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Gynecological Endocrinology : the... Oct 2023Polycystic ovary syndrome (PCOS) was known as the common endocrine disease in women, featured as hyperandrogenism, ovulation disorders, etc. Fat mass and...
BACKGROUND
Polycystic ovary syndrome (PCOS) was known as the common endocrine disease in women, featured as hyperandrogenism, ovulation disorders, etc. Fat mass and obesity-associated protein (FTO), a m6A demethylase, is abnormal in the occurrence of ovarian diseases. However, the mechanism of FTO in the pathogenesis of PCOS is still unclear.
METHODS
The level of FTO in clinical samples, PCOS rat with hyperandrogenism and granulosa cells (GCs) lines effected by DHT were investigated by ELISA, qRT-PCR, WB, and IHC, while m6A RNA methylation level was studied by m6A Colorimetric and androgen level was tested through ELISA. Changes in steroid hormone synthetase and androgen receptor (AR)/prostate-specific antigen (PSA) levels were visualized by WB after transient transfection silenced FTO. The effect of DHT combined with FTO inhibitor meclofenamic acid (MA) on FTO, AR/PSA, and AKT phosphorylation were also demonstrated by WB. The co-localization of FTO and AR in KGN cells was analyzed by confocal microscopy, and the physiological interaction between FTO and AR was studied by Co-IP assay. The effect of FTO-specific inhibitor MA, AKT phosphorylation inhibitor LY294002, and the combined them on GCs proliferation and cell cycle were evaluated by drug combination index, EDU assay, and flow cytometry analysis.
RESULTS
FTO expression was upregulated in follicular fluid and GCs in PCOS patients clinically. The high FTO expression in patients was negative with the level of m6A, but positive with the level of androgen. The upregulation of FTO was accompanied with a decrease in the level of m6A in PCOS rat with hyperandrogenism. Dihydrotestosterone (DHT) promoted the FTO expression and inhibited m6A content as a dose-dependent way . In contrast, suppression of FTO with siRNA attenuated the expression of steroid hormone synthetase such as CYP11A1, CYP17A1, HSD11B1, HSD3B2 except CYP19A1 synthetase, ultimately inducing the decrease of androgen level. Suppression of FTO also decreased the biological activity of androgen through downregulation AR/PSA. MA treatment as the specific FTO antagonist decreased cell survival in time- and dose-dependent way in GCs lines. Correspondingly, MA treatment decreased the expression of FTO, AR/PSA expression, and AKT phosphorylation in the presence of DHT stimulation. Additionally, we also speculate there is a potential relation between FTO and AR according to FTO was co-localized and interacted with AR in KGN cells. Compared with AKT phosphorylation inhibitor LY294002 or MA alone, LY294002 combined with MA synergistically inhibited cell survival and increased G2/M phase arrest in GC line.
CONCLUSIONS
We first evaluated the correlation of FTO and m6A in PCOS clinically, and further explored the mechanism between FTO and hyperandrogenism in PCOS animal and cell models. These findings contributed the potential therapy by targeting the FTO for hyperandrogenism in PCOS.
Topics: Animals; Female; Humans; Rats; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Androgens; Dihydrotestosterone; Granulosa Cells; Hyperandrogenism; Ligases; Polycystic Ovary Syndrome; Prostate-Specific Antigen; Proto-Oncogene Proteins c-akt
PubMed: 37931646
DOI: 10.1080/09513590.2023.2276167 -
Research Square Aug 2023gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these...
BACKGROUND
gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear.
METHODS
Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types.
RESULTS
In total, 540 CRPC patients who received ARTA and had tissue-based (n=321) and/or blood-based (n=244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with amplifications (25.7 months) compared to those without an alteration (9.6 months; p=0.03). In the post-ARTA group (n=406), mutations and amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was (9.9%).
CONCLUSION
To our knowledge, this is the largest real-world clinicogenomics database-driven study exploring the development of alterations and their association with ARTA treatment outcomes. Our study showed that amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with alterations.
PubMed: 37609284
DOI: 10.21203/rs.3.rs-3201150/v1 -
BioRxiv : the Preprint Server For... Oct 2023Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor...
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor , among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.
PubMed: 37905039
DOI: 10.1101/2023.09.28.560025 -
British Journal of Cancer Dec 2023Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular...
BACKGROUND
Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer.
METHODS
Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist's cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding.
RESULTS
We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth.
CONCLUSION
Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients.
Topics: Humans; Male; Androgen Antagonists; Androgens; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Microfilament Proteins; Prostatic Neoplasms; Receptors, Androgen; Neuroendocrine Tumors
PubMed: 37875732
DOI: 10.1038/s41416-023-02449-x -
Endocrine Journal Oct 2023Optimizing the glucocorticoid dosage has been a major concern in classic 21OHD (21-hydroxylase deficiency) treatment, as it is essential to adjust it meticulously to the... (Review)
Review
Optimizing the glucocorticoid dosage has been a major concern in classic 21OHD (21-hydroxylase deficiency) treatment, as it is essential to adjust it meticulously to the needs of the individual patient. Insufficient glucocorticoid treatment will cause adrenal insufficiency, including life-threatening adrenal crisis, while excess of androgen could cause precocious pubertal growth in children, virilization in female patients, and infertility in male and female adult patients. Meanwhile, overtreatment with glucocorticoids causes iatrogenic Cushing's syndrome which could result in growth impairment, obesity, osteoporosis, and hypertension. The dilemma of 21OHD treatment is that glucocorticoid supplementation therapy at physiological dosage does not sufficiently suppress ACTH, consequently leading to adrenal androgen excess. Accordingly, the window for the appropriate glucocorticoid treatment would have to be substantially narrower than that of other types of adrenal insufficiency without androgen excess, such as adrenal hypoplasia. For the appropriate management of classic 21OHD, the physician has to be well versed in the physiology of the adrenal cortex, growth, and reproductive function. Comprehensive understanding of patients' requirements according to their life stage and sex is essential. Furthermore, female patients with 46,XX need to be cared for as differences in sex development (DSD) with careful psychological management. In this review, we aimed to comprehensively summarize the current status of classic 21OHD treatment, including the initial treatment during the neonatal period, management of adrenal insufficiency, maintenance therapy of each life stage, and the importance of clinical management as DSD for 46,XX female patients. The recently developed agents, Chronocort, and Crinecerfont, are also discussed.
Topics: Adult; Child; Infant, Newborn; Humans; Male; Female; Glucocorticoids; Androgens; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Steroid 21-Hydroxylase
PubMed: 37380491
DOI: 10.1507/endocrj.EJ23-0075 -
EBioMedicine Sep 2023Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of...
BACKGROUND
Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear.
METHODS
ACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues.
FINDINGS
Discriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis.
INTERPRETATION
This study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS.
FUNDING
JSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JSTA-STEP, JST-Moonshot, and Ono Medical Research Foundation.
Topics: Humans; Female; Adrenal Gland Neoplasms; Hydrocortisone; Androgens; Androsterone; Cushing Syndrome; Glucuronides; Steroids; Osteoporosis; Steroid 21-Hydroxylase
PubMed: 37543511
DOI: 10.1016/j.ebiom.2023.104733 -
Cell Reports Jan 2024Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy....
Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy. Unfortunately, despite initial treatment response, resistance nearly always develops, and disease progresses to castration-resistant prostate cancer (CRPC), which remains driven by non-gonadal androgens synthesized in prostate cancer tissues. 3β-Hydroxysteroid dehydrogenase/Δ isomerase 1 (3βHSD1) catalyzes the rate-limiting step in androgen synthesis. However, how 3βHSD1, especially the "adrenal-permissive" 3βHSD1(367T) that permits tumor synthesis of androgen from dehydroepiandrosterone (DHEA), is regulated at the protein level is not well understood. Here, we investigate how hypoxia regulates 3βHSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3βHSD1 protein by suppressing autophagy. Autophagy inhibition promotes 3βHSD1-dependent tumor progression. Hypoxia represses transcription of autophagy-related (ATG) genes by decreasing histone acetylation. Inhibiting deacetylase (HDAC) restores ATG gene transcription under hypoxia. Therefore, HDAC inhibition may be a therapeutic target for hypoxic tumor cells.
Topics: Male; Humans; Androgens; Prostatic Neoplasms; Androgen Antagonists; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Cell Line, Tumor
PubMed: 38181788
DOI: 10.1016/j.celrep.2023.113575 -
The Journal of Sexual Medicine Nov 2023Pelvic pain has been reported in transmasculine individuals taking testosterone. There is a need for further investigation to increase understanding of the prevalence...
BACKGROUND
Pelvic pain has been reported in transmasculine individuals taking testosterone. There is a need for further investigation to increase understanding of the prevalence and risk factors of this pain.
AIM
We sought to determine the prevalence of pelvic pain reported by transmasculine individuals who had both a uterus and ovaries and were taking testosterone.
METHODS
We conducted an institutional review board-approved retrospective study of all transmasculine individuals who had been taking testosterone for at least 1 year and had a uterus and ovaries at the time of testosterone initiation. Charts of participating patients were reviewed to determine patient characteristics, testosterone use, and pelvic pain symptoms both before and after initiation of testosterone.
OUTCOMES
Patients reported experiences of pelvic pain while on testosterone.
RESULTS
Of 280 individuals who had been on testosterone for at least 1 year, 100 (36%) experienced pelvic pain while on testosterone. Of those patients, 71% (n = 71) had not experienced pelvic pain prior to starting testosterone. There were 42 patients (15%) who had pelvic pain prior to starting testosterone, 13 (31%) of whom no longer experienced pain once starting testosterone. The median (IQR) age at initiation of testosterone was 22 (19-41) years and duration of testosterone treatment was 48 (27-251) months.Those patients who experienced pelvic pain while on testosterone were significantly more likely to have also reported pelvic pain prior to starting testosterone (29% vs 7%, P < .001). These patients were also more likely to have a pre-existing diagnosis of dysmenorrhea (27% vs 7%, P < .001), endometriosis (6% vs 2%, P = .049), or ovarian cysts and/or masses (12% vs 2% P < .001). Patients with pelvic pain were also more likely to have been on a menstrual suppression agent prior to and overlapping testosterone initiation (22% vs 12%, P = .03) and to have used menstrual suppression for longer durations (median [IQR] 18 [6-44] vs 8 [4-15] months, P = .04).
CLINICAL IMPLICATIONS
Pelvic pain is common in transmasculine individuals who are initiating testosterone treatment, although testosterone has both positive and negative effects on pelvic pain in different individuals.
STRENGTHS AND LIMITATIONS
The major strengths of this study included large numbers of patients, ability to assess for documentation of pelvic pain prior to testosterone, and ability to determine an actual prevalence of pelvic pain. Major limitations included the study being a retrospective analysis in a single tertiary care center, the limitations of clinical documentation, and the lack of a standard pelvic pain evaluation process.
CONCLUSION
More than one-third of transmasculine patients with a uterus and ovaries had pelvic pain while on testosterone, with the majority reporting onset of pain after initiating testosterone.
Topics: Female; Humans; Testosterone; Retrospective Studies; Transgender Persons; Prevalence; Pelvic Pain
PubMed: 37837637
DOI: 10.1093/jsxmed/qdad135 -
Redox Report : Communications in Free... Dec 2023The present study evaluated the effect of lead exposure with and without zinc therapy on male sexual and erectile function.
AIM
The present study evaluated the effect of lead exposure with and without zinc therapy on male sexual and erectile function.
METHODS
Twenty male Wistar rats were randomly assigned into four groups; the control, zinc-treated, lead-exposed, lead + zinc-treated groups. Administrations were per os daily for 28 days.
RESULTS
Zinc co-administration significantly improved absolute and relative penile weights and the latencies and frequencies of mount, intromission, and ejaculation in lead-exposed rats. Also, zinc ameliorated lead-induced reductions in motivation to mate and penile reflex/erection. These findings were accompanied by attenuation of lead-induced suppression of circulating nitric oxide (NO), penile cyclic guanosine monophosphate (cGMP), dopamine, serum luteinizing hormone, follicle-stimulating hormone, and testosterone. In addition, zinc alleviated lead-induced upregulation of penile activities of acetylcholinesterase and xanthine oxidase (XO), and uric acid (UA) and malondialdehyde (MDA) levels. Furthermore, zinc ameliorated the lead-induced decline in penile nuclear factor erythroid 2-related factor 2 (Nrf2) and reduced glutathione (GSH) levels, and catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) activities.
CONCLUSION
This study revealed that co-administration of zinc improves lead-induced sexual and erectile dysfunction by suppressing XO/UA-driven oxidative stress and upregulating testosterone via Nrf2-mediated signaling.
Topics: Male; Rats; Animals; Humans; Testosterone; Zinc; Erectile Dysfunction; Acetylcholinesterase; NF-E2-Related Factor 2; Rats, Wistar; Uric Acid
PubMed: 37345699
DOI: 10.1080/13510002.2023.2225675 -
Oncology Research 2023The androgen receptor (AR) is a critical target in all the clinical stages of prostate cancer. To identify a new AR inhibitor, we constructed a new screening system...
The androgen receptor (AR) is a critical target in all the clinical stages of prostate cancer. To identify a new AR inhibitor, we constructed a new screening system using the androgen-dependent growth of prostate cancer cell lines as a screening indicator. We screened 50,000 culture broths of microorganisms using this screening system and found that the fermentation broth produced by a fungus inhibited androgen-dependent growth of human prostate cancer LNCaP cells without cytotoxicity. Purification of this culture medium was performed, and this resulted in deoxynortryptoquivaline (DNT) being identified as a novel inhibitor of AR function. DNT showed potent inhibition of androgen-dependent growth of human prostate cancer LNCaP cells. The AR competitor assay was performed, and DNT did not act as an AR antagonist. However, DNT inhibited AR-dependent transcriptional activity and AR nuclear translocation, it suggested that the suppression of AR function leads to inhibition activity against androgen-dependent growth.
Topics: Male; Humans; Androgens; Prostatic Neoplasms; Cell Line
PubMed: 37744273
DOI: 10.32604/or.2023.030266