Carter JR, Lawrence JE, Klein JC. Menstrual cycle alters sympathetic neural responses to orthostatic stress in young, eumenorrheic women. Am J Physiol Endocrinol Metab 297: E85-E91, 2009. First published April 28, 2009 doi:10.1152/ajpendo.00019.2009.-Sympathetic baroreflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA) responses during early follicular (EF) and midluteal (ML) phases of the menstrual cycle are controversial. We hypothesize an augmented sympathetic BRS and MSNA response to orthostatic stress during the ML phase of the menstrual cycle. MSNA, mean arterial pressure (MAP), and heart rate (HR) were recorded during progressive lower body negative pressure (LBNP) (Ϫ5, Ϫ10, Ϫ15, Ϫ20, Ϫ30, and Ϫ40 mmHg; 3 min/stage) in 13 healthy, eumenorrheic women (age 21 Ϯ 1 yr). Sympathetic BRS was assessed by examining relations between spontaneous fluctuations of diastolic arterial pressure and MSNA at rest and during progressive LBNP. Plasma estradiol (42 Ϯ 6 vs. 112 Ϯ 12 pg/ml; P Ͻ 0.01) and progesterone (2 Ϯ 0 vs. 10 Ϯ 2 ng/ml; P Ͻ 0.04) were elevated during the ML phase. Resting MSNA (8 Ϯ 1 vs. 11 Ϯ 1 bursts/min), MAP (79 Ϯ 2 vs. 78 Ϯ 2 mmHg), and HR (58 Ϯ 2 vs. 60 Ϯ 2 beats/min) were not different during EF and ML phases. MSNA and HR increased during progressive LBNP (P Ͻ 0.001), and the increases in MSNA burst frequency (bursts/min) and HR were similar during both phases. In contrast, increases in total MSNA (arbitrary units) during progressive LBNP were augmented during the ML phase (P Ͻ 0.04), but this response does not appear to be linked to differences in sympathetic BRS. Progressive LBNP did not change MAP during either phase. Our results demonstrate an augmentation of the MSNA response to progressive LBNP during the ML phase of the menstrual cycle. These findings suggest that hormonal fluctuations of eumenorrheic women may influence sympathoexcitation during an orthostatic challenge, but not through sympathetic baroreflex-mediated pathways. muscle sympathetic nerve activity; arterial blood pressure; lower body negative pressure; baroreflex; estrogen EVIDENCE SUGGESTS THAT ORTHOSTATIC intolerance is more prevalent in women compared with men (3,5,7,19,(21)(22)(23). The mechanisms responsible for this apparent sex difference are presently unclear, but altered patterns of sympathoexcitation have been suggested. Shoemaker et al. (22) reported a blunted muscle sympathetic nerve activity (MSNA) response to orthostatic stress in women compared with men, suggesting MSNA responses to an orthostatic challenge may contribute to the higher incidence of orthostatic intolerance in women. In contrast, Fu et al. (9) recently reported that sex did not affect MSNA responses to an orthostatic challenge. The influence of sex on MSNA responses to orthostatic stress remains debatable.Shoemaker et al. (22) and Fu et al. (8) did not control for menstrual phase in their female subjects; thus, it is possible that differences between these two studies were due to hormonal fluctuations associated with the menstrua...

The influence of the menstrual cycle on resting muscle sympathetic nerve activity (MSNA) remains controversial, and the effect of the menstrual cycle on MSNA responses to mental stress is unknown. We examined MSNA, mean arterial pressure (MAP), and heart rate (HR) responses to mental stress (via mental arithmetic) in 11 healthy females during the early follicular (EF) and mid-luteal (ML) phases of the menstrual cycle. The menstrual cycle did not alter resting MSNA (EF, 13 ± 3 bursts min −1 versus ML, 13 ± 2 bursts min −1 ), MAP (EF, 79 ± 3 mmHg versus ML, 81 ± 2 mmHg) and HR (EF, 66 ± 3 beats min −1 versus ML, 64 ± 2 beats min −1 ). 5 min of mental stress increased MSNA, MAP and HR during both the EF (Δ4 ± 2 bursts min −1 , Δ12 ± 2 mmHg, Δ18 ± 2 beats min −1 ; P < 0.05) and ML (Δ4 ± 2 bursts min −1 , Δ13 ± 3 mmHg and Δ20 ± 2 beats min −1 ; P < 0.05) phases. These responses were not different between phases. In contrast, MSNA responses were different between phases during the 10 min recovery from mental stress. MSNA remained elevated during the initial 5 min of recovery in both the EF (Δ6 ± 1 bursts min −1 ; P < 0.01) and ML (Δ7 ± 1 bursts min −1 ; P < 0.01) phases, but only remained elevated during the ML phase (Δ6 ± 1 bursts min −1 ; P < 0.01) during the final 5 min of recovery. Our results demonstrate that MSNA, MAP and HR responses at rest or during mental stress are not different during the EF and ML phases of the menstrual cycle in young, healthy females. However, MSNA activation during recovery from mental stress is prolonged during the ML phase compared to the EF phase.

Evidence suggests that both the arterial baroreflex and vestibulosympathetic reflex contribute to blood pressure regulation, and both autonomic reflexes integrate centrally in the medulla cardiovascular center. A previous report indicated increased sympathetic baroreflex sensitivity during the midluteal (ML) phase of the menstrual cycle compared with the early follicular (EF) phase. On the basis of this finding, we hypothesize an augmented vestibulosympathetic reflex during the ML phase of the menstrual cycle. Muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), and heart rate responses to head-down rotation (HDR) were measured in 10 healthy females during the EF and ML phases of the menstrual cycle. Plasma estradiol (Delta72 +/- 13 pg/ml, P < 0.01) and progesterone (Delta8 +/- 2 ng/ml, P < 0.01) were significantly greater during the ML phase compared with the EF phase. The menstrual cycle did not alter resting MSNA, MAP, and heart rate (EF: 13 +/- 3 bursts/min, 80 +/- 2 mmHg, 65 +/- 2 beats/min vs. ML: 14 +/- 3 bursts/min, 81 +/- 3 mmHg, 64 +/- 3 beats/min). During the EF phase, HDR increased MSNA (Delta3 +/- 1 bursts/min, P < 0.02) but did not change MAP or heart rate (Delta0 +/- 1 mmHg and Delta1 +/- 1 beats/min). During the ML phase, HDR increased both MSNA and MAP (Delta4 +/- 1 bursts/min and Delta3 +/- 1 mmHg, P < 0.04) with no change in heart rate (Delta0 +/- 1 beats/min). MSNA and heart rate responses to HDR were not different between the EF and ML phases, but MAP responses to HDR were augmented during the ML phase (P < 0.03). Our results demonstrate that the menstrual cycle does not influence the vestibulosympathetic reflex but appears to alter MAP responses to HDR during the ML phase.

Extent of resection of glioblastoma (GBM) correlates with overall survival. Fluorescence-guided resection (FGR) using 5-aminolevulinic acid (5-ALA) can improve the extent of resection. Unfortunately not all patients given 5-ALA accumulate sufficient quantities of protoporphyrin IX (PpIX) for successful FGR. In this study, we investigated the effects of dexamethasone, desipramine, phenytoin, valproic acid, and levetiracetam on the production and accumulation of PpIX in U87MG cells. All of these drugs, except levetiracetam, reduce the total amount of PpIX produced by GBM cells (p < 0.05). When dexamethasone is mixed with another drug (desipramine, phenytoin, valproic acid or levetiracetam) the amount of PpIX produced is further decreased (p < 0.01). However, when cells are analyzed for PpIX cellular retention, dexamethasone accumulated significantly more PpIX than the vehicle control (p < 0.05). Cellular retention of PpIX was not different from controls in cells treated with dexamethasone plus desipramine, valproic acid or levetiracetam, but was significantly less for dexamethasone plus phenytoin (p < 0.01). These data suggest that medications given before and during surgery may interfere with PpIX accumulation in malignant cells. At this time, levetiracetam appears to be the best medication in its class (anticonvulsants) for patients undergoing 5-ALA-mediated FGR.

The hormone leptin has a variety of functions. Originally known for its role in satiety and weight loss, leptin more recently has been shown to augment tumor growth in a variety of cancers. Within gliomas, there is a correlation between tumor grade and tumor expression of leptin and its receptor. This suggests that autocrine signaling within the tumor microenvironment may promote the growth of high-grade gliomas. Leptin does this through stimulation of cellular pathways that are also advantageous for tumor growth and recurrence: antiapoptosis, proliferation, angiogenesis, and migration. Conversely, a loss of leptin expression attenuates tumor growth. In animal models of colon cancer and melanoma, a decline in the expression and secretion of leptin resulted in a reduction of tumor growth. In these models, positive mental stimulation through environmental enrichment decreased leptin secretion and improved tumor outcome. This review explores the link between leptin and glioblastoma.