optimal, whereas bilateral idiopathic hyperplasia warrants treatment with mineralocorticoid antagonists (MRAs). This review amalgamates established and emerging insights into the management of primary aldosteronism.
Topics: Humans; Aldosterone; Hyperplasia; Renin; Hypertension; Adrenocortical Adenoma; Hyperaldosteronism
PubMed: 38255973
DOI: 10.3390/ijms25020900 -
Metabolites Dec 2023Serum liquid chromatography-tandem mass spectrometry (LC-MS/MS) steroid profiling is used for the diagnosis of adrenocortical carcinoma (ACC). Guidelines recommend...
Serum liquid chromatography-tandem mass spectrometry (LC-MS/MS) steroid profiling is used for the diagnosis of adrenocortical carcinoma (ACC). Guidelines recommend endocrine work-up in addition to radiological imaging for follow-up in ACC, but data on this topic are scarce. Patients were included in this retrospective study if pre-therapeutic hormone values, regular tumour evaluation by imaging, steroid measurements by LC-MS/MS, and details on therapies were available. The utility of steroid profiles in detecting recurrence or disease progression was assessed, whereby "endocrine progress" was defined by an elevation of at least 3 of 13 analysed hormones. Cohort A included 47 patients after R0 resection, of whom 15 experienced recurrence and 32 did not. In cohort B, 52 patients with advanced disease (including 7 patients of cohort A with recurrence) could be evaluated on 74 visits when progressive disease was documented. In 20 of 89 cases with documented disease progression, "endocrine progress" was detectable prior to radiological progress. In these cases, recurrence/progression was detected at a median of 32 days earlier by steroid measurement than by imaging, with 11-deoxycortisol and testosterone being the most sensitive markers. Notably, these patients had significantly larger tumour burden. In conclusion, steroid profiling by LC-MS/MS is of value in detecting recurrent/progressive disease in ACC.
PubMed: 38248823
DOI: 10.3390/metabo14010020 -
Frontiers in Immunology 2023Tubulin epsilon and delta complex 2 (TEDC2) is widely expressed in various human tissues and primarily governs centriole stability. However, the biological significance...
INTRODUCTION
Tubulin epsilon and delta complex 2 (TEDC2) is widely expressed in various human tissues and primarily governs centriole stability. However, the biological significance of TEDC2 in pan-cancer is unclear.
METHODS
In this study, we employed R software and various online bioinformatics analysis tools to investigate the functional attributes of TEDC2 in human tumours and its potential involvement in immune response. The status of TEDC2 expression was evaluated in samples from the TCGA and GEO datasets, as well as in tumour and corresponding normal samples from the TCGA database. Subsequently, Kaplan-Meier estimates, clinical correlations, and univariate Cox regressions were used to analyze the 33 types of tumors from TCGA and determine the prognostic significance of TEDC2. Moreover, nomogram models were formulated using three distinct tumours, namely kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), and liver hepatocellular carcinoma (LIHC), to evaluate the prognostic significance of TEDC2 in tumours. Furthermore, TEDC2 was investigated for its correlation with the levels of immune cell infiltration, and a functional enrichment analysis was conducted to identify potential signalling pathways involving TEDC2.
RESULTS
Differential analysis revealed that 16 tumour types expressed TEDC2 to a greater extent than normal tissues. The abnormal expression of TEDC2 can predict survival outcomes in patients with adrenocortical carcinoma (ACC), KIRC, kidney renal papillary cell carcinoma (KIRP), LUAD, LIHC, lower grade glioma (LGG), and thymoma (THYM). Subsequent results indicated that TEDC2 has the ability to influence ECM regulators, cell cycle, and Immune checkpoint-associated signalling pathways, which could potentially lead to a poor prognosis and tumour progression.
DISCUSSION
TEDC2 has been identified as a potential therapeutic target that could predict the prognosis of multiple tumour types, making it a promising target for reversing tumour development.
Topics: Humans; Tubulin; Prognosis; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Adenocarcinoma of Lung; Thymus Neoplasms; Liver Neoplasms; Kidney Neoplasms; Lung Neoplasms; Adrenal Cortex Neoplasms
PubMed: 38239349
DOI: 10.3389/fimmu.2023.1272108 -
Endocrine Connections Mar 2024Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered...
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression.
AIM
The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort.
METHODS
Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI.
RESULTS
Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1-133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: -19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups.
CONCLUSION
Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.
PubMed: 38236710
DOI: 10.1530/EC-23-0159