RESUMEN
Melatonin is a pineal hormone that regulates testicular activity (i.e., steroidogenesis and spermatogenesis) through two complementary mechanisms, indirect effects exerted via the hypothalamic-adenohypophyseal axis and direct actions that take place on the different cell populations of the male gonad. The effects of increased age on the testis and the general mechanisms involved in testicular pathology leading to infertility are still only poorly understood. However, there is growing evidence that link testicular aging and idiopathic male infertility to local inflammatory and oxidative stress events. Because literature data strongly indicate that melatonin exhibits anti-inflammatory and anti-oxidant properties, this review focuses on the potential benefits exerted by this indoleamine at testicular level in male reproductive fertility and aging. Taking into account that the effects of melatonin supplementation on testicular function are currently being investigated, the overview covers not only promising prospects but also many questions concerning the future therapeutic value of this indoleamine as an anti-aging drug as well as in the management of cases of male infertility for which there are no medical treatments currently available.
Asunto(s)
Envejecimiento , Antiinflamatorios , Antioxidantes , Infertilidad Masculina , Melatonina , Testículo , Masculino , Melatonina/uso terapéutico , Melatonina/farmacología , Humanos , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Testículo/efectos de los fármacos , Testículo/metabolismo , Infertilidad Masculina/tratamiento farmacológico , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Animales , Estrés Oxidativo/efectos de los fármacosRESUMEN
The evolutionary theory of aging supports a trade-off relationship between reproduction and aging. Aging of the male reproductive system primarily affects the testes, leading to a decrease in the levels of sexual hormones, alterations in sperm quality and production, and a decline in fertility that does not necessarily involve a complete cessation of spermatogenesis. Inflammation, oxidation, and apoptosis are events considered as predictors of pathogenesis and the development of age-related diseases that are frequently observed in aged testes. Although the molecular mechanisms are still poorly understood, accumulating evidence points toward pro-inflammatory molecules and reactive oxygen species as primary contributing factors for testicular aging. However, the real impact of aging-related testicular alterations on fertility, reproductive health, and life span is far from being fully revealed. This work discusses the current knowledge on the impact of aging in the testis, particularly of aging-related dysregulated inflammation and oxidative damage on the functioning of its different cell populations. More interestingly, this review covers the potential benefits of anti-aging interventions and therapies using either pharmacological compounds (such as non-selective non-steroidal anti-inflammatory medication) or more natural alternatives (such as various nutraceuticals or even probiotics) that exhibit anti-inflammatory, antioxidant, and anti-apoptotic properties. Some of these are currently being investigated or are already in clinical use to delay or prevent testicular aging.
Asunto(s)
Envejecimiento/patología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Productos Biológicos/farmacología , Testículo/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Testículo/efectos de los fármacosRESUMEN
Catecholaminergic neuronal elements (CNE) and macrophages (MACs) are increased in testes of patients with idiopathic infertility. Now, we describe an anatomical proximity between CNE and MACs, expression of specific α- and ß-adrenergic receptors (ADRs) subtypes in MACs, and a positive correlation between the number of MACs and cyclooxygenase (COX2) expression - key enzyme in prostaglandin (PG) synthesis and an inflammatory marker - in testes of infertile men. To examine a potential effect of adrenergic input on COX2 expression, we used two additional experimental models: non-testicular human MACs (THP1 cell line) and non-human testicular MACs purified from adult Syrian hamsters. We found that epinephrine and norepinephrine up-regulate COX2 expression and PGD2 production through ß1-and ß2-ADRs. Our results demonstrate the existence of a yet unknown link between CNE and MACs in the human testis that could trigger inflammation and tissue homeostatic dysregulation associated with pathogenesis or maintenance of infertility states.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Infertilidad Masculina/patología , Macrófagos/patología , Prostaglandinas/metabolismo , Receptores Adrenérgicos beta/metabolismo , Testículo/patología , Testosterona/metabolismo , Adulto , Animales , Células Cultivadas , Ciclooxigenasa 2/genética , Humanos , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Macrófagos/metabolismo , Masculino , Mesocricetus , Receptores Adrenérgicos beta/genética , Testículo/metabolismoRESUMEN
Stress activates the sympathetic nervous system and is linked to impaired fertility in man. We hypothesized that catecholamines by acting on testicular cells have a role in these events, possibly by fostering an inflammatory environment. The cells of the wall of seminiferous tubules, human testicular peritubular cells (HTPCs), express adrenergic receptors (ADRs) α1B, α1D, ß1 and ß2. A selective α1-ADR agonist, phenylephrine, increased intracellular Ca2+-levels in cultured HTPCs and induced COX-2, IL-6 and MCP-1 mRNA expression without affecting IL-1ß mRNA. These changes were paralleled by a significant increase in the secretion of IL-6 and MCP-1. Epinephrine was also effective, but salbutamol, a selective ß2-ADR agonist was not. Our results suggest that stress-associated elevation of catecholamines may be able to promote inflammatory events by targeting peritubular cells in the human testis. Blockage of α1-ADRs may therefore be a novel way to interfere with stress-related impairment of male reproductive functions.
Asunto(s)
Inflamación/metabolismo , Inflamación/patología , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta/metabolismo , Testículo/patología , Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Albuterol/farmacología , Supervivencia Celular/efectos de los fármacos , Quimiocina CCL2/metabolismo , Agonismo Inverso de Drogas , Epinefrina/farmacología , Humanos , Interleucina-6/metabolismo , Masculino , Fenilefrina/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
In man, blockage of prostaglandin (PG)-production e.g. by non-steroidal anti-inflammatory drug (NSAIDs) may have negative testicular side effects, implying beneficial actions of PGs in the testis. We examined human testicular samples and isolated human testicular peritubular cells (HTPCs) to explore sites of PG-synthesis and targets. HTPCs express cyclooxygenase 1 (COX1) and secrete PGE2. Receptors (EP1, 2, 4) were specifically identified in peritubular cells. In HTPCs PGE2 significantly increased mRNA levels of the contractility protein calponin, but did not induce contractions. PGE2, as well as EP1 and EP4 receptor agonists, significantly increased glia cell line derived neurotrophic factor (GDNF) mRNA and/or protein levels. Importantly, the NSAID ibuprofen reduced PGE2 and this action also lowered SMA and calponin mRNA levels and levels of secreted GDNF protein. The results reveal an unknown PGE2 system in the human testis, in involving peritubular cells, which may be prone to interference by NSAIDs.
Asunto(s)
Dinoprostona/metabolismo , Homeostasis , Testículo/metabolismo , Actinas/genética , Actinas/metabolismo , Biomarcadores/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Ciclooxigenasa 1/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Homeostasis/efectos de los fármacos , Humanos , Ibuprofeno/farmacología , Masculino , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Contracción Muscular/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Testículo/efectos de los fármacos , CalponinasRESUMEN
The pineal hormone melatonin regulates testicular function through the hypothalamic-adenohypophyseal axis. In addition, direct actions of melatonin in somatic cells of the testis have been described. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin influences cellular growth, proliferation, energy metabolism and the oxidation state, and consequently may regulate spermatogenesis. These data pinpoint melatonin as a key player in the regulation of testicular physiology (i.e., steroidogenesis, spermatogenesis) mostly in seasonal breeders. In patients with idiopathic infertility, melatonin exerts anti-proliferative and anti-inflammatory effects on testicular macrophages, and provides protective effects against oxidative stress in testicular mast cells. Consequently, melatonin is also involved in the modulation of inflammatory and oxidant/anti-oxidant states in testicular pathology. Overall, the literature data indicate that melatonin has important effects on testicular function and male reproduction.
Asunto(s)
Células Intersticiales del Testículo/metabolismo , Melatonina/metabolismo , Células de Sertoli/metabolismo , Testículo/metabolismo , Animales , Humanos , Masculino , Modelos Biológicos , Espermatogénesis , Testículo/citología , Testosterona/metabolismoRESUMEN
We have previously described a stimulatory effect of testosterone on cyclooxygenase 2 (COX2) expression and prostaglandin (PG) synthesis, and the involvement of PGs in the modulation of testosterone production in Leydig cells of the seasonal breeder Syrian hamster. In this study, we investigated the existence of a COX2/PGs system in hamster Sertoli cells, its regulation by testosterone and FSH, and its effect on glucose uptake. COX2 expression was observed in Sertoli cells of both reproductively active and inactive adult hamsters. Testosterone and the plasma membrane-impermeable testosterone-BSA significantly induced COX2 expression, mitogen activated protein kinases 1/2 (MAPK1/2) phosphorylation and 15d-Δ(12,14)PGJ(2) production in Sertoli cells purified from photoperiodically regressed hamsters. These actions were abolished by the antiandrogen bicalutamide and by the inhibitor of MAPK kinase (MEK1/2) U0126, suggesting that testosterone exerts its stimulatory effect on COX2/PGs through a non-classical mechanism that involves the presence of androgen receptors and MAPK1/2 activation. FSH also stimulated COX2/PGs via MAPK1/2 phosphorylation. FSH and testosterone stimulate, whereas 15d-Δ(12,14)PGJ(2) via PPARγ inhibits, [2,6-(3)H]-2-deoxy-d-glucose ([(3)H]-2-DOG) uptake. Meloxicam, a selective COX2 inhibitor, further increases [(3)H]-2-DOG uptake in the presence of FSH or testosterone. Thus, in addition to their positive effect, FSH and testosterone may also exert an indirect negative regulation on glucose uptake which involves the COX2/15d-Δ(12,14)PGJ(2)/PPARγ system. Overall, these results demonstrate the presence of a COX2/PG system in hamster Sertoli cells which might act as a local modulator of FSH and testosterone actions.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Hormona Folículo Estimulante/fisiología , Glucosa/metabolismo , Mesocricetus/fisiología , Prostaglandina D2/análogos & derivados , Testosterona/fisiología , Antagonistas de Andrógenos/farmacología , Anilidas/farmacología , Animales , Butadienos/farmacología , Cricetinae , Desoxiglucosa/metabolismo , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/antagonistas & inhibidores , MAP Quinasa Quinasa 2/metabolismo , Masculino , Meloxicam , Nitrilos/farmacología , Fosforilación , Prostaglandina D2/biosíntesis , Prostaglandina D2/fisiología , Células de Sertoli/metabolismo , Tiazinas/farmacología , Tiazoles/farmacología , Compuestos de Tosilo/farmacologíaRESUMEN
Serum prolactin (PRL) variations play a crucial role in the photoperiodic-induced testicular regression-recrudescence transition in hamsters. We have previously shown that cyclooxygenase 2 (COX2), a key enzyme in the biosynthesis of prostaglandins (PGs), is expressed mostly in Leydig cells of reproductively active hamsters with considerable circulating and pituitary levels of PRL. In this study, we describe a stimulatory effect of PRL on COX2/PGs in hamster Leydig cells, which is mediated by IL-1ß and prevented by P38-MAPK and JAK2 inhibitors. Furthermore, by preparative isoelectric focusing (IEF), we isolated PRL charge analogues from pituitaries of active [isoelectric points (pI): 5.16, 4.61, and 4.34] and regressed (pI: 5.44) hamsters. More acidic PRL charge analogues strongly induced COX2 expression, while less acidic ones had no effect. Our studies suggest that PRL induces COX2/PGs in hamster Leydig cells through IL-1ß and activation of P38-MAPK and JAK2. PRL microheterogeneity detected in active/inactive hamsters may be responsible for the photoperiodic variations of COX2 expression in Leydig cells.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Células Intersticiales del Testículo/metabolismo , Prolactina/fisiología , Prostaglandinas/biosíntesis , Animales , Cricetinae , Ciclooxigenasa 2/genética , Expresión Génica , Interleucina-1beta/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Fosforilación , Fotoperiodo , Hipófisis/metabolismo , Prolactina/farmacología , Isoformas de Proteínas/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Prolactina/metabolismo , Testículo/citología , Testículo/fisiología , Testosterona/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
As we previously reported, testes of men suffering from hypospermatogenesis and germ cell arrest or Sertoli cell-only syndrome show a major increase in the number of macrophages expressing interleukin-1ß (IL-1ß) and abundant expression of cyclooxygenase-2 (COX-2), the inducible isoform of the key enzyme in the biosynthesis of prostaglandins (PGs), in Leydig cells. In the present study we report [1] a positive correlation between IL-1ß levels and COX-2 expression in testes of infertile patients, [2] the induction of COX-2 by IL-1ß in mouse Leydig cells (TM3) and human macrophages (THP-1), and therefore [3] evidence for an IL-1ß-dependent induction of testicular inflammatory states.