Influence of menstrual cycle and oral contraceptives on tolerance to uncompensable heat stress

In this study we examined the influence of menstrual cycle phase and oral contraceptive use on thermoregulation and tolerance during uncompensable heat stress. Eighteen women (18-35 years), who differed only with respect to oral contraceptive use (n = 9) or non-use (n = 9), performed light intermittent exercise at 40 degrees C and 30% relative humidity while wearing nuclear, biological and chemical protective clothing. Their responses were compared during the early follicular (EF, days 2-5) and mid-luteal (ML, days 19-22) phases of the menstrual cycle. Since oral contraceptives are presumed to inhibit ovulation, a quasi-early follicular (q-EF) and quasi-mid-luteal (q-ML) phase was assumed for the users. Estradiol and progesterone measurements verified that all subjects were tested during the desired phases of the menstrual cycle. Results demonstrated that rectal temperature (Tre) was elevated in ML compared with EF among the non-users at the beginning and throughout the heat-stress trial. For the users, Tre was higher in q-ML compared with q-EF at the beginning, and for 75 min of the heat-stress exposure. Tolerance times were significantly longer during EF [128.1 (13.4) min, mean (SD)] compared with ML [107.4 (8.6) min] for the nonusers, indicating that these women are at a thermoregulatory advantage during the EF phase of their menstrual cycle. For the users, tolerance times were similar in both the q-EF [113.0 (5.8) min] and q-ML [116.8 (11.2) min] phases and did not differ from those of the non-users. It was concluded that oral contraceptive use had little or no influence on tolerance to uncompensable heat stress, whereas tolerance was increased during EF for non-users of oral contraceptives.     

No effect of menstrual cycle phase on glucose kinetics and fuel oxidation during moderate-intensity exercise

Resting and exercise fuel metabolism was assessed in three different phases of the menstrual cycle, characterized by different levels of estrogen relative to progesterone: early follicular (EF, low estrogen and progesterone), midfollicular (MF, elevated estrogen, low progesterone), and midluteal (ML, elevated estrogen and progesterone). It was hypothesized that exercise glucose utilization and whole body carbohydrate oxidation would decrease sequentially from the EF to the MF to the ML phase. Normal-weight healthy females, experiencing a regular menstrual cycle, were recruited. Subjects were moderately active but not highly trained. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting (2 h) and exercise (50% maximal O(2) uptake, 90 min) measurements of whole body substrate oxidation, tracer-determined glucose flux, and substrate and hormone concentrations were made. No significant difference was observed in whole body fuel oxidation during exercise in the three phases (nonprotein respiratory exchange ratio: EF 0.84 +/- 0.01, MF 0.85 +/- 0.01, ML 0.85 +/- 0.01) or in rates of glucose appearance or disappearance. There were, however, significantly higher glucose (P < 0.05) and insulin (P < 0.001) concentrations during the first 45 min of exercise in the ML phase vs. EF and MF phases. In conclusion, whole body substrate oxidation and glucose utilization did not vary significantly across the menstrual cycle in moderately active women, either at rest or during 90 min of moderate-intensity exercise. During the ML phase, however, this similar pattern of substrate utilization was associated with greater glucose and insulin concentrations. Both estrogen and progesterone are elevated during the ML phase of the menstrual cycle, suggesting that one or both of these sex steroids may play a role in this response.     

Vestibulosympathetic reflex during the early follicular and midluteal phases of the menstrual cycle

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.     

No effect of menstrual cycle phase on glycerol or palmitate kinetics during 90 min of moderate exercise.

The systemic flux of glycerol and palmitate [a representative nonesterified free fatty acid (NEFA)] was assessed in three different phases of the menstrual cycle at rest and during moderate-intensity exercise. It was hypothesized that circulating glycerol and NEFA turnover would be greatest in the midfollicular (MF) phase of the menstrual cycle, when estrogen is elevated but progesterone low, followed by the midluteal phase (ML; high estrogen and progesterone), and lowest in the early follicular (EF) phase of the menstrual cycle (low estrogen and progesterone). Subjects included moderately active, eumenorrheic, healthy women. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting and exercise (50% maximal oxygen uptake, 90 min) measurements of tracer-determined glycerol and palmitate kinetics were made. There was a significant increase in both glycerol and palmitate turnover from rest to exercise in all phases of the menstrual cycle (P<0.0001). No significant differences, however, were observed between cycle phases in the systemic flux of glycerol or palmitate, at rest or during exercise. Maximal peripheral lipolysis during exercise, as represented by glycerol rate of appearance at 90 min, equaled 8.45+/-0.96, 8.35+/-1.12, and 7.71+/-0.96 micromol.kg-1.min-1 in the EF, MF, and ML phases, respectively. Circulating free fatty acid utilization also peaked at 90 min of exercise, as indicated by the palmitate rate of disappearance (3.31+/-0.35, 3.17+/-0.39, and 3.47+/-0.26 micromol.kg-1.min-1) in the EF, MF, and ML phases, respectively. In conclusion, systemic rates of glycerol and NEFA turnover (as represented by palmitate flux) were not significantly affected by the cyclic fluctuations in estrogen and progesterone that occur throughout the normal menstrual cycle, either at rest or during 90 min of moderate exercise.     

Hemodynamics of orthostatic intolerance: implications for gender differences

Women have a greater incidence of orthostatic intolerance than men. We hypothesized that this difference is related to hemodynamic effects on regulation of cardiac filling rather than to reduced responsiveness of vascular resistance during orthostatic stress. We constructed Frank-Starling curves from pulmonary capillary wedge pressure (PCWP), stroke volume (SV), and stroke index (SI) during lower body negative pressure (LBNP) and saline infusion in 10 healthy young women and 13 men. Orthostatic tolerance was determined by progressive LBNP to presyncope. LBNP tolerance was significantly lower in women than in men (626.8 +/- 55.0 vs. 927.7 +/- 53.0 mmHg x min, P < 0.01). Women had steeper maximal slopes of Starling curves than men whether expressed as SV (12.5 +/- 2.0 vs. 7.1 +/- 1.5 ml/mmHg, P < 0.05) or normalized as SI (6.31 +/- 0.8 vs. 4.29 +/- 0.6 ml.m-2.mmHg-1, P < 0.05). During progressive LBNP, PCWP dropped quickly at low levels, and reached a plateau at high levels of LBNP near presyncope in all subjects. SV was 35% and SI was 29% lower in women at presyncope (both P < 0.05). Coincident with the smaller SV, women had higher heart rates but similar mean arterial pressures compared with men at presyncope. Vascular resistance and plasma norepinephrine concentration were similar between genders. We conclude that lower orthostatic tolerance in women is associated with decreased cardiac filling rather than reduced responsiveness of vascular resistance during orthostatic challenges. Thus cardiac mechanics and Frank-Starling relationship may be important mechanisms underlying the gender difference in orthostatic tolerance.     

Effects of time of day, gender, and menstrual cycle phase on the human response to a water load

Estrogen and progesterone interference with renal actions of arginine vasopressin (AVP) has been shown. Thus we hypothesized that women will have a higher water turnover than men and that the greatest difference will be during the luteal phase of the menstrual cycle. Seven men (32 +/- 3 yr) and six women (33 +/- 2 yr) drank 12 ml water/kg lean body mass on different days at 0800 and at 2000 following 10 h of fast and a standardized meal at 0600 and 1800. Women participated on days 4-11 and 19-25 of the menstrual cycle. Initial urine and plasma osmolalities and urine flow rates were similar in all experiments. The cumulative urine voided over 3 h following the morning drink was less in men (73 +/- 12% of the water load) compared with women in either the follicular (100 +/- 3%) or luteal phases (102 +/- 10%) of the menstrual cycle. Nighttime values (30-43% of the water load) were lower in all experiments and were not different between sexes or menstrual cycle phases. Plasma AVP was higher at night and may contribute to this diurnal response. The data are generally consistent with the stated hypothesis; however, possibly owing to the greatly reduced urine flow in both sexes at night, a difference between sexes was not observed at that time.     

Influence of menstrual cycle on baroreflex control of heart rate: comparison with male volunteers

This study was designed to determine baroreflex control of heart rate (HR) to hypotensive and hypertensive stimuli during the early follicular (EF), preovulation (PreOV), and midluteal (ML) phases of the menstrual cycle and to test the hypothesis that cardiovagal reflex responses to hypertensive stimuli would be altered depending on the plasma estradiol levels in healthy women. In addition, these results were compared with those of male volunteers. Fifteen healthy women with regular menstrual cycles and thirteen male volunteers were recruited. Cardiovagal baroreflex sensitivity was defined as the slope of the linear portion relating R-R interval and systolic blood pressure triggered by bolus injections of nitroprusside and phenylephrine, from the overshoot phase of the Valsalva maneuver, and during spontaneous fluctuations. Three measurements were averaged in each test as a representative at each phase, and the order of phases was counterbalanced. Baroreflex sensitivities by the phenylephrine pressor test and Valsalva maneuver during the PreOV phase were significantly greater than those during the EF and ML phases but were similar to those of men. Depressor test sensitivities by nitroprusside and down-sequence spontaneous cardiac baroreflex sensitivity during the EF phase were significantly greater than those of the ML phase and of men. Significant correlations were observed between plasma estradiol concentrations and baroreflex sensitivities assessed by phenylephrine and the Valsalva maneuver. Our results indicate that baroreflex control of HR is altered during the regular menstrual cycle, and estradiol appears to exert cardiovagal modulation in healthy women.     

Effects of menstrual cycle and oral contraceptive use on calf venous compliance

Numerous studies have shown that the female sex hormones estrogen and progesterone have multiple effects on the vasculature. Thus our goal was to investigate the effects of estrogen and progesterone on calf venous compliance by looking for cyclic changes during the early follicular, ovulatory, and midluteal phases of the menstrual cycle and during high and low hormone phases of oral contraceptive use. Additionally, we wanted to compare the venous compliance of normally menstruating women, oral contraceptive users, and men. We studied eight normally menstruating women (23 +/- 1 yr of age) during the early follicular, ovulatory, and midluteal phases of the menstrual cycle. Nine triphasic oral contraceptive users (21 +/- 1 yr of age) were studied during weeks of high and low hormone concentrations. Eight men (23 +/- 1 yr of age) were studied twice within 2-4 wk. With the use of venous occlusion plethysmography with mercury in-Silastic strain gauges, lower limb venous compliance was measured by inflating a venous collection cuff that was placed on the thigh to 60 mmHg for 8 min and then reducing the pressure to 0 mmHg at a rate of 1 mmHg/s. Venous compliance was calculated as the derivative of the pressure-volume curves. There were no differences between early follicular, ovulatory, and midluteal phases of the menstrual cycle or between high and low hormone phases of oral contraceptive use (P > 0.05). Male venous compliance was significantly greater than in normally menstruating women (P < 0.001) and oral contraceptive users (P < 0.002). These data support a sex difference but also suggest that venous compliance does not change with menstrual cycle phase or during the course of oral contraceptive use.     

Sex differences in the modulation of vasomotor sympathetic outflow during static handgrip exercise in healthy young humans

Sex differences in sympathetic neural control during static exercise in humans are few and the findings are inconsistent. We hypothesized women would have an attenuated vasomotor sympathetic response to static exercise, which would be further reduced during the high sex hormone [midluteal (ML)] vs. the low hormone phase [early follicular (EF)]. We measured heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) in 11 women and 10 men during a cold pressor test (CPT) and static handgrip to fatigue with 2 min of postexercise circulatory arrest (PECA). HR increased during handgrip, reached its peak at fatigue, and was comparable between sexes. BP increased during handgrip and PECA where men had larger increases from baseline. Mean ± SD MSNA burst frequency (BF) during handgrip and PECA was lower in women (EF, P < 0.05), as was ΔMSNA-BF smaller (main effect, both P < 0.01). ΔTotal activity was higher in men at fatigue (EF: 632 ± 418 vs. ML: 598 ± 342 vs. men: 1,025 ± 416 a.u./min, P < 0.001 for EF and ML vs. men) and during PECA (EF: 354 ± 321 vs. ML: 341 ± 199 vs. men: 599 ± 327 a.u./min, P < 0.05 for EF and ML vs. men). During CPT, HR and MSNA responses were similar between sexes and hormone phases, confirming that central integration and the sympathetic efferent pathway was comparable between the sexes and across hormone phases. Women demonstrated a blunted metaboreflex, unaffected by sex hormones, which may be due to differences in muscle mass or fiber type and, therefore, metabolic stimulation of group IV afferents.     

Effects of gender and hypovolemia on sympathetic neural responses to orthostatic stress

We tested the hypothesis that women have blunted sympathetic neural responses to orthostatic stress compared with men, which may be elicited under hypovolemic conditions. Muscle sympathetic nerve activity (MSNA) and hemodynamics were measured in eight healthy young women and seven men in supine position and during 6 min of 60 degrees head-up tilt (HUT) under normovolemic and hypovolemic conditions (randomly), with approximately 4-wk interval. Acute hypovolemia was produced by diuretic (furosemide) administration approximately 2 h before testing. Orthostatic tolerance was determined by progressive lower body negative pressure to presyncope. We found that furosemide produced an approximately 13% reduction in plasma volume, causing a similar increase in supine MSNA in men and women (mean +/- SD of 5 +/- 7 vs. 6 +/- 5 bursts/min; P = 0.895). MSNA increased during HUT and was greater in the hypovolemic than in the normovolemic condition (32 +/- 6 bursts/min in normovolemia vs. 44 +/- 15 bursts/min in hypovolemia in men, P = 0.055; 35 +/- 9 vs. 45 +/- 8 bursts/min in women, P < 0.001); these responses were not different between the genders (gender effect: P = 0.832 and 0.814 in normovolemia and hypovolemia, respectively). Total peripheral resistance increased proportionately with increases in MSNA during HUT; these responses were similar between the genders. However, systolic blood pressure was lower, whereas diastolic blood pressure was similar in women compared with men during HUT, which was associated with a smaller stroke volume or stroke index. Orthostatic tolerance was lower in women, especially under hypovolemic conditions. These results indicate that men and women have comparable sympathetic neural responses during orthostatic stress under normovolemic and hypovolemic conditions. The lower orthostatic tolerance in women is predominantly because of a smaller stroke volume, presumably due to less cardiac filling during orthostasis, especially under hypovolemic conditions, which may overwhelm the vasomotor reserve available for vasoconstriction or precipitate neurally mediated sympathetic withdrawal and syncope.     

Changes in plasma volume during bed rest: effects of menstrual cycle and estrogen administration

Bed rest (BR) is associated with a decrease in plasma volume (PV), which may contribute to the impaired orthostatic and exercise tolerances seen immediately after BR. The purpose of this study was to determine whether increases in blood estrogen concentration, either during normal menstrual cycles or during exogenous estrogen administration, would attenuate this loss of PV. Nineteen healthy women (21-39 yr of age) completed the study. Twelve women underwent duplicate 11-day BR without estrogen supplementation. PV decreased significantly (P less than or equal to 0.01) during both BR's, from 2,531 +/- 113 to 2,027 +/- 102 ml during BR1 and from 2,445 +/- 115 to 2,244 +/- 96 ml during BR2. The women who began BR in the periovulatory stage of the menstrual cycle (n = 3), a time of elevated endogenous estrogens, had a transient delay in loss of PV during the first 5 days of BR. Women who began BR during other stages of the menstrual cycle (n = 17) showed the established trend to decrease PV primarily during the first few days of BR. Seven additional women underwent a single 12-day BR while taking estrogen supplementation (1.25 mg/day premarin). PV decreased during the first 4-5 days of BR, then returned toward the pre-BR level during the remainder of the BR (pre-BR PV, 2,525 +/- 149 ml; post-BR PV, 2,519 +/- 162 ml). Thus menstrual fluctuations in endogenous estrogens appear to have only small transient effects on the loss of PV during BR, whereas exogenous estrogen supplementation significantly attenuates PV loss.     

The resting frontal alpha asymmetry across the menstrual cycle: a magnetoencephalographic study

Gonadotropic hormones play an important role in the regulation of emotion. Previous studies have demonstrated that estrogen can modulate appetitive (approach/positive) and aversive (avoidance/negative) affective behaviors during the menstrual cycle. Frontal alpha asymmetry (a measure of relative difference of the alpha power between the two anterior hemispheres) has been associated with the trait and state reactivity of different affective styles. We studied the pattern change of frontal alpha asymmetry across the menstrual cycle. 16 healthy women participated in this resting magneto-encephalographic (MEG) study during the peri-ovulatory (OV) and menstrual (MC) phases. Our results showed significant interaction of resting MEG alpha activity between hemispheric side and menstrual phases. Difference in spontaneous frontal alpha asymmetry pattern across the menstrual cycle was also noted. Relatively higher right frontal activity was found during the OV phase; relatively higher left frontal activity was noted during the MC phase. The alteration of frontal alpha asymmetry might serve a sub-clinical correlate for hormonal modulation effect on dynamic brain organization for the predisposition and conceptualization of different affective styles across the menstrual cycle.     

Gender affects calf venous compliance at rest and during baroreceptor unloading in humans

Leg venous compliance is a determinant of peripheral venous pooling during orthostatic stress such that high venous compliance could contribute to reduced orthostatic tolerance. We tested the hypotheses that 1) calf venous compliance is reduced during baroreceptor unloading, and 2) calf venous compliance is greater in women than men. Twelve men (27 +/- 2 yr) and 12 women (25 +/- 2 yr) were studied in the supine posture. Calf venous compliance was determined by inflating a thigh venous collecting cuff to 60 mmHg for 8 min and then decreasing cuff pressure at a rate of 1 mmHg/s to 0 mmHg. The slope of the pressure-compliance relation (compliance = beta(1) + 2.beta(2).cuff pressure), which is the first derivative of the quadratic pressure-volume relation [(Deltalimb volume) = beta(0) + beta(1).(cuff pressure) + beta(2).(cuff pressure)(2)] during the reduction in collecting cuff pressure, was used to assess venous compliance at baseline and during one-legged lower body negative pressure (LBNP; -50 mmHg). At baseline, calf venous compliance was 48% lower (P < 0.001) in women than men and decreased in men (Delta-25 +/- 8%; P < 0.05) but not women (Delta1 +/- 11%) during LBNP. Rhythmic ischemic handgrip (Delta6 +/- 9%) and cold pressor testing (Delta-9 +/- 7%) did not alter calf venous compliance in a subgroup of men (n = 6). These data indicate gender-dependent effects on calf venous compliance under conditions associated with low sympathetic outflow (i.e., rest) and high sympathetic outflow (i.e., LBNP). However, they cannot explain gender-associated differences in orthostatic tolerance.     

Reproducibility of an oral fat tolerance test is influenced by phase of menstrual cycle.

Knowledge of the reproducibility of oral fat tolerance tests is important for experimental design and data interpretation. In this study, seven normolipidaemic men underwent two fat tolerance tests (blood taken fasting and for six hours after a meal containing 1.2 g fat, 1.2 g carbohydrate per kg body mass) with an interval of one week. Eleven normolipidaemic women underwent two fat tolerance tests--one during the follicular phase of the menstrual cycle, the other during the mid-luteal phase. Dietary intake was controlled for two days and subjects refrained from exercise for three days before each test. There was no significant difference in postprandial triglyceride responses between the two tests in the men (10.20 +/- 3.45 mmol/l.h vs. 9.68 +/- 2.77 mmol/l.h, NS) (mean +/- SD); intraclass correlation coefficient between the two tests was 0.93, and within-subject coefficient of variation was 10.1 %. In the women, the postprandial triglyceride response was lower in the luteal phase (6.75 +/- 1.83 mmol/l.h) than in the follicular phase (8.36 +/- 3.71 mmol/l.h) (p = 0.05), intraclass correlation was 0.65 and within-subject coefficient of variation was 23.2 %. These results suggest that, with adequate control of preceding lifestyle, reproducibility of postprandial triglyceride responses is high in men, but menstrual phase should be taken into consideration when studying these responses in women.     

Female menstrual phases modulate human prefrontal asymmetry: A magnetoencephalographic study

We previously reported that the trait/baseline prefrontal cortex (PFC) activity expresses a dynamic plasticity during female menstrual cycle. The shift of asymmetric lateralization of PFC baseline activity pinpoints a possible emotional regulation of negative affection. The current emotional Go/NoGo study aimed to investigate the state PFC responses of different menstrual phases during fear facial stimulation in fourteen healthy women. Our data disclosed that the menstrual cycle was coupled with a shift of asymmetric lateralization of frontal activation across different menstrual phases. Evoked magnetic field activity in the time window 200-300 ms (M1) and 300-450 ms (M2) after stimulus onset demonstrated significant interactions between hemispheric side and menstrual phase. The right hemispheric dominance in periovulatory phase (OV) changed to left hemispheric dominance in menstrual (MC) phase. Significant association between the anxiety score and the left PFC activation was particularly observed in MC phase. Our study revealed a plastic resilience of functional organization of human brain and a dynamic automaticity of inter-hemispheric synergism for possible adaptive regulation under the aversive confrontation in accordance with hormonal fluctuation during the menstrual cycle.     

Gender differences in cardiovascular tolerance to short radius centrifugation

In preparing for the NASA Artificial Gravity Pilot Study the planned centrifuge loading protocol was tested in 11 ambulatory subjects (6 men, 5 women). Each was subjected to a single 60 min trial with 2.5G of equivalent gravitational load feet and 1G at the level of the mediastinum. Amongst the men, 5/6 completed the trial successfully with no adverse sequelae. However, amongst the women, 4/5 tests were stopped early because of presyncope. Women are known to have a greater predisposition to syncope following orthostatic stress under normal tilt table conditions, during lower body negative pressure and following space flight. Amongst the factors which may have contributed to their lower tolerance to centrifugation are anthropometric factors, the vasoactive effects of sex hormones, catecholamine levels, ability to augment total peripheral resistance in response to orthostatic stress, and structural differences in cardiac anatomy and physiology. However, determining the true cause of this difference will require further investigation.     

Resting and exercise ventilatory chemosensitivity across the menstrual cycle

We hypothesized that resting and exercise ventilatory chemosensitivity would be augmented in women when estrogen and progesterone levels are highest during the luteal phase of the menstrual cycle. Healthy, young females (n = 10; age = 23 ± 5 yrs) were assessed across one complete cycle: during early follicular (EF), late follicular (LF), early luteal, and mid-luteal (ML) phases. We measured urinary conjugates of estrogen and progesterone daily. To compare values of ventilatory chemosensitivity and day-to-day variability of measures between sexes, males (n = 10; age = 26 ± 7 yrs) were assessed on 5 nonconsecutive days during a 1-mo period. Resting ventilation was measured and hypoxic chemosensitivity assessed using an isocapnic hypoxic ventilatory response (iHVR) test. The hypercapnic ventilatory response was assessed using the Read rebreathing protocol and modified rebreathing tests. Participants completed submaximal cycle exercise in normoxia and hypoxia. We observed a significant effect of menstrual-cycle phase on resting minute ventilation, which was elevated in the ML phase relative to the EF and LF phases. Compared with males, resting end-tidal CO(2) was reduced in females during the EF and ML phases but not in the LF phase. We found that iHVR was unaffected by menstrual-cycle phase and was not different between males and females. The sensitivity to chemical stimuli was unaffected by menstrual-cycle phase, meaning that any hormone-mediated effect is of insufficient magnitude to exceed the inherent variation in these chemosensitivity measures. The ventilatory recruitment threshold for CO(2) was generally lower in women, which is suggestive of a hormonally related lowering of the ventilatory recruitment threshold. We detected no effect of menstrual-cycle phase on submaximal exercise ventilation and found that the ventilatory response to normoxic and hypoxic exercise was quantitatively similar between males and females. This suggests that feed-forward and feed-back influences during exercise over-ride the effects of naturally occurring changes in sex hormones.     

Effect of sex and ovarian hormones on carotid baroreflex resetting and function during dynamic exercise in humans

To date, no studies have examined whether there are either sex- or ovarian hormone-related alterations in arterial baroreflex resetting and function during dynamic exercise. Thus we studied 16 young men and 18 young women at rest and during leg cycling at 50% heart rate (HR) reserve. In addition, 10 women were studied at three different phases of the menstrual cycle. Five-second pulses of neck pressure (NP) and neck suction (NS) from +40 to -80 Torr were applied to determine full carotid baroreflex (CBR) stimulus response curves. An upward and rightward resetting of the CBR function curve was observed during exercise in all groups with a similar magnitude of CBR resetting for mean arterial pressure (MAP) and HR between sexes (P > 0.05) and at different phases of the menstrual cycle (P > 0.05). For CBR control of MAP, women exhibited augmented pressor responses to NP at rest and exercise during mid-luteal compared with early and late follicular phases. For CBR control of HR, there was a greater bradycardic response to NS in women across all menstrual cycle phases with the operating point (OP) located further away from centering point (CP) on the CBR-HR curve during rest (OP-CP; in mmHg: -13 ± 3 women vs. -3 ± 3 men; P < 0.05) and exercise (in mmHg: -31 ± 2 women vs. -15 ± 3 men; P < 0.05). Collectively, these findings suggest that sex and fluctuations in ovarian hormones do not influence exercise resetting of the baroreflex. However, women exhibited greater CBR control of HR during exercise, specifically against acute hypertension, an effect that was present throughout the menstrual cycle.     

Decreased thermal conductance during the luteal phase of the menstrual cycle in women

To study the influence of the menstrual cycle on whole body thermal balance and on thermoregulatory mechanisms, metabolic heat production (M) was measured by indirect calorimetry and total heat losses (H) were measured by direct calorimetry in nine women during the follicular (F) and the luteal (L) phases of the menstrual cycle. The subjects were studied while exposed for 90 min to neutral environmental conditions (ambient temperature 28 degrees C, relative humidity 40%) in a direct calorimeter. The values of M and H were not modified by the phase of the menstrual cycle. Furthermore, in both phases the subjects were in thermal equilibrium because M was similar to H (69.7 +/- 1.8 and 72.1 +/- 1.8 W in F and 70.4 +/- 1.9 and 71.4 +/- 1.7 W in L phases, respectively). Tympanic temperature (Tty) was 0.24 +/- 0.07 degrees C higher in the L than in the F phase (P less than 0.05), whereas mean skin temperature (Tsk) was unchanged. Calculated skin thermal conductance (Ksk) was lower in the L (17.9 +/- 0.6 W.m-2.degrees C-1) than in the F phase (20.1 +/- 1.1 W.m-2.degrees C-1; P less than 0.05). Calculated skin blood flow (Fsk) was also lower in the L (0.101 +/- 0.008 l.min-1.m-2) than in the F phase (0.131 +/- 0.015 l.min-1.m-2; P less than 0.05). Differences in Tty, Ksk, and Fsk were not correlated with changes in plasma progesterone concentration. It is concluded that, during the L phase, a decreased thermal conductance in women exposed to a neutral environment allows the maintenance of a higher internal temperature.     

Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function

Norepinephrine transporter (NET) function has a central role in the regulation of synaptic norepinephrine concentrations. Clinical observations in orthostatic intolerance patients suggest a gender difference in NET function. We compared the cardiovascular response to selective NET inhibition with reboxetine between 12 healthy men and 12 age-matched women. Finger blood pressure, brachial blood pressure, and heart rate were measured. The subjects underwent cardiovascular autonomic reflex testing and a graded head-up tilt test. In a separate study, we applied incremental concentrations of tyramine and isoproterenol through subcutaneous microdialysis catheters in eight men and in eight women. NET inhibition elicited a threefold greater increase in supine blood pressure in men than women (P < 0.05). The pressor response was driven by an increased cardiac output. The orthostatic heart rate increase during NET inhibition was greater in men than women (56 +/- 5 beats/min in men, 42 +/- 4 beats/min in women, P < 0.001). In contrast, NET inhibition resulted in a similar suppression in the cold pressor and handgrip response, low-frequency blood pressure oscillations, and venous norepinephrine in the supine position. Men and women were similarly sensitive to the lipolytic effect of isoproterenol and tyramine. We conclude that NET inhibition results in more pronounced changes in cardiac regulation in men than women. Our observations suggest that the NET contribution to cardiac norepinephrine turnover may be decreased in women. The gender difference in NET function may not be expressed in tissues that are less NET dependent than the heart.