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Progesterone's role in sperm The female steroid hormone progesterone is produced by the ovaries and the placenta, and supports gestation and embryogenesis through its actions on a well-characterized nuclear progesterone receptor. But progesterone released by cells surrounding the egg also stimulates sperm cells within the Fallopian tubes and increases their fertilizing ability, and the mechanism of this action of progesterone has remained elusive. Two independent research groups now report that progesterone potently activates CatSper, the principal Ca 2+ channel of the sperm flagellum. Their data demonstrate that the CatSper channel or a directly associated membrane protein serves as a novel progesterone receptor that can mediate a fast, non-genomic effect of progesterone at the level of the sperm plasma membrane. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Progesterone stimulates an increase in Ca 2+ levels in human sperm, but the underlying signalling mechanism is poorly understood. Two studies now show that progesterone activates the sperm-specific, pH-sensitive CatSper calcium channel, leading to a rapid influx of Ca 2+ ions into the spermatozoa. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg’s protective vestments 1 . Progesterone induces Ca 2+ influx into spermatozoa 1 , 2 , 3 and triggers multiple Ca 2+ -dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg 4 , 5 , 6 , 7 , 8 . As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor 9 . However, the effect of progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane progesterone receptor 5 , 10 . The identity of this non-genomic progesterone receptor and the mechanism by which it causes Ca 2+ entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of progesterone on human spermatozoa by identifying the Ca 2+ channel activated by progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of progesterone dramatically potentiate CatSper, a pH-dependent Ca 2+ channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic progesterone receptor of sperm. Given that the CatSper-associated progesterone receptor is sperm specific and structurally different from the genomic progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.

During pregnancy, progesterone inhibits the growth-promoting actions of estrogen in the uterus. However, the mechanism for this is not clear. The attenuation of estrogen-mediated proliferation of the uterine epithelium by progesterone is a prerequisite for successful implantation. Our study reveals that progesterone-induced expression of the basic helix-loop-helix transcription factor Hand2 in the uterine stroma suppresses the production of several fibroblast growth factors (FGFs) that act as paracrine mediators of mitogenic effects of estrogen on the epithelium. In mouse uteri lacking Hand2, continued induction of these FGFs in the stroma maintains epithelial proliferation and stimulates estrogen-induced pathways, resulting in impaired implantation. Thus, Hand2 is a critical regulator of the uterine stromal-epithelial communication that directs proper steroid regulation conducive for the establishment of pregnancy.

Outlining the 'brain-belly' connection that describes how sticky fat cells send mixed messages to the brain - and cause us to get fat as a result - Larry McCleary offers a unique approach that enables us to get in touch with the signals our bodies generate so that we work with, not against, our innate metabolic machinery.

The maximal lactate steady state (MLSS) and the critical power (CP) are two widely used indices of the highest oxidative metabolic rate that can be sustained during continuous exercise and are often considered to be synonymous. However, while perhaps having similarities in principle, methodological differences in the assessment of these parameters typically result in MLSS occurring at a somewhat lower power output or running speed and exercise at CP being sustainable for no more than approximately 20–30 min. This has led to the view that CP overestimates the ‘actual’ maximal metabolic steady state and that MLSS should be considered the ‘gold standard’ metric for the evaluation of endurance exercise capacity. In this article we will present evidence consistent with the contrary conclusion: i.e., that (1) as presently defined, MLSS naturally underestimates the actual maximal metabolic steady state; and (2) CP alone represents the boundary between discrete exercise intensity domains within which the dynamic cardiorespiratory and muscle metabolic responses to exercise differ profoundly. While both MLSS and CP may have relevance for athletic training and performance, we urge that the distinction between the two concepts/metrics be better appreciated and that comparisons between MLSS and CP, undertaken in the mistaken belief that they are theoretically synonymous, is discontinued. CP represents the genuine boundary separating exercise in which physiological homeostasis can be maintained from exercise in which it cannot, and should be considered the gold standard when the goal is to determine the maximal metabolic steady state. The maximal lactate steady state (MLSS) and the critical power (CP) are two indices of the highest oxidative metabolic rate that can be sustained during continuous exercise and are often considered to be synonymous. We discuss evidence consistent with the interpretation that CP provides a more robust representation of the boundary separating exercise domains wherein a metabolic steady‐state can or cannot be achieved.

Progesterone's role in sperm The female steroid hormone progesterone is produced by the ovaries and the placenta, and supports gestation and embryogenesis through its actions on a well-characterized nuclear progesterone receptor. But progesterone released by cells surrounding the egg also stimulates sperm cells within the Fallopian tubes and increases their fertilizing ability, and the mechanism of this action of progesterone has remained elusive. Two independent research groups now report that progesterone potently activates CatSper, the principal Ca 2+ channel of the sperm flagellum. Their data demonstrate that the CatSper channel or a directly associated membrane protein serves as a novel progesterone receptor that can mediate a fast, non-genomic effect of progesterone at the level of the sperm plasma membrane. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Progesterone stimulates an increase in Ca 2+ levels in human sperm, but the underlying signalling mechanism is poorly understood. Two studies now show that progesterone activates the sperm-specific, pH-sensitive CatSper calcium channel, leading to a rapid influx of Ca 2+ ions into the spermatozoa. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca 2+ increase by a non-genomic mechanism 1 , 2 , 3 . The Ca 2+ signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm 4 , 5 , 6 , 7 , 8 . However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca 2+ channel 9 , 10 , 11 . We found that both progesterone and alkaline pH stimulate a rapid Ca 2+ influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca 2+ signals evoked by alkaline pH and progesterone are inhibited by the Ca v channel blockers NNC 55-0396 and mibefradil. Patch-clamp recordings from sperm reveal an alkaline-activated current carried by mono- and divalent ions that exhibits all the hallmarks of sperm-specific CatSper Ca 2+ channels 10 , 11 . Progesterone substantially enhances the CatSper current. The alkaline- and progesterone-activated CatSper current is inhibited by both drugs. Our results resolve a long-standing controversy over the non-genomic progesterone signalling. In human sperm, either the CatSper channel itself or an associated protein serves as the non-genomic progesterone receptor. The identification of CatSper channel blockers will greatly facilitate the study of Ca 2+ signalling in sperm and help to define further the physiological role of progesterone and CatSper.

Testosterone is one of the most potent naturally secreted androgenicanabolic hormones, and its biological effects include promotion of muscle growth. In muscle, testosterone stimulates protein synthesis (anabolic effect) and inhibits protein degradation (anti-catabolic effect); combined, these effects account for the promotion of muscle hypertrophy by testosterone. These physiological signals from testosterone are modulated through the interaction of testosterone with the intracellular androgen receptor (AR). Testosterone is important for the desired adaptations to resistance exercise and training; in fact, testosterone is considered the major promoter of muscle growth and subsequent increase in muscle strength in response to resistance training in men. The acute endocrine response to a bout of heavy resistance exercise generally includes increased secretion of various catabolic (breakdown- related) and anabolic (growth-related) hormones including testosterone. The response of testosterone and AR to resistance exercise is largely determined by upper regulatory elements including the acute exercise programme variable domains, sex and age. In general, testosterone concentration is elevated directly following heavy resistance exercise in men. Findings on the testosterone response in women are equivocal with both increases and no changes observed in response to a bout of heavy resistance exercise. Age also significantly affects circulating testosterone concentrations. Until puberty, children do not experience an acute increase in testosterone from a bout of resistance exercise; after puberty some acute increases in testosterone from resistance exercise can be found in boys but not in girls. Aging beyond 35–40 years is associated with a 1–3% decline per year in circulating testosterone concentration in men; this decline eventually results in the condition known as andropause. Similarly, aging results in a reduced acute testosterone response to resistance exercise in men. In women, circulating testosterone concentration also gradually declines until menopause, after which a drastic reduction is found. In summary, testosterone is an important modulator of muscle mass in both men and women and acute increases in testosterone can be induced by resistance exercise. In general, the variables within the acute programme variable domains must be selected such that the resistance exercise session contains high volume and metabolic demand in order to induce an acute testosterone response.

The female hormones, oestrogen and progesterone, fluctuate predictably across the menstrual cycle in naturally cycling eumenorrhoeic women. Other than reproductive function, these hormones influence many other physiological systems, and their action during exercise may have implications for exercise performance. Although a number of studies have found exercise performance — and in particular, endurance performance — to vary between menstrual phases, there is an equal number of such studies reporting no differences. However, a comparison of the increase in the oestrogen concentration (E) relative to progesterone concentration (P) as the E/P ratio (pmol/ nmol) in the luteal phase in these studies reveals that endurance performance may only be improved in the mid-luteal phase compared with the early follicular phase when the E/P ratio is high in the mid-luteal phase. Furthermore, the late follicular phase, characterized by the pre-ovulatory surge in oestrogen and suppressed progesterone concentrations, tends to promote improved performance in a cycling time trial and future studies should include this menstrual phase. Menstrual phase variations in endurance performance may largely be a consequence of changes to exercise metabolism stimulated by the fluctuations in ovarian hormone concentrations. The literature suggests that oestrogen may promote endurance performance by altering carbohydrate, fat and protein metabolism, with progesterone often appearing to act antagonistically. Details of the ovarian hormone influences on the metabolism of these macronutrients are no longer only limited to evidence from animal research and indirect calorimetry but have been verified by substrate kinetics determined with stable tracer methodology in eumenorrhoeic women. This review thoroughly examines the metabolic perturbations induced by the ovarian hormones and, by detailed comparison, proposes reasons for many of the inconsistent reports in menstrual phase comparative research. Often the magnitude of increase in the ovarian hormones between menstrual phases and the E/P ratio appear to be important factors determining an effect on metabolism. However, energy demand and nutritional status may be confounding variables, particularly in carbohydrate metabolism. The review specifically considers how changes in metabolic responses due to the ovarian hormones may influence exercise performance. For example, oestrogen promotes glucose availability and uptake into type I muscle fibres providing the fuel of choice during short duration exercise; an action that can be inhibited by progesterone. A high oestrogen concentration in the luteal phase augments muscle glycogen storage capacity compared with the low oestrogen environment of the early follicular phase. However, following a carbo-loading diet will super-compensate muscle glycogen stores in the early follicular phase to values attained in the luteal phase. Oestrogen concentrations of the luteal phase reduce reliance on muscle glycogen during exercise and although not as yet supported by human tracer studies, oestrogen increases free fatty acid availability and oxidative capacity in exercise, favouring endurance performance. Evidence of oestrogen’s stimulation of 50-AMPactivated protein kinase may explain many of the metabolic actions of oestrogen. However, both oestrogen and progesterone suppress gluconeogenic output during exercise and this may compromise performance in the latter stages of ultra-long events if energy replacement supplements are inadequate. Moreover, supplementing energy intake during exercise with protein may be more relevant when progesterone concentration is elevated compared with menstrual phases favouring a higher relative oestrogen concentration, as progesterone promotes protein catabolism while oestrogen suppresses protein catabolism. Furthermore, prospective research ideas for furthering the understanding of the impact of the menstrual cycle on metabolism and exercise performance are highlighted.

Sex‐specific differences in mitochondrial function and free radical homeostasis are reported in the context of aging but not well‐established in pathogeneses occurring early in life. Here, we examine if sex disparity in mitochondria function, morphology, and redox status starts early and hence can be implicated in sexual dimorphism in cardiac as well as neurological disorders prevalent at young age. Although mitochondrial activity in the heart did not significantly vary between sexes, female brain exhibited enhanced respiration and higher reserve capacity. This was associated with lower H2O2 production in female cardiac and brain tissues. Using transmission electron microscopy, we found that the number of female cardiac mitochondria is moderately greater (117 ± 3%, P = 0.049, N = 4) than male's, which increased significantly for cortical mitochondria (134 ± 4%, P = 0.001, N = 4). However, male's cardiac mitochondria exhibited fragmented, circular, and smaller mitochondria relative to female's mitochondria, while no morphologic sex‐dependent differences were observed in cortical mitochondria. No sex differences were detected in Nox2 and Nox4 proteins or O2‐consuming/H2O2‐producing activities in brain homogenate or synaptosomes. However, a strong trend of increased EPR‐detected NOX superoxide in male synaptosomes hinted at higher superoxide dismutase activity in female brains, which was confirmed by two independent protocols. We also provide direct evidence that respiring mitochondria generally produce an order‐of‐magnitude lower reactive oxygen species (ROS) proportions than currently estimated. Our results indicate that sex differences in mitochondrial biogenesis, bioenergetics, and morphology may start at young age and that sex‐dependent SOD capacity may be responsible for differences in ROS homeostasis in heart and brain. This study examines if sex disparity in mitochondrial function, morphology, and redox status starts early and hence can be implicated in sexual dimorphism in cardiac as well as neurological disorders prevalent at young age. Our results indicate that sex differences in mitochondrial biogenesis, bioenergetics, and morphology may start at young age and that sex‐dependent SOD capacity may be responsible for differences in reactive oxygen species (ROS) homeostasis in heart and brain.