RESUMO
In birds, maternal hormones deposited into eggs in response to environmental stimuli can impact offspring phenotype. Although less studied, environmental conditions can also influence females' incubation behavior, which might play a role in regulating embryo exposure to maternal hormones through changes in incubation temperature that affect the activity of the enzymes responsible for converting testosterone (T) to 5α-dihydrotestosterone (DHT) or estradiol. Here, we tested the hypothesis that the initial T content of the yolk and incubation temperature determine exposure to T metabolites during early embryo development. In the Japanese quail (Coturnix japonica), we experimentally manipulated yolk T and incubation temperature (38° C versus 36° C) and analyzed DHT and estradiol titers on day four of incubation. We found that eggs with experimentally increased T and those incubated at 36° C showed higher DHT concentration in egg yolk (with no synergistic effect of the two treatments). Estradiol titers were not affected by T manipulation or incubation temperature. Our study suggests that incubation temperature influences DHT titers and may act as an understudied source of maternal influence on offspring phenotype.
Assuntos
Coturnix , Di-Hidrotestosterona , Feminino , Animais , Di-Hidrotestosterona/metabolismo , Coturnix/fisiologia , Temperatura , Herança Materna , Testosterona/metabolismo , Gema de Ovo/metabolismo , Estradiol/metabolismoRESUMO
PURPOSE: Evaluate the therapeutic effect of a tomato lipidic extract (STE) in combination with selenium (Se) on rats with prostatic hyperplasia (PH) and to observe its possible mechanisms of action and synergism versus finasteride. MATERIALS AND METHODS: 54 male Wistar rats of nine weeks old were divided in Control (C), PH, Finasteride (F), STE, Se, F + STE, F + Se, STE + Se and F + STE + Se with testosterone enanthate (except C). After 4 weeks of treatment administration, prostate weight, bladder weight, diuresis, prooxidant and antioxidant activity, dihydrotestosterone (DHT), androgen receptor (AR) expression and anatomopathological analysis were determined. RESULTS: STE + Se decreased prostate weight 53.8% versus 28% in F group, also STE + Se decreased significatively glandular hyperplasia, prooxidant activity, DHT and AR expression and increased diuresis and antioxidant activity versus finasteride which increased MDA in prostate. CONCLUSIONS: These results demonstrate a greater therapeutic and beneficial effect of tomato lipidic extract in combination with Se in young rats with PH with respect to finasteride without increase prooxidant activity.
Assuntos
Hiperplasia Prostática , Selênio , Solanum lycopersicum , Animais , Masculino , Ratos , Androgênios/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Di-Hidrotestosterona/metabolismo , Finasterida/farmacologia , Finasterida/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , Ratos Wistar , Receptores Androgênicos/metabolismo , Selênio/farmacologia , Selênio/uso terapêutico , Testosterona/uso terapêuticoRESUMO
Anabolic androgenic steroids (AAS) are substances with androgenic and anabolic characteristics. Among the many side effects of hormone therapy with AAS, the following stand out: heart problems, adrenal gland disorders, aggressive behavior, increased risk of prostate cancer, problems related to lack of libido and impotence. Such substances vary in the relationship between androgenic activity, and the activation of the androgen receptor (AR) is of fundamental importance for the singularity of the action of each AAS. In this sense, our study evaluates the aspects that comprise the interactions of testosterone agonists (TES), dihydrotestosterone (DHT) and tetrahydrogestrinone (THG) in complex with the AR. In addition, we also evaluated the impact of ligand-receptor affinity differences in a mutation model. We apply computational techniques based on density functional theory (DFT) and use, as methodology, Molecular Fractionation with Conjugate Caps (MFCC). The energetic specificities present in the interaction between the analyzed complexes attest that the highest affinity with the AR receptor is found for AR-THG, followed by AR-DHT, AR-TES and AR-T877A-DHT, respectively. Our results also show the differences and equivalences between the different agonists, in addition to evaluating the difference between the DHT ligand in complex with the wild-type and mutant receptor, presenting the main amino acid residues that involve the interaction with the ligands. The computational methodology used proves to be an operative and sophisticated choice to help in the search for pharmacological agents for various therapies that have androgen as a target.
Assuntos
Androgênios , Receptores Androgênicos , Masculino , Humanos , Ligantes , Receptores Androgênicos/metabolismo , Di-Hidrotestosterona/química , Testosterona/química , MutaçãoRESUMO
BACKGROUND: Staphylococcus aureus (S. aureus) is a pathogen responsible for a wide range of clinical manifestations and potentially fatal conditions. There is a paucity of information on the influence of androgens in the immune response to S. aureus infection. In this study, we evaluated the influence of the hormone 5α-dihydrotestosterone (DHT) on mouse peritoneal macrophages (MPMs) and human peripheral blood monocytes (HPBMs) induced by S. aureus. METHODS: An in vitro model of MPMs from BALB/c sham males, orchiectomised (OQX) males, and females was used. Cells were inoculated with 10 µL of S. aureus, phage-type 80 or sterile saline (control) for 6 h. The MPMs of OQX males and females were pre-treated with 100 µL of 10-2 M DHT for 24 h before inoculation with S. aureus. The concentration of the cytokines TNF-α, IL-1α, IL-6, IL-8, and IL-10; total nitrites (NO-2); and hydrogen peroxide (H2O2) were measured in the supernatant of MPM cultures. In addition, the toll-like receptor 2 (TLR2) and nuclear factor kappa B (NF-kB) genes that are involved in immune responses were analysed. For the in vitro model of HPBMs, nine men and nine women of childbearing age were selected and HPBMs were isolated from samples of the volunteers' peripheral blood. In women, blood was collected during the periovulatory period. The HPBMs were inoculated with S. aureus for 6 h and the supernatant was collected for the analysis of cytokines TNF-α, IL-6, IL-12; and GM-CSF, NO-2, and H2O2. The HPBMs were then removed for the analysis of 84 genes involved in the host's response to bacterial infections by RT-PCR array. GraphPad was used for statistical analysis with a p value < 0.05. RESULTS: Our data demonstrated that MPMs from sham males inoculated with S. aureus displayed higher concentrations of inflammatory cytokines and lower concentrations of IL-10, NO-2, and H2O2 when compared with MPMs from OQX males and females. A similar result was observed in the HPBMs of men when compared with those of women. Previous treatment with DHT in women HPBMs increased the production of pro-inflammatory cytokines and decreased the levels of IL-10, NO-2, and H2O2. The analysis of gene expression showed that DHT increased the activity of the TLR2 and NF-kB pathways in both MPMs and HPBMs. CONCLUSIONS: We found that DHT acts as an inflammatory modulator in the monocyte/macrophage response induced by S. aureus and females exhibit a better immune defence response against this pathogen.
Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Masculino , Humanos , Feminino , Animais , Camundongos , Staphylococcus aureus/metabolismo , Di-Hidrotestosterona/farmacologia , NF-kappa B/genética , NF-kappa B/metabolismo , Interleucina-10 , Monócitos/metabolismo , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa , Peróxido de Hidrogênio , Interleucina-6 , Citocinas/metabolismo , Infecções Estafilocócicas/microbiologia , Macrófagos/metabolismoRESUMO
Introduction: Resistance exercise can significantly increase serum steroid concentrations after an exercise bout. Steroid hormones are involved in the regulation of several important bodily functions (e.g., muscle growth) through both systemic delivery and local production. Thus, we aimed to determine whether resistance exercise-induced increases in serum steroid hormone concentrations are accompanied by enhanced skeletal muscle steroid concentrations, or whether muscle contractions per se induced by resistance exercise can increase intramuscular steroid concentrations. Methods: A counterbalanced, within-subject, crossover design was applied. Six resistance-trained men (26 ± 5 years; 79 ± 8 kg; 179 ± 10 cm) performed a single-arm lateral raise exercise (10 sets of 8 to 12 RM - 3 min rest between sets) targeting the deltoid muscle followed by either squat exercise (10 sets of 8 to 12 RM - 1 min rest) to induce a hormonal response (high hormone [HH] condition) or rest (low hormone [LH] condition). Blood samples were obtained pre-exercise and 15 min and 30 min post-exercise; muscle specimens were harvested pre-exercise and 45 min post-exercise. Immunoassays were used to measure serum and muscle steroids (total and free testosterone, dehydroepiandrosterone sulfate, dihydrotestosterone, and cortisol; free testosterone measured only in serum and dehydroepiandrosterone only in muscle) at these time points. Results: In the serum, only cortisol significantly increased after the HH protocol. There were no significant changes in muscle steroid concentrations after the protocols. Discussion: Our study provides evidence that serum steroid concentration increases (cortisol only) seem not to be aligned with muscle steroid concentrations. The lack of change in muscle steroid after protocols suggests that resistance-trained individuals were desensitized to the exercise stimuli. It is also possible that the single postexercise timepoint investigated in this study might be too early or too late to observe changes. Thus, additional timepoints should be examined to determine if RE can indeed change muscle steroid concentrations either by skeletal muscle uptake of these hormones or the intramuscular steroidogenesis process.
Assuntos
Hidrocortisona , Músculo Esquelético , Humanos , Masculino , Di-Hidrotestosterona , Músculo Esquelético/fisiologia , Esteroides , Testosterona , Estudos Cross-OverRESUMO
Androgens are steroids that modulate various processes in the body, ranging from reproduction, metabolism, and even immune response. The main androgens are testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA). These steroids modulate the development and function of immune response cells. Androgens are generally attributed to immunosuppressive effects; however, this is not always the case. Variations in the concentrations of these hormones induce differences in the innate, humoral, and cell-mediated immune response, which is concentration dependent. The androgens at the highest concentration in the organism that bind to the androgen receptor (AR) are DHEA and testosterone. Therefore, in this work, we review the effects of DHEA and testosterone on the immune response. The main findings of this review are that DHEA and testosterone induce similar but also opposite effects on the immune response. Both steroids promote the activation of regulatory T cells, which suppresses the Th17-type response. However, while testosterone suppresses the inflammatory response, DHEA promotes it, and this modulation is important for understanding the involvement of androgens in infectious (bacterial, viral and parasitic) and autoimmune diseases, as well as in the sexual dimorphism that occurs in these diseases.
Assuntos
Desidroepiandrosterona , Testosterona , Testosterona/farmacologia , Testosterona/metabolismo , Desidroepiandrosterona/farmacologia , Androgênios/farmacologia , Di-Hidrotestosterona/farmacologia , Di-Hidrotestosterona/metabolismo , Imunidade AdaptativaRESUMO
Sex steroid hormones have an important physiological role in humans. They can also affect the gene expression of many organisms, including bacteria. In Mexico, Nocardia brasiliensis is the main causative agent of actinomycetoma, a granulomatous disease more frequent in men than women, which is thought to be related to a higher occupational risk in men. Therefore, it has been suggested that differences in clinical presentation could be related to sex steroid hormone levels. Attempting to explain the differences in actinomycetoma prevalence between men and women, in this work, the effect of progesterone and dihydrotestosterone on the genetic expression of N. brasiliensis was investigated using a differential display polymerase chain reaction assay. The results showed that both hormones affected the expression of genes encoding proteins related to central metabolism and hypothetical proteins with unknown functions. This study also demonstrated the utility of differential display in this modern era and provided a first approach to the effect of sex hormones on N. brasiliensis gene expression.
Assuntos
Micetoma , Nocardiose , Di-Hidrotestosterona/farmacologia , Feminino , Humanos , Masculino , Micetoma/microbiologia , Nocardia , Nocardiose/microbiologia , Reação em Cadeia da Polimerase , Progesterona/farmacologiaRESUMO
Fetal or neonatal androgen exposure has a programming effect on ovarian function inducing a polycystic ovarian syndrome-like condition. Its effects on uterine structure and function are poorly studied. The aim of this work was to characterize the temporal course of changes in the rat uterine structure induced by neonatal exposure to aromatizable or not aromatizable androgens. Rats were daily treated with testosterone, dihydrotestosterone or vehicle during follicle assembly period (postnatal days 1 to 5). Uterine histoarchitecture, hormonal milieu, endometrial stromal collagen and capillary density were analyzed at prepubertal, pubertal and adult ages. Our data shows that neonatal androgen exposure induces early and long-lasting deleterious effects on uterine development, including altered adenogenesis and superficial epithelial alterations and suggest a role for altered serum estradiol levels in the maintenance and worsening of the situation. Our results suggest that alterations of the neonatal androgenic environment on the uterus could be responsible for alterations in the processes of implantation and maintenance of the embryo in women with polycystic ovary syndrome.
Assuntos
Androgênios , Síndrome do Ovário Policístico , Humanos , Feminino , Ratos , Animais , Androgênios/farmacologia , Di-Hidrotestosterona/farmacologia , Testosterona/farmacologia , Síndrome do Ovário Policístico/induzido quimicamente , Útero , VirilismoRESUMO
Canine pituitary-dependent hypercortisolism (PDH) management with trilostane usually demands lifelong therapy. The greater the dose needed, the greater the risk of side effects. Selegiline therapy has been previously described but not commonly used for PDH treatment. The present work aimed to assess the efficacy of selegiline and trilostane combined therapy for canine PDH treatment. Fifteen client-owned dogs diagnosed with spontaneous PDH were enrolled. The patients were treated with trilostane (Tri group, n = 8, initial dose of 0.5 mg/kg, PO, q12h), or with trilostane and selegiline (Tri + Sel group, n = 7, initial trilostane dose of 0.5 mg/kg, PO, q12h and selegiline 1 mg/kg, PO, q24h). Dogs underwent clinical examination, serum biochemical analysis, urinalysis, abdominal ultrasound, and eACTH and post-ACTH cortisol measurements on treatment days zero (D0), 30 (D30), 90 (D90), and 180 (D180). There was a lack of adverse effects due to the combined therapy. Both groups showed a similar clinical response and lower post-ACTH cortisol levels at the study's end. There was no significant difference in trilostane dosage at D180 between groups. There was no documented increase in either right or left adrenal gland thickness in the Tri + Sel group in contrast with patients in the Tri group. However, there was no statistical difference between the groups regarding eACTH at D0 and D180. Patients in the Tri + Sel group achieved better serum triglycerides control at the end of the study. The association of selegiline with trilostane might be a feasible therapy for canine PDH; however, its eventual advantages need larger studies.
Assuntos
Síndrome de Cushing , Doenças do Cão , Hipersecreção Hipofisária de ACTH , Hormônio Adrenocorticotrópico/uso terapêutico , Animais , Síndrome de Cushing/veterinária , Di-Hidrotestosterona/análogos & derivados , Doenças do Cão/tratamento farmacológico , Cães , Hidrocortisona , Projetos Piloto , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/veterinária , Selegilina/uso terapêuticoRESUMO
The 5α-reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, playing a crucial role in male development. This enzyme is encoded by the SRD5A2 gene, which maps to chromosome 2 (2p23), consists of 5 exons and 4 introns, and encodes a 254 amino acid protein. Disruptions in this gene are the molecular etiology of a subgroup of differences of sex development (DSD) in 46,XY patients. Affected individuals present a large range of external genitalia undervirilization, ranging from almost typically female external genitalia to predominantly typically male external genitalia with minimal undervirilization, including isolated micropenis. This is an updated review of the implication of the SRD5A2 gene in 5α-reductase type 2 enzyme deficiency. For that, we identified 451 cases from 48 countries of this particular 46,XY DSD from the literature with reported variants in the SRD5A2 gene. Herein, we present the SRD5A2 mutational profile, the SRD5A2 polymorphisms, and the functional studies related to SRD5A2 variants to detail the molecular etiology of this condition.
Assuntos
Transtorno 46,XY do Desenvolvimento Sexual , Hipospadia , Erros Inatos do Metabolismo de Esteroides , Humanos , Masculino , Feminino , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Hipospadia/genética , Hipospadia/patologia , Di-Hidrotestosterona , Mutação/genética , Proteínas de Membrana/genéticaRESUMO
Background: Chlordecone is an endocrine-disrupting chemical with well recognized estrogenic and progestagenic properties. This organochlorine insecticide was extensively used in the French West Indies from 1973 to 1993 to control the banana root borer. Due to its poor degradation in the environment, permanently polluted soil is responsible for the current contamination of the food chain and human beings. We aimed to examine the relationship of in utero exposure to chlordecone and thyroid (thyroid stimulating hormone [TSH], free tri-iodothyronine [FT3], free thyroxine [FT4]), metabolic (insulin growth-factor 1, leptin, adiponectin), and sex-steroid (dehydroepiandrosterone [DHEA], total testosterone [TT], dihydrotestosterone [DHT], estradiol [E2]) hormone levels in children at the age of seven years who participated in TIMOUN, an ongoing birth cohort in Guadeloupe. Methods: Chlordecone concentrations were measured in cord-blood at delivery. Thyroid, metabolic, and sex-steroid hormone levels were determined in the blood of children at seven years of age. Associations between in utero chlordecone exposure and hormone levels at seven years of age were assessed by multiple linear or logistic regression, controlling for confounding factors. Results: Among the study population (210 boys and 228 girls), chlordecone and hormone measurements were available for 124 boys and 161 girls. We found the third quartile of in utero chlordecone exposure relative to the lowest quartile to be associated with elevated TSH levels in girls and elevated DHEA, TT, and DHT levels in both sexes. Complementary non-linear analysis (spline regression) confirmed a significant non-linear trend for TSH in girls and DHEA and DHT in boys. Conclusion: In utero chlordecone exposure was associated with elevated levels of selected thyroid (TSH) and sex-steroid (DHEA, TT, and DHT) hormones at seven years in a non-monotonic dose response (inverted U) relationship. The implications for future health and reproductive function in puberty and adulthood should be determined.
Assuntos
Clordecona/toxicidade , Exposição Ambiental , Inseticidas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/sangue , Glândula Tireoide/efeitos dos fármacos , Adiponectina/sangue , Criança , Desidroepiandrosterona/sangue , Di-Hidrotestosterona/sangue , Estradiol/sangue , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Masculino , Gravidez , Testosterona/sangue , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Androgens are relevant in order to achieve a normal growth and maturation of the follicle and oocyte, since both excess and absence of androgens may affect the correct ovarian function. The current study analyzes the impact of neonatal androgenization in the first ovulation and oocyte maturation in response to exogenous gonadotrophin stimulation. Neonatal rats were daily treated with testosterone, dihydrotestosterone, or vehicle during follicle assembly period (days 1 to 5). At juvenile period, rats were stimulated sequentially with PMSG and hCG. Ovulation, ovarian histology, hormonal milieu, morphological characteristics of meiotic spindle, and in vitro fertilization rate in oocytes were analyzed. Our data shows that oocytes from androgenized rats displayed a major proportion of aberrant spindles and altered meiotic advance that control animals. These alterations were accompanied with an increase in both fertilization rate and aberrant embryos after 48 h of culture. Our findings showed a direct impact of neonatal androgens on oocyte development; their effects may be recognized at adulthood, supporting the idea of a programming effect exerted by neonatal androgens. These results could be relevant to explain the low fertility rate seen in polycystic ovary syndrome patients after in vitro fertilization procedures.
Assuntos
Androgênios/toxicidade , Di-Hidrotestosterona/toxicidade , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Testosterona/toxicidade , Virilismo/induzido quimicamente , Animais , Animais Recém-Nascidos , Técnicas de Cocultura , Feminino , Masculino , Oócitos/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Ovulação/efeitos dos fármacos , Ovulação/fisiologia , Gravidez , Ratos , Ratos Wistar , Virilismo/patologiaRESUMO
Androgen-dependent LNCaP and androgen-independent DU-145 cells, were treated with different concentrations of ergosterol (15 µM and 25 µM) and its respective cell viability was measured by MTT bioassay. While ergosterol showed an antiproliferative effect on LNCaP, on DU-145 promoted cell proliferation. This differential effect suggests that the effect of ergosterol might be related to its ability to act as an Androgen Receptor ligand. In silico Molecular Dynamics simulations were performed to analyze the interaction mechanism between androgen receptor and ergosterol, in comparison with natural ligands, 5α-dihydrotestosterone and testosterone. Our model suggests that the binding of androgen receptor with ergosterol is thermodinamically feasible, which is concordant with our experimental results.
Assuntos
Ergosterol , Neoplasias da Próstata , Androgênios , Linhagem Celular Tumoral , Di-Hidrotestosterona , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológicoRESUMO
Benign prostatic hyperplasia (BPH) is a disorder related to hormone imbalance, local angiogenesis, and prostate growth, which can be treated surgically (orchiectomy) or medically (most commonly with finasteride). However, finasteride therapy is not completely established in dogs regarding local action and posology. This study aimed to evaluate the effect of different doses of finasteride and orchiectomy on hormonal profile, prostate apoptosis, blood flow, and biometry in dogs with BPH. Dogs were assigned to the following groups: untreated, 0.1 mg, 0.2 mg, and 0.5 mg/kg/d of finasteride and orchiectomy. All dogs were assessed monthly: day 0 (before treatment), day 30, and day 60 and subjected to prostate B-mode and Doppler ultrasonography and hormonal analysis (testosterone and dihydrotestosterone). After 60 d, prostatic biopsy was performed for histology and immunohistochemical evaluation for apoptosis (caspase-3). On day 60, percentage reduction of prostatic volume was greater in orchiectomized dogs than that in finasteride groups, which, conversely, was greater than untreated dogs. On day 60, 0.2-mg finasteride, 0.5-mg finasteride, and orchiectomy groups had higher prostatic blood flow than 0.1-mg finasteride and untreated groups. In addition, both 0.5-mg finasteride and orchiectomy groups had an increase in prostate artery resistance. Orchiectomy significantly decreased androgen concentrations at 30 d onward, differing from the remaining groups. The orchiectomy group had lower caspase-3 immunostaining, however, not different from untreated and 0.5-mg finasteride. In conclusion, 0.5 mg/kg finasteride promoted more effective prostate apoptosis and hemodynamic effects among medical treatments, whereas orchiectomy caused prostate atrophy and sharp endocrine changes in dogs with BPH.
Assuntos
Doenças do Cão , Hiperplasia Prostática , Animais , Di-Hidrotestosterona , Doenças do Cão/tratamento farmacológico , Cães , Finasterida/farmacologia , Finasterida/uso terapêutico , Masculino , Próstata/patologia , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/veterinária , Testosterona/farmacologiaRESUMO
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.
Assuntos
Doenças do Cão/tratamento farmacológico , Finasterida/uso terapêutico , Hormônios/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Di-Hidrotestosterona/metabolismo , Cães , Estrogênios/metabolismo , Masculino , Testosterona/metabolismoRESUMO
BACKGROUND: The formation of the male urethra depends to enzyme-mediated testosterone (T) conversion into 5α-dihydrotestosterone (DHT). Two metabolic pathways could be operating in the fetal testis to synthesize androgens: 1) the "classic" route (TâDHT) mediated by SRD5A2 and 2) a "backdoor" pathway in which DHT is synthesized by aldo-keto reductase family 1, member C2 (AKR1C2), AKR1C3, and AKR1C4 enzymes without formation of a T intermediate. OBJECTIVE: We studied four genes of the "backdoor" pathway in karyotypic males with hypospadias to ascertain whether gene defects in AKRs impair urethral DHT formation that result in hypospadias. DESIGN AND PATIENTS: The coding regions of the AKR1C2-4 and HSD17B6 genes were analyzed by PCR-SSCP and sequencing in a cohort of 25 Mexican patients (0.3-9 year-old-children) with 46,XY-hypospadias. Chi-squared tests was performed to evaluate the distribution of genotypes, alleles, and the Hardy-Weinberg (H-W) equilibrium. The effect of the genetic variants was investigated by in silico studies. RESULTS: Screening studies revealed distinct genotypic patterns at different exons of AKR1C2-4 whereas HSD17B6 presented a wild-type sequence. The DNA analyses detected two synonymous variants (c.327C>T, c.666T>C/unreported) in AKR1C2. The AKR1C3 had two variants (c.15C>G, c.230A>G), two unreported variants (c.538T>C, c.596G>A), and one silent variant (c.312G>A). Two variants (c.434C>G, c.931C>G) were identified in AKR1C4. All variants were in H-W equilibrium without structural changes. DISCUSSION: Hypospadias have been associated with defects that alter androgen biosynthesis in the human fetal testis, specifically 5α-DHT. We selected four candidate genes involved in the "backdoor" pathway for the formation of 5α-DHT. Molecular assays of the AKR1C2, AKR1C3, and AKR1C4 genes revealed a total of nine genetic single nucleotide variants. Several variants in the AKR1C genes have been associated with a variety of human pathologies. However, our studies suggest that active steroid biosynthesis via AKR1C might not be involved in hypospadias. Additionally, genetic research suggests a low involvement in the "backdoor" 5α-DHT pathway during human sexual development, specifically, the differentiation of male external genitalia. CONCLUSION: These results indicate that substitutions in AKR1C2-4 are polymorphisms and all genetic variants lacks deleterious significant association with hypospadias. The data suggest that inactivating mutations in the AKR1C2-4 and HSD17B6 genes are an infrequent cause of hypospadias, which might weaken the contribution of the "backdoor" pathway to embryonic urethral masculinization.
Assuntos
Hipospadia , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Membro C3 da Família 1 de alfa-Ceto Redutase , Androgênios , Criança , Pré-Escolar , Di-Hidrotestosterona , Feminino , Humanos , Hidroxiesteroide Desidrogenases/genética , Hipospadia/genética , Lactente , Masculino , Proteínas de Membrana , Biologia Molecular , Oxirredutases , Racemases e Epimerases , TestosteronaRESUMO
In previous studies, carried out in humans, we showed that females are resistant to Leishmania mexicana infection. We also showed that 17ß-estradiol (E2) induces killing of parasites inside of murine macrophages. In this work, we compared, for the first time, L mexicana survival inside of male (male BMDM) and female (female BMDM) bone marrow-derived macrophages (BMDM) treated in vitro with E2 or dihydrotestosterone (DHT). We also compared their levels of nitric oxide (NO), interleukin (IL)-6, IL-10, IL-12p70 and tumour necrosis factor (TNF-α). We found that female BMDM are a lot less susceptible to infection as compared with male BMDM. 17ß-estradiol induced killing of most parasites inside of female BMDM. Dihydrotestosterone, on the other hand, induced some parasite killing inside of some infected male BMDM. Interleukin-6 levels were higher in female BMDM treated with either hormone. Neither TNF-α nor IL-10 levels showed significant differences compared with sham controls. Interestingly IL-12p70 was more abundantly produced by sham female BMDM as compared with sham male BMDM. Only female BMDM treated with E2 trigger a robust IL-12p70 production, but it was significantly reduced in male BMDM. This suggests IL-12p70 is an important factor in female-macrophage resistance to L mexicana parasites.
Assuntos
Estradiol/metabolismo , Interleucina-12/imunologia , Leishmania mexicana/fisiologia , Leishmaniose Cutânea/imunologia , Macrófagos/imunologia , Animais , Citocinas/análise , Di-Hidrotestosterona/administração & dosagem , Estradiol/administração & dosagem , Feminino , Humanos , Leishmaniose Cutânea/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Óxido Nítrico/análise , Fatores SexuaisRESUMO
Sex hormone binding globulin (SHBG) is a homodimeric glycoprotein and is the major carrier protein for sex steroids in plasma, regulating sex hormone availability in most vertebrate groups. Although it was initially thought that human dimeric SHBG bound a single ligand at the homodimer interface, studies demonstrated that dimeric SHBG binds a ligand to each subunit with similar affinity. In fact, the findings from recent experimental studies suggest that ligand binding to the SHBG dimer involves a complex allosteric mechanism involving conformational changes that limit observations of the presence of allosteric regulation. Therefore, we combined structural data with molecular dynamics simulations using Molecular Mechanics Generalized-Born Surface Area (MMGBSA) to dissect the structural and energetic basis for molecular recognition between five ligands whose affinities and binding positions on SHBG are known, i.e., 3ß,17α-diol; 3ß,17ß-diol; DHT; norgestrel (NOG); and estradiol (E2), and monomeric and dimeric SHBG. Protein-ligand complexes, involving dimeric SHBG saturated with two ligands on each subunit, reproduce the experimental affinity tendency and allow the observation that dimerization exerts disparate effects on binding affinity, characteristic of negative cooperativity for E2, DHT, and NOG, whereas 3ß-17α-diol and 3ß-17ß-diol lack allostery.
Assuntos
Androstenodióis/metabolismo , Di-Hidrotestosterona/metabolismo , Estradiol/metabolismo , Norgestrel/metabolismo , Globulina de Ligação a Hormônio Sexual/química , Globulina de Ligação a Hormônio Sexual/metabolismo , Androstenodióis/química , Di-Hidrotestosterona/química , Estradiol/química , Humanos , Ligantes , Modelos Moleculares , Simulação de Dinâmica Molecular , Norgestrel/química , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização ProteicaRESUMO
Introduction: The androgen receptor (AR) plays an important role in normal development of the prostate gland, as well as in prostatic neoplasms. Transcriptional regulation by AR is modulated by its interaction with co-activators or co-repressors, such as NCoR1 (nuclear receptor co-repressor 1), which is involved in reducing AR activity over the target gene transcription. Methods: To identify the role of NCoR1 in the prostate cancer androgen independence in a cell line model, we aimed to evaluate the effects of silencing NCoR1 on prostate-specific antigen (PSA) gene expression, the proliferative response and PSA secretion on the supernatant of C4-2B and LNCaP cells that were submitted to small interfering RNAs (siRNAs) transfection, and to treatments with different androgen dosages. Results: In LNCaP and C4-2B cells with no dihydrotestosterone (DHT) treatment, a decrease in PSA mRNA expression was observed 48 hours and 72 hours after gene silencing in the siNCoR group when compared to the control and siNC groups. The LNCaP and C4-2B cells showed a biphasic pattern in response to dihydrotestosterone treatment in transfected groups (siNCoR and siNC) as well as in the control condition (without transfection). The secretion of PSA in cell supernatant of LNCaP and C4-2B cells was higher in the siNCoR group, and, in relation to hormonal treatment, higher in the 10-8 M DHT group. Conclusions: A reduction in the NCoR1 levels seems to have a double influence on the activity of AR in PCa cells. These results suggest that NCoR may act as an AR co-repressor depending upon hormonal stimulation.(AU)
Assuntos
Humanos , Masculino , Neoplasias da Próstata , Antígeno Prostático Específico , Proliferação de Células , Correpressor 1 de Receptor Nuclear , Di-Hidrotestosterona , Receptores Androgênicos , Linhagem Celular , Proteínas CorrepressorasRESUMO
During the transition to menopause, women experience a variety of physical and psychological symptoms that are directly or indirectly linked to changes in hormone secretion. Establishing animal models with intact ovaries is essential for understanding these interactions and finding new therapeutic targets. In this study, we assessed the endocrine profile, as well as the estrous cycle, in the 4-vinylcyclohexene diepoxide (VCD)-induced follicular depletion rat model in 10-day intervals over 1 month to accurately establish the best period for studies of the transition period. Twenty-eight-day-old female rats were injected daily with VCD or oil s.c. for 15 days and euthanized in the diestrus phase approximately 70, 80, 90 and 100 days after the onset of treatment. The percentage of rats showing irregular cycles and the plasma level of FSH increased only in the 100-day VCD group. Plasma anti-Müllerian hormone (AMH) and progesterone were lower in all VCD groups compared to control groups, while estradiol remained unchanged or higher. As in control groups, dihydrotestosterone (DHT) progressively decreased in the 70-90-day VCD groups; however, it was followed by a sharp increase only in the 100-day VCD group. No changes were found in plasma corticosterone, prolactin, thyroid hormones or luteinizing hormone. Based on the estrous cycle and endocrine profile, we conclude that 1) the time window from 70 to 100 days is suitable to study a perimenopause-like state in this model, and 2) regular cycles with low progesterone and AMH and normal FSH can be used as markers of the early/mid-transition period, whereas irregular cycles associated with higher FSH and DHT can be used as markers of the late transition period to estropause.