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International Journal of Molecular... Feb 2023Hexaconazole is widely used as a fungicide for agricultural purposes. However, the endocrine-disrupting potential of hexaconazole is still under investigation. In...
Hexaconazole is widely used as a fungicide for agricultural purposes. However, the endocrine-disrupting potential of hexaconazole is still under investigation. In addition, an experimental study found that hexaconazole may disrupt the normal synthesis of steroidal hormones. The potency of hexaconazole to bind with sex hormone-binding globulin (SHBG), a plasma carrier protein that binds androgens and oestrogens, is unknown. In this study, we evaluated the efficacy of hexaconazole to bind with SHBG by molecular interaction, a molecular dynamics method. In addition, principal component analysis was performed to understand the dynamical behaviour of hexaconazole with SHBG in comparison with dihydrotestosterone and aminoglutethimide. The binding scores of hexaconazole, dihydrotestosterone, and aminoglutethimide with SHBG were found to be -7.12 kcal/mol, -11.41 kcal/mol, and -6.84 kcal/mol, respectively. With respect to stable molecular interaction, hexaconazole showed similar molecular dynamics patterns of root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and hydrogen bonding. The solvent surface area (SASA) and principal component analysis (PCA) of hexaconazole exhibit similar patterns in comparison with dihydrotestosterone and aminoglutethimide. These results show that hexaconazole has a stable molecular interaction with SHBG, which may acquire the active site of the native ligand, resulting in significant endocrine disruption during agricultural work.
Topics: Aminoglutethimide; Androgens; Dihydrotestosterone; Sex Hormone-Binding Globulin; Triazoles
PubMed: 36835294
DOI: 10.3390/ijms24043882 -
The Journal of Urology Jul 2015Erythrocytosis is the most common dose limiting adverse effect of testosterone therapy but the mechanisms of testosterone mediated erythropoiesis remain unclear. In this...
PURPOSE
Erythrocytosis is the most common dose limiting adverse effect of testosterone therapy but the mechanisms of testosterone mediated erythropoiesis remain unclear. In this study we examine risk factors for erythrocytosis associated with testosterone therapy.
MATERIALS AND METHODS
A retrospective review was performed of 179 hypogonadal men on testosterone therapy at a single andrology clinic. Demographic data, testosterone therapy formulation and duration of treatment, and 5α-reductase inhibitor use were assessed. Serum dihydrotestosterone, total testosterone, free testosterone, follicle-stimulating hormone, luteinizing hormone, hematocrit and lipid levels were extracted, and changes during treatment were determined. Spearman's rank correlation was used to identify relationships between change in hematocrit and study variables.
RESULTS
Of 179 patients 49 (27%) experienced a 10% or greater change in hematocrit and erythrocytosis (hematocrit 50% or greater) developed in 36 (20.1%) at a median followup of 7 months. Topical gels were used by 41.3% of patients, injectable testosterone by 52.5% and subcutaneous pellets by 6.1%. More men who experienced a change in hematocrit of 10% or greater used injectable testosterone than men with a change in hematocrit of less than 10% (65% vs 48%, p=0.035), and were less likely to be on a 5α-reductase inhibitor (2% vs 15%, p=0.017). Men with a change in hematocrit of 10% or greater had higher posttreatment dihydrotestosterone levels (605.0 vs 436.0 ng/dl, p=0.017) and lower luteinizing hormone and follicle-stimulating hormone levels than men with a change in hematocrit of less than 10%. Spearman's rank correlations yielded relationships between change in hematocrit and posttreatment dihydrotestosterone ρ=0.258, p=0.001) and total testosterone (ρ=0.171, p=0.023).
CONCLUSIONS
Dihydrotestosterone may have a role in testosterone therapy related erythrocytosis and monitoring dihydrotestosterone levels during testosterone therapy should be considered. In men in whom erythrocytosis develops, 5α-reductase inhibitors may be therapeutic.
Topics: Adult; Dihydrotestosterone; Hormone Replacement Therapy; Humans; Male; Middle Aged; Polycythemia; Retrospective Studies; Risk Factors; Testosterone
PubMed: 25596360
DOI: 10.1016/j.juro.2015.01.038 -
Scientific Reports Aug 2021Hyperandrogenic women with PCOS show disrupted decidualization (DE) and placentation. Dihydrotestosterone (DHT) is reported to enhance DE in non-PCOS endometrial stromal...
Hyperandrogenic women with PCOS show disrupted decidualization (DE) and placentation. Dihydrotestosterone (DHT) is reported to enhance DE in non-PCOS endometrial stromal cells (eSC); however, this has not been assessed in PCOS cells (eSC). Therefore, we studied the transcriptome profile of non-decidualized (non-DE) and DE eSCs from women with PCOS and Ctrl in response to short-term estradiol (E2) and/or progesterone (P4) exposure with/without (±) DHT. The non-DE eSCs were subjected to E2 ± DHT treatment, whereas the DE (0.5 mM 8-Br-cAMP, 96 h) eSCs were post-treated with E2 and P4 ± DHT, and RNA-sequenced. Validation was performed by immunofluorescence and immunohistochemistry. The results showed that, regardless of treatment, the PCOS and Ctrl samples clustered separately. The comparison of DE vs. non-DE eSC without DHT revealed PCOS-specific differentially expressed genes (DEGs) involved in mitochondrial function and progesterone signaling. When further adding DHT, we detected altered responses for lysophosphatidic acid (LPA), inflammation, and androgen signaling. Overall, the results highlight an underlying defect in decidualized eSC, present with or without DHT exposure, and possibly linked to the altered pregnancy outcomes. We also report novel factors which elucidate the mechanisms of endometrial dysfunction in PCOS.
Topics: Adult; Androgens; Dihydrotestosterone; Endometrium; Estradiol; Female; Humans; Polycystic Ovary Syndrome; Pregnancy; Progesterone; Signal Transduction; Stromal Cells
PubMed: 34381107
DOI: 10.1038/s41598-021-95705-0 -
Parasite Immunology Mar 2018A strong sex-associated susceptibility towards Leishmania has been reported in males, yet little is known on the effect of hormones in Leishmania physiopathogenicity....
A strong sex-associated susceptibility towards Leishmania has been reported in males, yet little is known on the effect of hormones in Leishmania physiopathogenicity. Due to the enhanced susceptibility of males to Leishmania mexicana infections, we were interested in analysing the effect exerted by the main androgen produced in males (DHT) on L. mexicana promastigotes. Thus, the aim of this study was to assess the regulation exerted by dihydrotestosterone (DHT) on L. mexicana replication, infectivity, survival and development of tissue lesions. Experiments included growth curves of L. mexicana promastigotes incubated with different doses of DHT, their infection rate, intracellular survival and lesion development in BALB/c mice. Our data show that DHT significantly enhances parasite replication, infection rate and survival in bone marrow-derived macrophages (BMMФ). Promastigotes in the presence of DHT produced significantly larger lesions in BALB/c earlobes. These results suggest that DHT probably plays a critical role during L. mexicana infections, and the higher susceptibility of males possibly relates to benefits gained by the parasite from host-derived hormones. Our data shed new light on the physiopathology of Leishmania infections and are the first attempt to understand the direct interaction between Leishmania and androgens, particularly DHT. Understanding this trans-regulation process employed by parasites to exploit host molecules sheds new light on L. mexicana physiopathogenesis and opens a possible field for studies on drug development.
Topics: Animals; Dihydrotestosterone; Host-Parasite Interactions; Leishmania mexicana; Leishmaniasis; Macrophages; Male; Mice; Mice, Inbred BALB C
PubMed: 29272044
DOI: 10.1111/pim.12512 -
Breast Cancer Research : BCR Nov 2014Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a... (Review)
Review
Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a significant but not yet fully understood role for androgens has also been suggested. The principal androgen, testosterone, is the obligate steroidal precursor of estradiol, but can equally be metabolized into dihydrotestosterone, a more potent, pure androgen. Both androgens exert their distinctive biological effects via the androgen receptor, which is coexpressed with estrogen receptor alpha in 80 to 90% of breast cancers. The hormonal control of breast development and pathology has been examined experimentally through the use of animal models, notably mice and rats. This review summarizes the data from experimental rodent models on the effects of androgens in experimental breast cancer, aiming to address the importance of androgens and the androgen receptor in the origins and pathogenesis of breast cancers, as well as to discuss potential biomarker and therapeutic opportunities arising from novel insights based on the experimental research.
Topics: Adenocarcinoma; Androgens; Animals; Carcinogenesis; Dihydrotestosterone; Female; Mammary Neoplasms, Experimental; Mice; Rats; Receptors, Androgen; Testosterone
PubMed: 25928046
DOI: 10.1186/s13058-014-0483-x -
The Journal of Biological Chemistry Nov 2018Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues...
Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues when tumors engage metabolic processes that produce sustained androgen levels in the tissue. However, the molecular mechanisms involved in this resistance process are unclear, and functional imaging modalities that predict impending resistance are lacking. Here, using the human LNCaP and C4-2 cell line models of prostate cancer, we show that castration treatment-sensitive prostate cancer cells that normally have an intact glucuronidation pathway that rapidly conjugates and inactivates dihydrotestosterone and thereby limits androgen signaling, become glucuronidation deficient and resistant to androgen deprivation. Mechanistically, using CRISPR/Cas9-mediated gene ablation, we found that loss of UDP glucuronosyltransferase family 2 member B15 (UGT2B15) and UGT2B17 is sufficient to restore free dihydrotestosterone, sustained androgen signaling, and development of castration resistance. Furthermore, loss of glucuronidation enzymatic activity was also detectable with a nonsteroid glucuronidation substrate. Of note, glucuronidation-incompetent cells and the resultant loss of intracellular conjugated dihydrotestosterone were detectable by F-dihydrotestosterone PET. Together, these findings couple a mechanism with a functional imaging modality to identify impending castration resistance in prostate cancers.
Topics: Animals; Cell Line, Tumor; Dihydrotestosterone; Fluorine Radioisotopes; Glucuronosyltransferase; Glycosylation; Humans; Male; Mice; Minor Histocompatibility Antigens; Positron-Emission Tomography; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Receptors, Androgen; Signal Transduction; Testosterone
PubMed: 30262668
DOI: 10.1074/jbc.RA118.004846 -
Anti-cancer Agents in Medicinal... 2022Triple-negative breast cancer is challenging to treat due to its heterogeneity and lack of therapeutic targets. Hence, systemic chemotherapy is still the mainstay in...
BACKGROUND
Triple-negative breast cancer is challenging to treat due to its heterogeneity and lack of therapeutic targets. Hence, systemic chemotherapy is still the mainstay in TNBC treatment. Unfortunately, patients commonly develop chemoresistance. Androgen signalling through its receptor is an essential player in breast cancer, where it has been shown to confer chemoresistance to TNBC cells.
OBJECTIVE
The objective of the study was to elucidate the mechanistic effects of enzalutamide in the chemoresponse of TNBC cells to doxorubicin through the apoptosis pathway.
METHODS
MDA-MB-231 and MDA-MB-453 cells were used as model systems of TNBC. Cell viability and apoptosis were investigated upon treatment of cells with doxorubicin in the presence of dihydrotestosterone (DHT) and/or enzalutamide. Caspase 3/7 activity and TUNEL assays were performed to assess the induction of apoptosis. The expression of apoptosis-regulatory genes was assayed by qPCR for the detection of expression changes.
RESULTS
Enzalutamide decreased the viability of MDA-MB-231 and MDA-MB- 453 cells and reduced DHT-induced chemoresistance of both cell lines. It also increased the chemosensitivity towards doxorubicin in MDA-MB-231 cells. Increasing DNA degradation and caspase 3/7 activity were concomitant with these outcomes. Moreover, enzalutamide downregulated the expression of the anti-apoptosis genes, mcl1 and bcl2, in MDA-MB-231 cells, while increasing the expression of the pro-apoptotic gene bid. On the other hand, DHT upregulated the expression of the anti-apoptosis genes, mcl1 and bcl2, in both cell lines.
CONCLUSION
DHT increased the expression of the anti-apoptosis genes mcl1 and bcl2 in the TNBC cells, presumably leading to cell survival via the prevention of doxorubicin-induced apoptosis. On the other hand, enzalutamide may sensitize the cells to doxorubicin through downregulation of the bid/bcl2/mcl1 axis that normally activates the executive caspases, caspase 3/7. The activities of the latter enzymes were apparent in DNA degradation at the late stages of apoptosis.
Topics: Benzamides; Caspase 3; Cell Line, Tumor; Cell Proliferation; DNA; Dihydrotestosterone; Doxorubicin; Drug Resistance, Neoplasm; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Nitriles; Phenylthiohydantoin; Triple Negative Breast Neoplasms
PubMed: 35579133
DOI: 10.2174/1871520622666220509123505 -
Scientific Reports Sep 2020Benign prostatic hyperplasia (BPH) is one of the most important reproductive disorders in aging dogs. Therapeutic measures include orchiectomy and pharmacological...
Benign prostatic hyperplasia (BPH) is one of the most important reproductive disorders in aging dogs. Therapeutic measures include orchiectomy and pharmacological treatment, leading to reduction of prostate volume and clinical signs. One of the most common drugs used in BPH treatment is finasteride, but data regarding its possible side effects are scarce. Thus, the aim of this study was to evaluate the effects of BPH and short-term (2 months) finasteride therapy on clinical, endocrinological, and reproductive parameters in dogs. Dogs were allocated into four experimental groups: Non-affected (n = 5), BPH (n = 5), Non-Affected-Finasteride (n = 5) and BPH-Finasteride (n = 5) groups. Dogs were evaluated monthly during 2 months by a complete breeding soundness examination, B-mode ultrasound and Doppler ultrasonography of the testicular artery, hormonal profile (testosterone, estrogen and dihydrotestosterone) and oxidative profile of the prostatic fluid. After 2 months, dogs were gonadectomized and testicles were subjected to histologic analysis. Finasteride treatment reduced dihydrotestosterone concentrations, without negative influence on semen quality and also reverted testicular hemodynamics changes of BPH. On the other hand, BPH was accompanied by significant changes in testosterone and estrogen concentrations and semen quality, mainly related to sperm kinetics alterations. In conclusion, BPH dogs have important hormonal and sperm alterations, however, short-term finasteride treatment (2 months) was able to reduce overall effects of BPH, thus representing a method of therapy for BPH treatment.
Topics: Animals; Dihydrotestosterone; Dog Diseases; Dogs; Estrogens; Finasteride; Hormones; Male; Prostatic Hyperplasia; Reproduction; Spermatozoa; Testosterone
PubMed: 32908208
DOI: 10.1038/s41598-020-71691-7 -
European Journal of Medicinal Chemistry Mar 2023The synthesis of a 17α-linked C2-symmetric testosterone dimer and its dihydrotestosterone analog is reported. The dimers were synthesized using a short five-step...
Investigating a new C2-symmetric testosterone dimer and its dihydrotestosterone analog: Synthesis, antiproliferative activity on prostate cancer cell lines and interaction with CYP3A4.
The synthesis of a 17α-linked C2-symmetric testosterone dimer and its dihydrotestosterone analog is reported. The dimers were synthesized using a short five-step reaction sequence with 28% and 38% overall yield for the testosterone and dihydrotestosterone dimer, respectively. The dimerization reaction was achieved by an olefin metathesis reaction with 2nd generation Hoveyda-Grubbs catalyst. The dimers and their corresponding 17α-allyl precursors were tested for the antiproliferative activity on androgen-dependent (LNCaP) and androgen-independent (PC3) prostate cancer cell lines. The effects on cells were compared with that of the antiandrogen cyproterone acetate (CPA). The results showed that the dimers were active on both cell lines, with an increased activity towards androgen-dependent LNCaP cells. However, the testosterone dimer (11) was fivefold more active than the dihydrotestosterone dimer (15), with an IC of 11.7 μM vs. 60.9 μM against LNCaP cells, respectively, and more than threefold more active than the reference drug CPA (IC of 40.7 μM). Likewise, studies on the interaction of new compounds with drug-metabolizing cytochrome P450 3A4 (CYP3A4) showed that 11 was a fourfold stronger inhibitor than 15 (IC of 3 μM and 12 μM, respectively). This suggests that changes in the chemical structure of sterol moieties and the manner of their linkage could largely affect both the antiproliferative activity of androgen dimers and their crossreactivity with CYP3A4.
Topics: Male; Humans; Testosterone; Dihydrotestosterone; Androgens; Cytochrome P-450 CYP3A; Prostatic Neoplasms; Cell Line; Cell Line, Tumor
PubMed: 36848848
DOI: 10.1016/j.ejmech.2023.115222 -
International Journal of Molecular... Apr 2020Hormones and their receptors play an important role in the development and progression of breast cancer. Hormones regulate the proliferation of breast cancer cells... (Review)
Review
Hormones and their receptors play an important role in the development and progression of breast cancer. Hormones regulate the proliferation of breast cancer cells through binding between estrogen or progestins and steroid receptors that may reside in the cytoplasm or be transcriptionally activated as steroid-protein nuclear receptor complexes. However, receptors for nonpeptide hormones also exist in the plasma membrane. Via those receptors, hormones are able to stimulate breast cancer cell proliferation when activated. Integrins are heterodimeric structural proteins of the plasma membrane. Their primary functions are to interact with extracellular matrix proteins and growth factors. Recently, integrin αvβ3 has been identified as a receptor for nonpeptide hormones, such as thyroid hormone and dihydrotestosterone (DHT). DHT promotes the proliferation of human breast cancer cells through binding to integrin αvβ3. A receptor for resveratrol, a polyphenol stilbene, also exists on this integrin in breast cancer cells, mediating the anti-proliferative, pro-apoptotic action of the compound in these cells. Unrelated activities of DHT and resveratrol that originate at integrin depend upon downstream stimulation of mitogen-activated protein kinase (MAPK, ERK1/2) activity, suggesting the existence of distinct, function-specific pools of ERK1/2 within the cell. This review will discuss the features of these receptors in breast cancer cells, in turn suggesting clinical applications that are based on the interactions of resveratrol/DHT with integrin αvβ3 and other androgen receptors.
Topics: Androgens; Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dihydrotestosterone; Humans; Integrin alphaVbeta3; Protein Binding; Receptors, Androgen; Resveratrol; Signal Transduction
PubMed: 32326308
DOI: 10.3390/ijms21082906