RESUMO
BACKGROUND: We aimed to evaluate the effects of different therapeutic options to prevent the evolution of vaginal stenosis after pelvic radiotherapy in women with cervical cancer. METHODS: open-label randomized clinical trial of 195 women, stage I-IIIB, aged 18-75 years, using topical estrogen (66), topical testosterone (34), water-based intimate lubricant gel (66), and vaginal dilators (29) to assess the incidence and severity of vaginal stenosis after radiotherapy at UNICAMP-Brazil, from January/2013 to May/2018. The main outcome measure was vaginal stenosis assessed using the Common Terminology Criteria for Adverse Events (CTCAE) scale and percental changes in vaginal volume. The women were evaluated at four different times: shortly after the end of radiotherapy, and four, eight, and 12 months after the beginning of the intervention. Statistical analysis was carried out using Symmetry test, Kruskal-Wallis test and multiple regression. RESULTS: the mean age of women was 46.78 (±13.01) years, 61,03% were premenopausal and 73,84% had stage IIB-IIIB tumors. The mean reduction in vaginal volume in the total group was 25.47%, with similar worsening in the four treatment groups with no statistical difference throughout the intervention period. There was worsening of vaginal stenosis evaluated by CTCAE scale after 1 year in all groups (p < 0.01), except for the users of vaginal dilator (p = 0.37). CONCLUSIONS: there was a reduction in vaginal volume in all treatment groups analyzed, with no significant difference between them. However, women who used vaginal dilators had a lower frequency and severity of vaginal stenosis assessed by the CTCAE scale after one year of treatment. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials, RBR-23w5fv . Registered 10 January 2017 - Retrospectively registered.
Assuntos
Braquiterapia/efeitos adversos , Quimiorradioterapia/efeitos adversos , Lesões por Radiação/epidemiologia , Neoplasias do Colo do Útero/radioterapia , Doenças Vaginais/epidemiologia , Administração Tópica , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Quimiorradioterapia/métodos , Constrição Patológica/diagnóstico , Constrição Patológica/epidemiologia , Constrição Patológica/etiologia , Constrição Patológica/prevenção & controle , Dilatação/instrumentação , Dilatação/métodos , Estrogênios Conjugados (USP)/administração & dosagem , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Lesões por Radiação/diagnóstico , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Índice de Gravidade de Doença , Propionato de Testosterona/administração & dosagem , Resultado do Tratamento , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Vagina/efeitos dos fármacos , Vagina/patologia , Vagina/efeitos da radiação , Doenças Vaginais/diagnóstico , Doenças Vaginais/etiologia , Doenças Vaginais/prevenção & controle , Adulto JovemRESUMO
Telocytes are CD34-positive cells with a fusiform cell body and long, thin cytoplasmic projections called telopodes. These cells were detected in the stroma of various organs, including the prostate. The prostate is a complex gland capable of undergoing involution due to low testosterone levels; and this condition can be reversed with testosterone replacement. Telocyte function in the mature prostate remains to be dermined, and it is not known whether telocytes can take place in tissue remodeling during prostate involution and regrowth. The present study employed structural, ultrastructural and immunohistochemical methods to investigate the telocyte's phenotypes in the ventral prostate (VP) from control (CT), castrated (CS) and testosterone replacement (TR) groups of adult male Wistar rats. Telocytes were found in the subepithelial, perimuscular and interstitical regions around glandular acini. Telocytes from CT animals have condensed chromatin and long and thin telopodes. In CS group, telocytes appeared quiescent and exhibited layers of folded up telopodes. After TR, telocytes presented loose chromatin, abundant rough endoplasmic reticulum and enlarged telopodes, closely associated with bundles of collagen fibrils. We called these cells "telocytes with a synthetic phenotype". As testosterone levels and glandular morphology returned toward to the CT group parameters, after 10 days of TR, these telocytes progressively switched to the normal phenotype. Our results demonstrate that telocytes exhibit phenotypic plasticity upon androgen manipulation and interact with fibroblast and smooth muscle cells to maintain glandular architecture in control animals and during tissue remodeling after hormonal manipulation.
Assuntos
Próstata/citologia , Telócitos/citologia , Propionato de Testosterona/administração & dosagem , Animais , Antígenos CD34/metabolismo , Masculino , Orquiectomia , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Ratos , Ratos Wistar , Telócitos/efeitos dos fármacos , Telócitos/metabolismo , Testosterona/sangue , Propionato de Testosterona/farmacologiaRESUMO
OBJECTIVE: Vaginal atrophy is a common chronic condition among postmenopausal women that can affect their quality of life. Recent studies have evaluated new treatment alternatives for vaginal atrophy; however, few therapeutic options have been thoroughly evaluated. This study aimed to compare the effectiveness and adverse effects of estrogen, testosterone, polyacrylic acid, and placebo lubricant for the treatment of postmenopausal women with vaginal atrophy. METHODS: We conducted a randomized clinical trial with 80 postmenopausal women aged between 40 and 70 years who were being followed up at the Menopause Clinic of CAISM UNICAMP between November 2011 and January 2013. Women were randomly assigned to topical vaginal treatment with estrogen, testosterone, polyacrylic acid, and placebo lubricant, three times a week for 12 weeks. We used the vaginal maturation index, pH, vaginal health score, vaginal flora, laboratory tests, and ultrasound to evaluate changes of vaginal atrophy at baseline and after 6 and 12 weeks of treatment. RESULTS: After a 12-week treatment with topical estrogen and testosterone compared with the lubricant, an increased percentage of participants had vaginal pH less than 5, increased vaginal score, and an increase in the number of lactobacilli. Treatment with topical estrogen improved the vaginal maturation index and showed increased levels of estradiol in three women. No changes were observed in the endometrial evaluation of all treatment groups. CONCLUSIONS: After a 12-week treatment with testosterone and estrogen compared with placebo lubrication, there was a significant improvement in vaginal trophism in postmenopausal women with vaginal atrophy.
Assuntos
Resinas Acrílicas/administração & dosagem , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios/administração & dosagem , Propionato de Testosterona/administração & dosagem , Vagina/patologia , Doenças Vaginais/tratamento farmacológico , Administração Intravaginal , Adulto , Idoso , Atrofia/tratamento farmacológico , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Análise de Intenção de Tratamento , Pessoa de Meia-Idade , Pós-Menopausa , Método Simples-Cego , Resultado do Tratamento , Vagina/efeitos dos fármacos , Cremes, Espumas e Géis Vaginais/administração & dosagem , Doenças Vaginais/patologiaRESUMO
We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 µL); DHT (dihydrotestosterone of 1.0 mg/50 µL); EV (estradiol valerate of 0.1 mg/50 µL); and control (sesame oil of 50 µL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area.
Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Hormônios Esteroides Gonadais/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Di-Hidrotestosterona/administração & dosagem , Neurônios Dopaminérgicos/metabolismo , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Masculino , Núcleo Accumbens/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Substância Negra/metabolismo , Propionato de Testosterona/administração & dosagem , Área Tegmentar Ventral/metabolismoRESUMO
The aim of this research was to investigate the effect of testosterone propionate administration in the liver of rats. The rats were divided in the following groups: Initial control (SC), Aged control (SE) and Anabolic group (SA). Testosterone propionate was administered three times per week during 16 weeks. Using morphoquantitative techniques, we quantified the volume densities of lobular and non-lobular parenchyma, area and number of nuclei of hepatocytes. The data were analyzed statistically using mean and standard deviation, ANOVA one-way and level of significance about p0.05. Our results showed an increase in capillaries, perisinusoidal spaces and biliary ducts in SE group compared to SC. SA group showed a decrease in hepatic cells, non-lobular volume density and hepatocytes nuclei area, but also an increase in capillaries, perisinusoidal spaces, biliary ducts, number of hepatocytes and non-hepatocyte nuclei compared to SC. We conclude that a direct toxicity may have occurred, with consequent loss of the cells.
El objetivo fue investigar el efecto de la administración de propionato de testosterona en el hígado de ratas. Las ratas se dividieron en los siguientes grupos: control inicial (CI), control de Edad (CE) y grupo anabólico (GA). El propionato de testosterona se administró tres veces por semana durante 16 semanas. Utilizando técnicas morfocuantitativas, determinamos las densidades de volumen del parénquima lobular y no lobular, área y número de núcleos de los hepatocitos. Los datos fueron analizados estadísticamente con la media y desviación estándar, la prueba de ANOVA de una vía y un nivel de significación p0,05. Nuestros resultados mostraron un aumento en los capilares, espacios perisinusoidales y conductos biliares en el grupo CE en comparación con CI. El GA mostró una disminución en las células hepáticas, la densidad de volumen no lobular y el área de los núcleos de hepatocitos, como también un aumento en los capilares, espacios perisinusoidales, conductos biliares, número de hepatocitos y núcleos no hepatocíticos en comparación AL CI. Concluimos que una toxicidad directa puede haber ocurrido, con la consiguiente pérdida de las células.
Assuntos
Animais , Masculino , Ratos , Propionato de Testosterona/farmacologia , Fígado/efeitos dos fármacos , Envelhecimento , Análise de Variância , Ratos Wistar , Hepatócitos/efeitos dos fármacos , Propionato de Testosterona/administração & dosagemRESUMO
Environmental contaminants known as endocrine-disrupting chemicals (EDC) have been associated with adverse effects on reproductive processes. These chemicals may mimic or antagonize endogenous hormones, disrupting reproductive functions. Although preliminary studies focused on environmental estrogens, the presence of compounds with androgenic activity has also been described. This study examines exposure of female pregnant and lactating rats to low doses of androgens and assesses potential effects on female offspring. Pregnant Wistar rats were exposed to testosterone propionate (TP) at doses of 0.05, 0.1, or 0.2 mg/kg or corn oil (vehicle), subcutaneously, to determine influence on reproductive health of female offspring. There were two exposure groups: (1) rats treated from gestational day (GD) 12 until GD 20; and (2) animals treated from GD 12 until the end of lactation. Perinatal exposure to TP produced increased anogenital distance after birth and diminished height of uterine glandular epithelium at puberty in animals exposed to 0.2 mg/kg. However, these alterations were not sufficient to impair sexual differentiation and normal physiology of the female rat reproductive tract.
Assuntos
Androgênios/toxicidade , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Lactação , Efeitos Tardios da Exposição Pré-Natal , Desenvolvimento Sexual/efeitos dos fármacos , Anormalidades Urogenitais/induzido quimicamente , Androgênios/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Endométrio/anormalidades , Endométrio/efeitos dos fármacos , Poluentes Ambientais/administração & dosagem , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Injeções Subcutâneas , Exposição Materna/efeitos adversos , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Teratogênicos/toxicidade , Propionato de Testosterona/administração & dosagem , Propionato de Testosterona/toxicidadeRESUMO
Prenatal testosterone (T) excess leads to reproductive dysfunctions in sheep, which include increased ovarian follicular recruitment and persistence. To test the hypothesis that follicular disruptions in T sheep stem from changes in the developmental ontogeny of ovarian proliferation and apoptotic factors, pregnant Suffolk sheep were injected twice weekly with T propionate or dihydrotestosterone propionate (DHT; a nonaromatizable androgen) from Days 30 to 90 of gestation. Changes in developmental expression of proliferating cell nuclear antigen (PCNA), BCL2, BAX, activated CASP3, and FAS/FASLG were determined at Fetal Days 90 and 140, 22 wk, 10 mo, and 21 mo of age by immunocytochemisty. Prenatal T treatment induced changes in expression of proliferative and apoptotic markers in a follicle-, age-, and steroid-specific manner. Changes in BAX were evident only during fetal life and PCNA, BCL2, and CASP3 only postnatally. Prenatal T and not DHT increased PCNA and decreased BCL2 in granulosa/theca cells of antral follicles at 10 and 21 mo but decreased CASP3 in granulosa/theca cells of antral follicles at 22 wk (prepubertal) and 10 and 21 mo. Both treatments decreased BAX immunostaining in granulosa cells of Fetal Day 90 primordial/primary follicles. Neither treatment affected FAS expression at any developmental time point in any follicular compartment. Effects on BAX appear to be programmed by androgenic actions and PCNA, BCL2, and CASP3 by estrogenic actions of T. Overall, the findings demonstrate that fetal exposure to excess T disrupts the ovarian proliferation/apoptosis balance, thus providing a basis for the follicular disruptions evidenced in these females.
Assuntos
Ovário/efeitos dos fármacos , Ovário/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Propionato de Testosterona/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Di-Hidrotestosterona/administração & dosagem , Di-Hidrotestosterona/análogos & derivados , Proteína Ligante Fas/metabolismo , Feminino , Humanos , Ovário/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ovinos , Pesquisa Translacional Biomédica , Receptor fas/metabolismoRESUMO
The objective of this study was to investigate whether prenatal exposure to testosterone (T) could change the body weight (BW), anogenital distance (AGD), anogenital distance index (AGDI), puberty onset, social behavior, fertility, sexual behavior, sexual preference, and T level of male rats in adulthood. To test this hypothesis, pregnant rats received either 1 mg/animal of T propionate diluted in 0.1 ml peanut oil or 0.1 ml peanut oil, as control, on the 17th, 18th and 19th gestational days. No alterations in BW, AGD, AGDI, fertility, and sexual behavior were observed (p > 0.05). Delayed onset of puberty (p < 0.0001), increased aggressive behavior (p > 0.05), altered pattern of sexual preference (p < 0.05), and reduced T plasma level (p < 0.05) were observed for adult male rats exposed prenatally to T. In conclusion, the results showed that prenatal exposure to T was able to alter important aspects of sexual and social behavior although these animals were efficient at producing descendants. In this sense more studies should be carried to evaluated the real impact of this hormonal alteration on critical period of sexual differentiation on humans, because pregnant women exposed to hyperandrogenemia and then potentially exposing their unborn children to elevated androgen levels in the uterus can undergo alteration of normal levels of T during the sexual differentiation period, and, as a consequence, affect the reproductive and behavior patterns of their children in adulthood.
Assuntos
Agressão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Comportamento Sexual Animal/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Propionato de Testosterona/administração & dosagem , Animais , Feminino , Idade Gestacional , Masculino , Modelos Animais , Gravidez , Ratos , Ratos Wistar , Diferenciação Sexual/efeitos dos fármacos , Comportamento Social , Testosterona/sangueRESUMO
Steroid hormones play an important role in reproduction and the receptors through which they signal change in a developmental time, follicle stage, and cell-specific manner. Disruption in steroid receptor expression affects follicle formation and differentiation. In this study, using prenatal testosterone (T) and dihydrotestosterone (DHT)-treated female sheep as model systems, we tested the hypothesis that prenatal androgen excess disrupts the developmental ontogeny of ovarian steroid receptor protein expression. Pregnant Suffolk ewes were injected twice weekly with T propionate or DHT propionate (a non-aromatizable androgen) in cottonseed oil from days 30 to 90 of gestation. Changes in ovarian estrogen receptors (ER; ESR1, ESR2), androgen receptor (AR) and progesterone receptor (PGR) proteins were determined at fetal (days 90 and 140), postpubertal (10 months), and adult (21 months; only prenatal T-treated sheep studied) ages by immunohistochemistry. Prenatal T and DHT treatment induced selective increase in AR but not ER or PGR expression in the stroma and granulosa cells of fetal days 90 and 140 ovaries. An increase in ESR1 and decrease in ESR2 immunostaining coupled with increased AR expression were evident in granulosa cells of antral follicles of 10- and 21-month-old prenatal T but not DHT-treated females (analyzed only at 10 months). These findings provide evidence that an early increase in ovarian AR is the first step in the altered ovarian developmental trajectory of prenatal T-treated females, and manifestations of postnatal ovarian dysfunction are likely facilitated via altered equilibrium of antral follicular granulosa cell ER/AR protein expression.
Assuntos
Di-Hidrotestosterona/análogos & derivados , Ovário/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Receptores de Esteroides/efeitos dos fármacos , Propionato de Testosterona/administração & dosagem , Fatores Etários , Envelhecimento , Animais , Western Blotting , Di-Hidrotestosterona/administração & dosagem , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Feminino , Idade Gestacional , Imuno-Histoquímica , Ovário/citologia , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Gravidez , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Receptores de Progesterona/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Receptores de Esteroides/metabolismo , OvinosRESUMO
MK801, PCP, and ketamine are non-competitive NMDA receptor-antagonists drugs that in humans produce psychomimetic effects and neurocognitive disturbances reminiscent to those of schizophrenia. The administration of these drugs in animals has been used as a pharmacological model to study the NMDA receptor hypofunction-hypothesis of schizophrenia. In animals, the biological effect of MK801 is dose-dependent. Low doses induce behavioral disturbances and higher doses, in addition, promote neurotoxicity in many brain regions, particularly the granular retrosplenial cortex (RSG). The neurotoxic effect of MK801 is sexually dimorphic, being females markedly more sensitive than males; however, the involvement of gonadal hormones is elusive. Here we show that a single intraperitoneal injection of 5 mg/kg of MK801 induced overt neurodegeneration in RSG of female rats, including abundant somatic degeneration in layer 4, and somatodendritic and terminal degeneration in layers 1, 4, and 5. MK801-degeneration in males was scarce and mainly evidenced by the presence of few argirophilic somas in layer 4. Ovariectomized rats were not significantly different than intact females, while orchiectomized rats showed robust MK801-toxicity. Testosterone and dihydrotestosterone (DHT) inhibit MK801-toxicity in orchiectomized rats. In ovariectomized rats only DHT, but not testosterone, prevented MK801-induced degeneration, while in intact females, DHT was only partially protective. Treatment of intact males with estradiol benzoate significantly enhanced MK801-toxicity. Altogether, our experiments indicate that non-aromatizable androgens protect RSG from MK801-toxicity, while estrogens counteract this protection. Thus, the balance of androgens and estrogens delineate the sexual dimorphism of the RSG to the toxic effect of MK801.