RESUMEN
Testicular aging is linked to histological, morphological and functional alterations. In the present study, we investigated whether aging affects the inflammatory and oxidative status in the testis by comparing young adult, middle-aged adult and aged hamsters. The Syrian hamster, a thoroughly studied seasonal breeder, was chosen as the experimental model since it allows further investigations on the role of photoperiod and melatonin in testicular aging with a minimal impact of the experimental intervention on the animal well-being and the subsequent results achieved. In testes of aged hamsters, we found a decrease in melatonin concentration, a thickening of the wall of the seminiferous tubules as well as a significant increase in IL-1ß, NLRP3 and cyclooxygenase 2 expression, PGD2 production, macrophages numbers, lipid peroxidation and anti-oxidant enzyme catalase levels. Interestingly, when aged hamsters were transferred from a long day (LD) to a short day (SD) photoperiod for 16â¯weeks, testicular melatonin concentration increased while local inflammatory processes and oxidative stress were clearly reduced. Overall, these results indicate that melatonin might display anti-inflammatory and anti-oxidant capacities in the aged testes.
Asunto(s)
Envejecimiento/fisiología , Melatonina/fisiología , Estrés Oxidativo , Fotoperiodo , Testículo/patología , Animales , Cricetinae , Masculino , MesocricetusRESUMEN
Ageing is usually characterised by a mild chronic proinflammatory state. Despite the tight association between both processes, the phenomenon has recently been termed inflammageing. Inflammation in the male reproductive tract is frequently linked with bacterial or virus infections but also with a broad range of noninfectious processes. Prostatitis, epididymitis and orchitis, among others, can lead to infertility. However, in spite of the inflammation theory of disease, chronic inflammation in male urogenital system does not always cause symptoms. With advancing age, inflammatory processes are commonly observed in the male reproductive tract. Nevertheless, the incidence of inflammation in reproductive organs and ducts varies greatly among elderly men. Inflammageing is considered a predictor of pathogenesis and the development of age-related diseases. This article briefly summarises the current state of knowledge on inflammageing in the male reproductive tract. Yet, the precise aetiology of inflammageing in the male urogenital system, and its potential contribution not only to infertility but most importantly to adverse health outcomes remains almost unknown. Thus, further investigations are required to elucidate the precise cross-links between inflammation and male reproductive senescence, and to establish the impact of anti-inflammatory drug treatments on elder men's general health status.
Asunto(s)
Envejecimiento/inmunología , Antiinflamatorios/uso terapéutico , Enfermedades de los Genitales Masculinos/inmunología , Genitales Masculinos/inmunología , Inflamación/inmunología , Factores de Edad , Envejecimiento/patología , Enfermedades de los Genitales Masculinos/tratamiento farmacológico , Enfermedades de los Genitales Masculinos/epidemiología , Enfermedades de los Genitales Masculinos/patología , Genitales Masculinos/patología , Humanos , Incidencia , Inflamación/tratamiento farmacológico , Inflamación/epidemiología , Inflamación/patología , MasculinoRESUMEN
Melatonin acting through the hypothalamus and pituitary regulates testicular function. In addition, direct actions of melatonin at the testicular level have been recently suggested. We have described that melatonin inhibits androgen production in hamster Leydig cells via melatonin subtype 1a (mel1a) receptors and the local corticotrophin-releasing hormone (CRH) system. The initial events of the melatonin/CRH signalling pathway have also been established. Melatonin and all components of the melatonergic/CRH system were also detected in Leydig cells of infertile men. This study attempted to search for additional targets of melatonin in the human testis, and to investigate the effects of melatonin on proliferation and the oxidative state in these novel target cells. To this aim, evaluation of human testicular biopsies of patients suffering from hypospermatogenesis or Sertoli cell only syndrome and cell culture studies were performed. Melatonergic receptors were found in macrophages (MACs) and mast cells (MCs) of the human testis. In biopsies of patients suffering idiopathic infertility, melatonin testicular concentrations were negatively correlated with MAC number per mm(2) and TNFα, IL1ß and COX2 expression, but positively correlated with the expression of the anti-oxidant enzymes SOD1, peroxiredoxin 1 and catalase. Melatonin inhibited proliferation and the expression of pro-inflammatory cytokines and cyclooxygenase 2 (COX2) in both the human non-testicular THP-1 MAC cell line and primary cell cultures of hamster testicular MACs. In the human HMC-1 MC line, melatonin increased the expression of anti-oxidant enzymes and decreased reactive oxygen species (ROS) generation. The results reveal new testicular targets of melatonin and describe anti-proliferative and anti-inflammatory effects of this hormone on testicular MACs. Furthermore, melatonin might provide protective effects against oxidative stress in testicular MCs.
Asunto(s)
Infertilidad Masculina/metabolismo , Macrófagos/metabolismo , Mastocitos/metabolismo , Melatonina/metabolismo , Testículo/metabolismo , Adulto , Andrógenos/biosíntesis , Animales , Antiinflamatorios , Antioxidantes/metabolismo , Azoospermia/metabolismo , Catalasa/biosíntesis , Línea Celular , Proliferación Celular , Hormona Liberadora de Corticotropina/metabolismo , Cricetinae , Ciclooxigenasa 2/biosíntesis , Humanos , Interleucina-1beta/biosíntesis , Células Intersticiales del Testículo/metabolismo , Macrófagos/citología , Masculino , Mastocitos/citología , Oligospermia/metabolismo , Estrés Oxidativo , Peroxirredoxinas/biosíntesis , Especies Reactivas de Oxígeno/análisis , Receptores de Melatonina/antagonistas & inhibidores , Receptores de Melatonina/metabolismo , Síndrome de Sólo Células de Sertoli/metabolismo , Transducción de Señal , Superóxido Dismutasa/biosíntesis , Superóxido Dismutasa-1 , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
In Leydig cells, hormonal stimulation by LH/hCG entails increased intracellular Ca(2+) levels and steroid production, as well as hyperpolarization of the cell membrane. The large-conductance Ca(2+)-activated K(+)-channel (BK(Ca)) is activated by raised intracellular Ca(2+) and voltage and typically hyperpolarizes the cell membrane. Whether BK(Ca) is functionally involved in steroid production of Leydig cells is not known. In order to explore this point we first investigated the localization of BK(Ca) in human and hamster testes and then used a highly specific toxin, the BK(Ca) blocker iberiotoxin (IbTx), to experimentally dissect a role of BK(Ca). Immunohistochemistry and RT-PCR revealed that adult Leydig cells of both species are endowed with these channels. Ontogeny studies in hamsters indicated that BK(Ca) becomes strongly detectable in Leydig cells only after they acquire the ability to produce androgens. Using purified Leydig cells from adult hamsters, membrane potential changes in response to hCG were monitored. HCG hyperpolarized the cell membrane, which was prevented by the selective BK(Ca) blocker IbTx. Steroidogenic acute regulatory (StAR) mRNA expression and testosterone production were not affected by IbTx under basal conditions but markedly increased when hCG, in submaximal and maximal concentration or when db-cAMP was added to the incubation media. A blocker of K(V)4-channels, expressed by Leydig cells, namely phrixotoxin-2 (PhTx-2) was not effective. In summary, the data reveal BK(Ca) as a crucial part of the signaling cascade of LH/hCG in Leydig cells. The hyperpolarizing effect of BK(Ca) in the Leydig cell membrane appears to set in motion events limiting the production of testosterone evoked by stimulatory endocrine mechanisms.
Asunto(s)
Gonadotropina Coriónica/metabolismo , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Células Intersticiales del Testículo/metabolismo , Hormona Luteinizante/metabolismo , Transducción de Señal , Animales , Cricetinae , Fluorescencia , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Intersticiales del Testículo/citología , Células Intersticiales del Testículo/efectos de los fármacos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Mesocricetus , Péptidos/farmacología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Testosterona/biosíntesisRESUMEN
The golden (Syrian) hamster is a seasonal breeder, and exposure of adult animals to short days results in severe gonadal regression with morphological features that resemble the immature testis. The purpose of this study was to investigate testicular steroidogenic capacity in the golden hamster and to analyse the influence of age and photoperiod on this process. Hamsters aged 36 days were maintained on a long photoperiod (14L:10D), and adult animals were then exposed to a long or a short photoperiod (6L:18D) for 14 weeks (the period of time required to achieve maximal gonadal regression), to assess circulating levels and in vitro production of testosterone, dihydrotestosterone and androstane-3 alpha, 17 beta-diol. In peripubertal hamsters, androstane-3 alpha, 17 beta-diol was the main circulating androgen detected, whereas in active adult animals, testosterone showed the highest serum levels. In hamsters exposed to a short photoperiod, blood testosterone levels were significantly lower than levels in adult hamsters exposed to a long photoperiod. Exposure of adult hamsters to a short photoperiod produced a marked reduction in serum concentrations of dihydrotestosterone and androstane-3 alpha, 17 beta-diol, which was not accompanied by a decrease in testicular 5 alpha-reductase activity. In the in vitro experiments, active adult testes were less sensitive than inactive adult testes to stimulation of androgen production with hCG, but showed similar sensitivity to the gonads from hamsters aged 36 days. In accordance with circulating androgen concentrations, the principal androgens produced in the in vitro assays from peripubertal and normal adult testes were androstane-3 alpha, 17 beta-diol and testosterone, respectively. Unexpectedly, the main androgen produced from regressed testes under in vitro conditions was androstane-3 alpha, 17 beta-diol. Inactive gonads released more androstane-3 alpha, 17 beta-diol than did normal adult testes and total in vitro androgen production (testosterone + dihydrotestosterone + androstane-3 alpha, 17 beta-diol) from adult testes was not diminished by exposure to a short photoperiod. However, in spite of the significant increase detected in production of androstane-3 alpha, 17 beta-diol in vitro from regressed testes, inactive gonads produced less androstane-3 alpha, 17 beta-diol than did peripubertal testes. In summary, our studies suggest that testicular androgen biosynthetic capacity in adult hamsters exposed to short photoperiod is not reduced and these regressed testes represent an intermediate physiological state between peripubertal and active adult testes. The significant decrease detected in serum androgen concentrations during the involution phase could result from the absence of stimulating pituitary factors, together with a negative regulation of steroidogenesis by different non-steroidal signals originating within and/or outside of the testis.
Asunto(s)
Envejecimiento/fisiología , Andrógenos/biosíntesis , Fotoperiodo , Esteroides/biosíntesis , Testículo/fisiología , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Andrógenos/sangre , Androstano-3,17-diol/metabolismo , Animales , Peso Corporal , Gonadotropina Coriónica/farmacología , Cricetinae , Dihidrotestosterona/metabolismo , Técnicas In Vitro , Masculino , Mesocricetus , Tamaño de los Órganos , Maduración Sexual , Testículo/efectos de los fármacos , Testículo/enzimología , Testosterona/biosíntesisRESUMEN
Serotonin (5-HT) is found in the gonads and accessory reproductive organs of several species. The golden (Syrian) hamster is a seasonal breeder. Exposure of male adult hamsters to short days for 14 weeks results in a severe gonadal regression, while after a photoinhibition period of 22 weeks a spontaneous testicular recrudescence occurs. The aim of this study was to investigate the presence of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the gonads of golden hamsters, its immunolocation and its physiological role in the testis. The influence of age and photoperiod was also analyzed. Hamsters of 23, 36, 46, 60 and 90 days of age were kept in long photoperiod (LP: 14:10 h light/dark), and adult animals were exposed either to LP or to short photoperiod (SP: 6:18 h light/dark) for 14 and 22 weeks. Testicular parenchyma and capsule levels of 5-HT and 5-HIAA increased significantly at ages of 36 and 60-90 days, but decreased markedly during the exposure of adult hamsters to SP for 14 and 22 weeks. Mast cells were found exclusively in the testicular capsule. The testicular number of mast cells increased concomitantly with age, but decreased in adult hamsters exposed to SP. Mast and Leydig cells presented 5-HT-positive immunoreactivity. During sexual maturation as well as during the transfer of adult hamsters from LP to SP, the 5-HIAA/5-HT ratio showed the highest values in active adult animals, indicating that the increase in testicular 5-HT levels in adulthood is accompanied by an augment in 5-HT turnover. In vitro basal and hCG-stimulated testosterone production was significantly inhibited in presence of physiological concentrations of 5-HT. In conclusion, the present studies demonstrate the existence of 5-HT in mast cells and Leydig cells of hamster testes, as well as describe an inhibitory action of this neurotransmitter on gonadal testosterone production. Furthermore, the age-dependent and photoperiodic-related changes detected in testicular 5-HT levels suggest that this neurotransmitter might act as an important local modulator of the action of gonadotropins on steroidogenesis during sexual development and during the photoperiodic regression-recrudescence transition in the golden hamster.
Asunto(s)
Mesocricetus/fisiología , Fotoperiodo , Reproducción , Serotonina/metabolismo , Maduración Sexual , Testículo/metabolismo , Envejecimiento , Animales , Recuento de Células , Gonadotropina Coriónica/farmacología , Cricetinae , Ácido Hidroxiindolacético/análisis , Ácido Hidroxiindolacético/metabolismo , Células Intersticiales del Testículo/química , Masculino , Mastocitos/química , Serotonina/análisis , Serotonina/farmacología , Testículo/citología , Testículo/efectos de los fármacos , Testosterona/biosíntesisRESUMEN
While the hypothalamic-pituitary-gonadal axis is crucial for the function of the gonads, non-endocrine regulatory influences are exerted by other factors within the gonads. Among these factors are neurotransmitters, such as catecholamines. Several types of receptors for catecholamines exist in the gonads on vascular or endocrine cells. Their activation can alter blood flow, steroidogenesis and gene expression, depending on the target cells. Recently a neuronal-like cell type expressing catecholamine-biosynthetic enzymes and neuronal proteins was identified in testis and ovary of human and non-human primates. Together with the well-known sympathetic innervation, this gonadal nervous system may serve as a source of catecholamines. Dopamine is present in the follicular fluid. Oocytes, while not able to perform de novo synthesis of catecholamines, were shown to utilize dopamine to produce norepinephrine. This catecholamine then acts on beta-adrenoreceptors of follicular cells to increase cAMP. Oocytes may thus indirectly via dopamine and cAMP be able to control their own meiotic arrest. In addition, neurotransmitters may also be synthesized in other, non-neuronal ovarian cells. Thus, cultured human granulosa-luteal cells possess the acetylcholine synthesizing enzyme and the acetylcholine-specific vesicular transporter protein. These cells also express muscarinic-receptors (M1), which are linked to the mobilization of intracellular calcium and cell proliferation. This suggests involvement of the acetylcholine system in follicular growth and in the periovulatory events. In neurons, neurotransmitters alter the properties of the neuronal cell membrane. If this is the case in endocrine cells of the gonads is not yet clear, but the recent identification of voltage-activated potassium and sodium channels in human luteinized granulosa-luteal cells raises this question and opens a door to a new area of investigation.
Asunto(s)
Neurotransmisores/metabolismo , Ovario/fisiología , Testículo/fisiología , Acetilcolina/metabolismo , Animales , Catecolaminas/fisiología , Femenino , Humanos , Canales Iónicos/análisis , Masculino , Potenciales de la Membrana , OocitosRESUMEN
The exposure of golden hamsters to short days results in early regression of the reproductive organs and subsequent spontaneous recrudescence characterized by active cellular regeneration and differentiation. Thus, adult male hamsters were subjected to short photoperiod (SP, 6L:18D) for 9, 12, 14, 16, 18, and 22 weeks or maintained under long photoperiod (LP, 14L:10D) for 22 weeks, to assess photoperiodic-related changes in testicular and seminal vesicle (SV) levels of polyamines (PA) that are involved in cell growth and differentiation. During the regression phase, the weights of the organs and the circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, testosterone, dihydrotestosterone, and 5 alpha-androstane-3 alpha, 17 beta-diol were significantly diminished and, thereafter, during the recrudescence phase, they recovered total or partially their control values. In both tissues, the exposure to SP for 14-16 weeks resulted in an increase of PA concentrations, followed by a return to control levels in the recrudescence period. At the time of maximal tissue involution, the ornithine decarboxylase (ODC) activity (key regulatory enzyme of PA biosynthesis) showed a significant increase in testis, preceding the sharp peak of PA concentration. However, a marked decrease in ODC activity was detected in SV. The concentration of N-acetyl PA in SV showed an increment at 16 weeks of SP, while no modifications were detected in testicular concentration. When PA, N-acetyl PA, and ODC activity were expressed per testis and per SV, values fell significantly during the involution period, but in the recrudescence phase levels were recovered concomitantly with the restoration of the organ weight and function. In conclusion, the photoperiodic-related changes in PA and their N-acetyl derivatives might play a crucial role in regrowth and differentiation of the male sexual organs during the spontaneous recrudescence phase. Additionally, organ-specific regulation of the PA biosynthesis pathway could also take place.
Asunto(s)
Poliaminas Biogénicas/metabolismo , Reproducción/fisiología , Vesículas Seminales/enzimología , Testículo/enzimología , Andrógenos/sangre , Animales , Cricetinae , Hormona Folículo Estimulante/sangre , Hormona Luteinizante/sangre , Masculino , Mesocricetus , Tamaño de los Órganos , Ornitina Descarboxilasa/metabolismo , Fotoperiodo , Prolactina/sangre , Próstata/citología , Próstata/enzimología , Vesículas Seminales/citología , Conducta Sexual Animal/fisiología , Testículo/citologíaRESUMEN
Several factors, besides luteinizing hormone (LH), participate in the modulation of testicular function. A number of neurotransmitters are reported to be involved in this process, including a stimulatory action of gamma-aminobutyric acid (GABA) on steroidogenesis in the rat testis. The purpose of this study was to investigate the testicular pattern of GABA and glutamic acid, one of its main precursors, during sexual maturation in two seasonally breeding species: Syrian (golden) and Djungarian hamsters. Plasma androgen levels were also measured. The animals were maintained under long-day photoperiod (16:8, L:D) and were killed at 23, 30, 36, 46, 60, and 90 days of age. A different pattern of developmental changes in body and testicular weight was observed in these two species. GABA was present in the testes at all ages studied. GABA concentration and content showed a sharp elevation in the prepubertal period in golden as well as Djungarian hamsters. However, glutamic acid concentrations remained nearly constant during development in both species. Glutamic acid content increased gradually with age in the golden hamster, while a marked peak at 36 days of age was detected in the Djungarian hamster. Plasma testosterone and dihydrotestosterone levels were maximal at pubertal age in both species. The plasma levels of 5 alpha-androstane-3 alpha, 17 beta-diol increased significantly at 30 days of age in the golden hamster while in Djungarian hamsters this steroid remained unchanged. These results suggest that glutamic acid may serve as a precursor for GABA biosynthesis in the testis. In addition, changes in testicular GABA and plasma androgen levels might reflect a modulatory effect of this neurotransmitter in the acquisition of steroidogenic capability during development.
Asunto(s)
Andrógenos/sangre , Maduración Sexual , Testículo/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Peso Corporal , Cricetinae , Ácido Glutámico/metabolismo , Masculino , Mesocricetus , Tamaño de los Órganos , Phodopus , Especificidad de la EspecieRESUMEN
Gamma-aminobutyric acid (GABA) is found in the gonads and accessory reproductive organs, and a direct effect on steroidogenesis and sperm viability and motility has been described. The golden (Syrian) hamster is a seasonal breeder, and a pattern of regression-recrudescence in their reproductive organs is observed when adult animals are exposed to less than 12.5 h daylight for an extended period of time. The purpose of this study was to investigate: (1) the presence of GABA in the testis and epididymis of golden hamsters undergoing regression and spontaneous recrudescence; (2) glutamic acid levels and glutamate decarboxylase (GAD) activity in both tissues, and (3) testicular and epididymal testosterone, dihydrotestosterone and 5 alpha-androstane-3 alpha, 17 beta-diol concentrations. Adult golden hamsters were exposed to long (LP 14L:10D) or short (SP 6L:18D) photoperiods for 9, 12, 14, 16, 18 or 22 weeks. When animals were exposed to SP for 14-16 weeks, the testis and epididymis reached maximal involution. Testicular and epididymal androgen levels showed a marked decrease (p < 0.05) during the regression period, and after 18-22 weeks, values began to recover. Between 12 and 18 weeks in SP, the testicular and epididymal content of GABA and glutamic acid was reduced significantly. The concentration of GABA in both tissues showed a sharp rise (p < 0.05), while the concentration of glutamic acid diminished during the period of maximal involution (p < 0.05). In the testis, GAD activity was increased (p < 0.001) after 14 weeks in SP, with no change in the epididymis. In conclusion, glutamic acid via GAD activity could be the main source of GABA in the testis, but not in the epididymis. Furthermore, the presence of GABA in testicular cells and its subsequent photoperiodic variations might act as an important autocrine and/or paracrine modulatory signal in gonadal processes.
Asunto(s)
Epidídimo/efectos de la radiación , Glutamato Descarboxilasa/metabolismo , Ácido Glutámico/metabolismo , Testículo/efectos de la radiación , Ácido gamma-Aminobutírico/metabolismo , Andrógenos/metabolismo , Animales , Cricetinae , Epidídimo/enzimología , Epidídimo/metabolismo , Masculino , Mesocricetus , Testículo/enzimología , Testículo/metabolismoRESUMEN
This review covers some common aspects of the biosynthesis, interconversion pathways and biochemical functions of polyamines. A particular emphasis is given in experimental models as well as humans, to their presence in the male gonad, prostate gland, seminal vesicles, epididymis and semen. The interaction between hormones (androgens, LH, FSH and PRL) and the main enzymes involved on the polyamine biosynthesis, and the relationship of these compounds on cell growth and differentiation, are also discussed. In this regard, an attention is offered to the potential role of polyamines during early spermatogenesis stages and the use of some enzymes involved in their biosynthesis as sensitive and specific markers of the action of androgens and antiandrogens in the epididymis. Finally, a special issue is addressed to the controversial information documented on polyamines, their oxidation products and the relationship with male fertility.