The multifaceted role of mast cells in joint inflammation and arthritis.

OBJECTIVE: To review current knowledge surrounding the role of mast cells in joint inflammation and arthritis. METHOD: Narrative review. RESULTS: Mast cells (MCs) are commonly observed in the synovium of the joint, particularly surrounding blood vessels and nerve endings. Some studies have reported increased MC number and degranulation in patients with osteoarthritis (OA). In two studies, MCs were the only immune cell type found in higher concentrations in synovium of OA patients compared to rheumatoid arthritis patients. Activation of MCs in OA includes signaling pathways such as immunoglobulin E/Fc epsilon Receptor 1 (IgE/FcεR1), immunoglobulin G/Fc gamma receptor (IgG/FcγR), complement, and toll-like cell surface receptor-mediated signaling, resulting in context-dependent release of either pro-inflammatory and/or anti-inflammatory mediators within the joint. Activation of MCs results in the release of pro-inflammatory mediators that ultimately contribute to inflammation of the synovium, bone remodeling, and cartilage damage. However, some studies have proposed that MCs can also exhibit anti-inflammatory effects by secreting mediators that inactivate pro-inflammatory cytokines such as interleukin 6 (IL-6). CONCLUSIONS: MCs may play a role in mediating synovial inflammation and OA progression. However, the mechanisms governing MC activation, the downstream pro- and/or anti-inflammatory effects, and their impact on osteoarthritis pathogenesis remains to be elucidated and requires extensive further study. Furthermore, it is important to establish the pathways of MC activation in OA to determine whether MCs exhibit varying phenotypes as a function of disease stage. Ultimately, such research is needed before understanding whether MCs could be targeted in OA treatments.

Physical health of the female athlete: observations, effects, and causes of reproductive disorders.

This review begins by summarizing the state of knowledge about menstrual disorders in athletes at the turn of the 21st Century. It then highlights the most important developments of outstanding interest that have been reported in the 18 months since then. New observations of the characteristics of these disorders are followed by new reports of clinical consequences and recommendations for treatment, and discoveries about their physiological mechanism. In general, evidence is continuing to accumulate that exercise has no suppressive effect on the reproductive system beyond the impact of its energy cost on energy availability. These results encourage the hope that athletic women may be able to prevent or reverse menstrual disorders by dietary supplementation without any moderation of their exercise regimen.

Low energy availability, not exercise stress, suppresses the diurnal rhythm of leptin in healthy young women.

Because the effect of exercise on leptin was not established, we controlled energy intake (I) and exercise energy expenditure (E) to distinguish the independent effects of energy availability (A = I - E) and exercise stress (everything associated with exercise except its energy cost) on the diurnal leptin rhythm in healthy young women. In random order, we set A = 45 and 10 kcal. kg lean body mass(-1) (LBM) x day(-1) for 4 days during the early follicular phase of separate menstrual cycles in sedentary (S, n = 7) and exercising (X, n = 9: E = 30 kcal x kg LBM(-1) x day(-1)) women. Low energy availability suppressed the 24-h mean (P < 10(-6)) and amplitude (P < 10(-5)), whereas exercise stress did not (both P > 0.2). Suppressions of the 24-h mean (-72 +/- 3 vs. -53 +/- 3%, P < 0.001) and amplitude (-85 +/- 3 vs. -58 +/- 6%, P < 0.001) were more extreme in S vs. X than previously reported effects on luteinizing hormone pulsatility and carbohydrate availability. Thus the diurnal rhythm of leptin depends on energy, or carbohydrate, availability, not intake, and exercise has no suppressive effect on the diurnal rhythm of leptin beyond the impact of its energy cost on energy availability.

High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition.

The purposes of this investigation were to evaluate the characteristics of three consecutive menstrual cycles and to determine the frequency ofluteal phase deficiency (LPD) and anovulation in a sample of sedentary and moderately exercising, regularly menstruating women. For three consecutive menstrual cycles, subjects collected daily urine samples for analysis of FSH, estrone conjugates (E1C), pregnanediol-3-glucuronide (PdG), and creatinine (Cr). Sedentary (n=11) and exercising (n=24) groups were similar in age (27.0+/-1.3 yr), weight (60.3+/-3.1 kg), gynecological age (13.8+/-1.2 yr), and menstrual cycle length (28.3+/-0.8 days). Menstrual cycles were classified by endocrine data as ovulatory, LPD, or anovulatory. No sedentary women (0%) had inconsistent menstrual cycle classifications from cycle to cycle, but 46% of the exercising women were inconsistent. The sample prevalence of LPD in the exercising women was 48%, and the 3-month sample incidence was 79%. In the sedentary women, 90% of all menstrual cycles were ovulatory (SedOvul; n=28), whereas in the exercising women only 45% were ovulatory (ExOvul; n=30); 43% were LPD (ExLPD; n=28), and 12% were anovulatory (ExAnov; n=8). In ExLPD cycles, the follicular phase was significantly longer (17.9+/-0.7 days), and the luteal phase was significantly shorter (8.2+/-0.5 days) compared to ExOvul (14.8+/-0.9 and 12.9+/-0.3 days) and SedOvul (15.9+/-0.6 and 12.9+/-0.4 days) cycles. Luteal phase PdG excretion was lower (P < 0.001) in ExLPD (2.9+/-0.3 microg/mg Cr) and ExAnov (0.8+/-0.1 microg/mg Cr) cycles compared to SedOvul cycles (5.0+/-0.4 microg/mg Cr). ExOvul cycles also had less (P < 0.01) PdG excretion during the luteal phase (3.7+/-0.3 microg/mg Cr) than the SedOvul cycles. E1C excretion during follicular phase days 2-5 was lower (P=0.05) in ExOvul, ExLPD, and ExAnov cycles compared to SedOvul cycles and remained lower (P < 0.02) in the ExLPD and ExAnov cycles during days 6-12. The elevation in FSH during the luteal-follicular transition was lower (P < 0.007) in ExLPD (0.7+/-0.1 ng/mg Cr) cycles compared to SedOvul and ExOvul cycles (1.0+/-0.1 and 1.1+/-0.1 ng/mg Cr, respectively). Energy balance and energy availability were lower (P < 0.05) in ExAnov cycles than in other menstrual cycle categories. The blunted elevation in FSH during the luteal-follicular transition in exercising women with LPD may explain their lower follicular estradiol levels. These alterations in FSH may act in concert with disrupted LH pulsatility as a primary and proximate factor in the high frequency of luteal phase and ovulatory disturbances in regularly menstruating, exercising women.

Slow restoration of LH pulsatility by refeeding in energetically disrupted women.

In other energy-restricted mammals, a single large meal restores luteinizing hormone (LH) pulsatility within a few hours. To determine whether this is so in women, we measured LH pulsatility during the 5th day of low energy availability [dietary energy intake - exercise energy expenditure = 10 kcal . kg lean body mass (LBM)-1 . day-1] and during a 6th day of aggressive refeeding (90 kcal . kg LBM-1 . day-1) in 15 meals providing 4,100 kcal for an energy availability of 75 kcal . kg LBM-1 . day-1. Low energy availability raised beta-hydroxybutyrate 1,000% (P < 0.001) and reduced plasma glucose 15% (P < 0.01), insulin 63% (P < 0.001), and triiodothyronine 22% (P < 0.005). In five of eight subjects, low energy availability also unambiguously suppressed LH pulse frequency 57% to 8.2 +/- 1.5 pulses/24 h (P < 10(-4)) and raised LH pulse amplitude 94% to 3.1 +/- 0.3 IU/l (P < 10(-4)), levels below the 5th and above the 95th percentile, respectively, in energy-balanced women. Aggressive refeeding restored beta-hydroxybutyrate, glucose, and insulin, but not triiodothyronine. In the five women with unambiguously disrupted LH pulsatility, aggressive refeeding had no effect on LH pulse amplitude (P > 0.9) and raised LH pulse frequency only slightly (2.4 +/- 0.6 pulses/24 h, P = 0.04) and not above the fifth percentile. This striking contrast between women and other mammals may be another clue to the unidentified mechanism mediating the effect of energy availability on LH pulsatility.

Low energy availability, not stress of exercise, alters LH pulsatility in exercising women.

We tested two hypotheses about the disruption of luteinizing hormone (LH) pulsatility in exercising women by assaying LH in blood samples drawn at 10-min intervals over 24 h from nine young, habitually sedentary, regularly menstruating women on days 8, 9, or 10 of two menstrual cycles after 4 days of intense exercise [E = 30 kcal.kg lean body mass (LBM)-1.day-1 at 70% of aerobic capacity]. To test the hypothesis that LH pulsatility is disrupted by low energy availability, we controlled the subjects' dietary energy intakes (I) to set their energy availabilities (A = I - E) at 45 and 10 kcal.kg LBM-1.day-1 during the two trials. To test the hypothesis that LH pulsatility is disrupted by the stress of exercise, we compared the resulting LH pulsatilities to those previously reported in women with similar controlled energy availability who had not exercised. In the exercising women, low energy availability reduced LH pulse frequency by 10% (P < 0.01) during the waking hours and increased LH pulse amplitude by 36% (P = 0.05) during waking and sleeping hours, but this reduction in LH pulse frequency was blunted by 60% (P = 0.03) compared with that in the previously studied nonexercising women whose low energy availability was caused by dietary restriction. The stress of exercise neither reduced LH pulse frequency nor increased LH pulse amplitude (all P > 0.4). During exercise, the proportion of energy derived from carbohydrate oxidation was reduced from 73% while A = 45 kcal.kg LBM-1.day-1 to 49% while A = 10 kcal.kg LBM-1.day-1 (P < 0.0001). These results contradict the hypothesis that LH pulsatility is disrupted by exercise stress and suggest that LH pulsatility in women depends on energy availability.

American College of Sports Medicine position stand. The Female Athlete Triad.

The Female Athlete Triad is a syndrome occurring in physically active girls and women. Its interrelated components are disordered eating, amenorrhea, and osteoporosis. Pressure placed on young women to achieve or maintain unrealistically low body weight underlies development of the Triad. Adolescents and women training in sports in which low body weight is emphasized for athletic activity or appearance are at greatest risk. Girls and women with one component of the Triad should be screened for the others. Alone or in combination, Female Athlete Triad disorders can decrease physical performance and cause morbidity and mortality. More research is needed on its causes, prevalence, treatment, and consequences. All individuals working with physically active girls and women should be educated about the Female Athlete Triad and develop plans to prevent, recognize, treat, and reduce its risks.

Circadian rhythm of cortisol confounds cortisol responses to exercise: implications for future research.

To investigate whether measurements of cortisol responses to exercise are confounded by neglect of the hormone's circadian rhythm, we measured the serum and salivary cortisol responses of eight women to 40 min of 70% maximal oxygen consumption treadmill exercise beginning at 0800 and 2000. Responses were calculated relative to the usually employed preexercise concentrations and also to concentrations at the same times of another day while subjects were at rest. Compared with areas under response curves (AUCs) calculated relative to their circadian baselines, AUCs for serum and salivary cortisol calculated by reference to preexercise concentrations were underestimated (serum, P < 0.001; salivary, P < 0.01) by 93 and 84% in the morning and by 37 and 35% in the evening, respectively. Calculated by the usual preexercise baseline method, rises in serum and salivary cortisol were similarly underestimated. More accurately calculated relative to their circadian baselines, serum and salivary cortisol AUCs were similar (P = 0.63 and P = 0.37, respectively) in the morning and evening, as were their rises (P = 0.23 and P = 0.70, respectively). In future investigations of the existence and magnitude of cortisol responses, those responses must be calculated relative to the hormone's circadian baseline.

Dietary restriction reduces luteinizing hormone (LH) pulse frequency during waking hours and increases LH pulse amplitude during sleep in young menstruating women.

To determine the effect of dietary energy restriction on gonadotropins, we assayed LH and FSH in samples drawn at 10- and 60-min intervals, respectively, over 24 h from seven young women (mean +/- SE gynecological age, 7.7 +/- 1.2 yr) on day 9, 10, or 11 of two menstrual cycles. Cortisol was measured in samples collected at 30-min intervals. During the 4 previous days and the day of sampling, dietary energy intake was set at either 45 or 10 Cal/kg lean body mass.day in random order. Beginning 2 days before treatment, blood was sampled daily at 0800 h and assayed for T3, insulin-like growth factor-I, and insulin. Estradiol was measured in samples collected daily and at 6-h intervals on the day of frequent sampling. By the day of frequent sampling, dietary restriction had reduced T3 20% (P < 0.01), insulin-like growth factor-I 58% (P < 0.001), and insulin 54% (P < 0.001). Twenty-four-hour transverse means for LH (P = 0.3), FSH (P = 0.2), estradiol (P = 0.3), and cortisol (P = 0.13) were unaffected, but LH pulse frequency was reduced 23% (P < 0.01), especially during waking hours, whereas LH pulse amplitude was increased 40% (P = 0.05), especially during sleep. These results support the hypothesis that LH pulsatility depends upon energy availability in women, as it does in other mammalian species.

Clinical tests explain blunted cortisol responsiveness but not mild hypercortisolism in amenorrheic runners.

To investigate mechanisms of blunted adrenocortical responsiveness to exercise and mild hypercortisolism in amenorrheic runners, adrenocorticotropic hormone [ACTH-(1-24) 0.25 mg Cortrosyn] stimulation tests were performed in the presence and absence of overnight dexamethasone (1 mg) suppression (DX and NDX condition, respectively) in six eumenorrheic sedentary women (ES), nine eumenorrheic runners (ER), and nine amenorrheic runners (AR). Before the NDX stimulation test, plasma cortisol was higher (P < 0.001) in AR than in ER and ES. The cortisol response to the NDX stimulation test was blunted (P < 0.001) in AR but reached similar (P > 0.7) peak levels in all groups. Dexamethasone suppressed (P < 0.001) cortisol to similar (P > 0.5) levels (approximately 20 nmol/l) in all groups. In AR, cortisol responses to the DX test were larger (P < 0.03) than to the NDX test and similar (P > 0.6) in the three groups, again reaching comparable (P > 0.8) peak levels. The blunted cortisol response to stimulation in AR in the presence of their mild hypercortisolism appears to be due to a normal limitation in maximal adrenal secretory capacity. Extrapituitary modulators of adrenal responsiveness to ACTH may explain the mild hypercortisolism observed in AR, but limitations of these tests prevent a central negative-feedback defect or an intrinsic adrenal abnormality from being excluded until results of additional studies with even lower doses of dexamethasone and submaximal doses of ACTH-(1-24) are available.

Induction of low-T3 syndrome in exercising women occurs at a threshold of energy availability.

To investigate the relationship between energy availability (dietary energy intake minus energy expended during exercise) and thyroid metabolism, we studied 27 untrained, regularly menstruating women who performed approximately 30 kcal.kg lean body mass (LBM)-1.day-1 of supervised ergometer exercise at 70% of aerobic capacity for 4 days in the early follicular phase. A clinical dietary product was used to set energy availability in four groups (10.8, 19.0, 25.0, 40.4 kcal.kg LBM-1.day-1). For 9 days beginning 3 days before treatments, blood was sampled once daily at 8 A.M. Initially, thyroxine (T4) and free T4 (fT4), 3,5,3'-triiodothyronine (T3) and free T3 (fT3), and reverse T3 (rT3) were in the normal range for all subjects. Repeated-measures one-way analysis of variance followed by one-sided, two-sample post hoc Fischer's least significant difference tests of changes by treatment day 4 revealed that reductions in T3 (16%, P < 0.00001) and fT3 (9%, P < 0.01) occurred abruptly between 19.0 and 25.0 kcal.kg LBM-1.day-1 and that increases in fT4 (11%, P < 0.05) and rT3 (22%, P < 0.01) occurred abruptly between 10.8 and 19.0 kcal.kg LBM-1.day-1. Changes in T4 could not be distinguished. If energy deficiency suppresses reproductive as well as thyroid function, athletic amenorrhea might be prevented or reversed by increasing energy availability through dietary reform to 25 kcal.kg LBM-1.day-1, without moderating the exercise regimen.

Induction and prevention of low-T3 syndrome in exercising women.

To investigate the influence of exercise on thyroid metabolism, 46 healthy young regularly menstruating sedentary women were randomly assigned to a 3 x 2 experimental design of aerobic exercise and energy availability treatments. Energy availability was defined as dietary energy intake minus energy expenditure during exercise. After 4 days of treatments, low energy availability (8 vs. 30 kcal.kg body wt-1.day-1) had reduced 3,5,3'-triiodothyronine (T3) by 15% and free T3 (fT3) by 18% and had increased thyroxine (T4) by 7% and reverse T3 (rT3) by 24% (all P < 0.01), whereas free T4 (fT4) was unchanged (P = 0.08). Exercise quantity (0 vs. 1,300 kcal/day) and intensity (40 vs. 70% of aerobic capacity) did not affect any thyroid hormone (all P > 0.10). That is, low-T3 syndrome was induced by the energy cost of exercise and was prevented in exercising women by increasing dietary energy intake. Selective observation of low-T3 syndrome in amenorrheic and not in regularly menstruating athletes suggests that exercise may compromise the availability of energy for reproductive function in humans. If so, athletic amenorrhea might be prevented or reversed through dietary reform without reducing exercise quantity or intensity.

Hypothalamic-pituitary-thyroidal function in eumenorrheic and amenorrheic athletes.

The impact of chronic high volume athletic training on thyroid hormone economy has not been defined. We investigated the status of the hypothalamic-pituitary-thyroid axis (H-P-T) in women athletes with regular menstrual cycles (CA) and with amenorrhea (AA). Their data were compared with each other and with those derived from cyclic sedentary women (CS) matched for a variety of confounding factors including the intensity of exercise, caloric intake, and body weight. Alterations of the H-P-T axis were observed in women athletes compared to CS. While serum levels of T4, T3, free T4, free T3 and rT3 were substantially reduced (P less than 0.01) in AA, only serum T4 levels were significantly decreased in CA. Further, remarkable differences were found between CA and AA in that serum levels of free T4 (P less than 0.01), free T3 (P less than 0.01), and rT3 (P less than 0.05) were significantly lower in AA than in CA. Thyroid binding globulin and sex-hormone binding globulin concentrations were within their normal ranges for all groups of subjects. Both 24-h mean TSH levels and the circadian rhythm of TSH secretion were also comparable. However, the TSH response to TRH stimulation was blunted (P less than 0.01) in AA when compared to CA, but not to CS. Whereas the underlying mechanism(s) to account for the "global" reduction of circulating thyroid hormone in the face of normal TSH levels in AA is presently unknown, these observations provide information of clinical significance: 1) chronic high volume athletic training in women athletes with menstrual cyclicity is accompanied by an isolated T4 reduction; 2) an impaired H-P-T axis occurs selectively in athletic women in whom chronic high volume athletic training is associated with compromised hypothalamic-pituitary-ovarian function and amenorrhea.

Marked augmentation of nocturnal melatonin secretion in amenorrheic athletes, but not in cycling athletes: unaltered by opioidergic or dopaminergic blockade.

Exercise of sufficient intensity during daylight hours has been demonstrated to result in an acute elevation of circulating melatonin levels. The possibility that repeated elevations of daytime melatonin secretion may result in alterations of the nocturnal maxima of the circadian rhythm in highly trained athletic women with and without amenorrhea was investigated. Twenty-four-hour melatonin profiles in matched cyclic sedentary (CS; n = 10) women, cyclic athletic (CA; n = 10) women, and amenorrheic athletic (AA; n = 8) women were compared. The roles of endogenous opioids and dopamine as potential modulators of melatonin secretion were also evaluated by comparing the melatonin profiles during sequential 24-h infusions of saline, followed by either naloxone or metoclopramide (both at 30 micrograms/kg.h). Elevated (P less than 0.05) mean daytime (1000-1700 h) melatonin levels were observed in both groups of athletic women compared to sedentary women. In contrast, nocturnal melatonin levels in sedentary and athletic cycling women were indistinguishable, while amenorrheic athletic women displayed a marked increase in nocturnal peak amplitude (P less than 0.001 vs. CS and CA) and a 2-h delay in offset (P less than 0.001 vs. CS and CA), which yielded a 2-fold amplification of the integrated nocturnal melatonin secretion (P less than 0.001 vs. CS and CA). The onset of the nocturnal rise did not differ among the three groups. Opioidergic and dopaminergic blockade with naloxone and metoclopramide at the doses used did not alter any parameter of melatonin secretion in any of the three groups of women. In conclusion, athleticism in women is associated with an elevation of daytime melatonin levels independent of menstrual status. AA women, but not CA women, display a 2-fold amplification of nocturnal melatonin secretion with a 2-h delay of offset, which does not seem to be linked to athleticism per se. The significance and neuroendocrine basis for the expanded melatonin secretion in athletic amenorrheic women remains to be elucidated.

Adrenal activation and the prolactin response to exercise in eumenorrheic and amenorrheic runners.

Adrenocorticotropic hormone (ACTH), cortisol, and prolactin responses following maximal and submaximal (40 min at 80% maximal O2 consumption) running were studied in eumenorrheic (ER; n = 8, 29.0 +/- 1.5 yr) and amenorrheic (AR; n = 8, 24.5 +/- 2.0 yr) runners. ER were studied in the early follicular and midluteal phases of the menstrual cycle. Physical, training, and gynecological characteristics were similar, and cardiorespiratory and metabolic responses to the exercises were indistinguishable in the groups. ACTH, cortisol, and prolactin data from the follicular luteal phases in ER were combined for comparison to AR, because no differences were noted between the menstrual phases at rest. Similar preexercise ACTH levels and responses following exercise occurred in both groups, but preexercise cortisol levels were elevated (ER = 293.1 +/- 46.3, AR = 479.6 +/- 42.4 nmol/l) and cortisol responses blunted in AR. Adrenal sensitivity was blunted in AR compared with ER after submaximal (ER = 121.9 +/- 17.4, AR = 51.7 +/- 13.6) and maximal exercise (ER = 27.9 +/- 9.2, AR = 12.1 +/- 3.8). Preexercise prolactin levels were reduced (ER = 16.4 +/- 2.7, AR = 10 +/- 2.3 micrograms/l), and prolactin responses to maximal exercises were blunted in AR, despite high lactate levels (11.4 +/- 0.4 mmol/l). We conclude that 1) control for menstrual phase in ER is important in studies of prolactin responses following exercise but not in studies of ACTH and cortisol responses following exercise, 2) cortisol responses following submaximal and maximal exercise in AR are blunted at the adrenal level, 3) prolactin responses following submaximal and maximal exercise are also blunted in AR, and 4) prolactin responses following exercise may be mediated by adrenal activation.