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. Author manuscript; available in PMC: 2020 May 1.
Published in final edited form as: Med Sci Sports Exerc. 2019 May;51(5):874–881. doi: 10.1249/MSS.0000000000001877

Influence of Sex, Menstrual Cycle, and Menopause Status on the Exercise Pressor Reflex

Joshua R Smith 1, Katlyn E Koepp 1, Jessica D Berg 1, Joshua G Akinsanya 1, Thomas P Olson 1
PMCID: PMC6467496  NIHMSID: NIHMS1516915  PMID: 30986812

Abstract

In this review, we highlight the underlying mechanisms responsible for the sex differences in the exercise pressor reflex, and, importantly, the impact of sex hormones and menopausal status. The exercise pressor reflex is attenuated in pre-menopausal women compared to age-matched men. Specifically, activation of the metaboreflex (a component of the exercise pressor reflex) results in attenuated increases in blood pressure and sympathetic vasomotor outflow compared to age-matched men. In addition, pre-menopausal women exhibit less transduction of sympathetic outflow to the peripheral vasculature than men. In stark contrast, post-menopausal women exhibit an augmented exercise pressor reflex arising from exaggerated metaboreflex-induced autonomic and cardiovascular reflexes. We propose that metaboreflex-induced autonomic and cardiovascular changes associated with menopause majorly contribute to the elevated blood pressure response during dynamic exercise in post-menopausal women. In addition, we discuss the potential mechanisms by which sex hormones in pre-menopausal women may impact the exercise pressor reflex as well as metaboreflex.

Keywords: metaboreflex, pre-menopause, sex differences, sympathetic nerve activity, blood pressure

Introduction:

Autonomic and cardiovascular adjustments occur in an integrative fashion such that oxygen delivery meets the metabolic demands of the active skeletal muscle tissue during exercise. These neurovascular adjustments are mediated by central command, a feedforward mechanism, and the exercise pressor reflex, a feedback mechanism, both of which are also modulated by the arterial baroreceptors. The exercise pressor reflex is comprised of feedback from stimulation of afferent nerve fiber endings within the skeletal muscle sensitive to mechanical and metabolic stimuli. The group III muscle afferents are primarily located in the adventia of the vasculature and predominately sensitive to mechanical distortion and stimulation thereof elicits the mechanoreflex (1). Group IV muscle afferents are predominately stimulated by metabolic products (e.g., lactic acid, potassium, prostaglandins, ATP) activating the metaboreflex (1). It is important to note that some skeletal muscle afferents are polymodal and thus are stimulated by both mechanical distortion and metabolite stimulation (2). Skeletal muscle afferent feedback is relayed to the cardiovascular control centers located in the brain stem via the dorsal horn of the spinal cord (3). The exercise pressor reflex and its components have been recently reviewed (4–8); however, those reviews primarily focused on studies investigating men and aging.

Sex differences clearly exist in neurovascular control at rest and during exercise in pre-menopausal women (9–13). Furthermore, the incidence of cardiovascular disease is lower in pre-menopausal women than age-matched men (14). With menopause, however, neurovascular control is augmented at rest and during exercise and the risk of cardiovascular disease increases dramatically (14). Understanding the underlying mechanisms responsible for the exercising blood pressure response is imperative as it is predictive of future cardiovascular disease development (15, 16).

Sex Differences in the Exercise Pressor Reflex:

Pre-menopausal women exhibit an attenuated increase in blood pressure during large and small muscle mass exercise, compared to men (12, 17–22). For example, Ogawa and colleagues found that pre-menopausal women had a lower blood pressure response than men during submaximal and maximal cycling exercise regardless of training status (19). Furthermore, this blood pressure response in women is congruent with the lower sympathetic vasomotor output during exercise compared to men (i.e. attenuated increase in muscle sympathetic nerve activity and catecholamines (21, 23, 24)). One of the primary factors responsible for this blunted increase in blood pressure during exercise is sex differences in the exercise pressor reflex. To date, previous studies have primarily investigated sex differences in the metaboreflex component of the exercise pressor reflex (9, 12, 25). Specifically, these studies have incorporated handgrip exercise followed immediately by circulatory occlusion to determine the contribution of the trapped metabolites to the autonomic and cardiovascular responses, while minimizing the contributions of the mechanoreflex and central command. These studies have found that pre-menopausal women exhibit an attenuated increase in blood pressure and muscle sympathetic nerve activity with isolated metaboreflex activation compared to men consistent with a blunted metaboreflex and exercise pressor reflex (9, 12). Furthermore, there is evidence that the mechanoreflex may also be attenuated in pre-menopausal women (26). Importantly, sex differences are not likely present in the central integration of vasomotor processes and their efferent pathways as the cold pressor-induced increase in muscle sympathetic nerve activity is similar between men and pre-menopausal women (9, 11, 12). There is also compelling evidence that metabolically sensitive afferents within the respiratory muscles also result in autonomic and cardiovascular adjustments (27). Specifically, fatiguing inspiratory muscle work (and the concomitant accumulation of metabolites) results in metaboreflex activation leading to sympathetically-mediated vasoconstriction and increases in blood pressure ultimately decreasing limb blood flow. Recent studies have found that the neural and cardiovascular consequences associated with inspiratory muscle activation are also attenuated in pre-menopausal women compared to men (23, 28, 29).

Potential mechanisms responsible for the attenuated metaboreflex in pre-menopausal women include muscle mass, metabolite concentration, and peripheral transduction. For example, Seals found a greater blood pressure response and sympathetic activation with larger compared to smaller muscle mass exercise (i.e. forearm versus dorsal interosseous) (30). As women tend to have smaller muscle mass than men, muscle mass has been suggested to be a significant contributor to the sex differences in the exercise pressor reflex (31). However, previous studies have found that women exhibit attenuated increases in blood pressure and muscle sympathetic nerve activity compared to men with metaboreflex activation when matched for maximal voluntary contraction (9, 29) suggesting muscle mass differences minimally contributes to these sex differences in the exercise pressor reflex.

Sex differences exist in the metabolite concentrations within the working muscle during exercise (9, 32). The seminal work by Ettinger and colleagues used 31P-nuclear magnetic resonance spectroscopy to measure H+ and H2PO4- during handgrip exercise and post-exercise circulatory occlusion in men and women (9). During exercise and isolated metaboreflex activation, women had blunted increases in H+ and H2PO4- (with menstrual phase not influencing these metabolite concentrations (33)) congruent with the attenuated increases in muscle sympathetic nerve activity and blood pressure (Figure 1). As H+ and H2PO4- are significantly related to muscle sympathetic nerve activity (34, 35), these data indicate women have lower metabolite concentrations resulting in lower metaboreflex-induced sympathoexcitation. However, it is important to note that other metabolites contribute to the metaboreflex and thus likely contribute to the sex differences. Two primary mechanisms implicated in the sex differences in metabolite concentration during exercise are muscle morphology and substrate utilization. Previous studies have found muscle morphology (e.g., fiber type distribution) significantly contributes to the blood pressure and sympathetic vasomotor outflow during exercise and with isolated metaboreflex activation (36–39). For example, Saito investigated the influence of muscle fiber type by comparing the increase in muscle sympathetic nerve activity between the forearm (primarily fast twitch, highly glycolytic) and soleus (primarily slow twitch, highly oxidative) during isometric exercise (37). The increase in muscle sympathetic nerve activity was accentuated during isometric exercise with the forearm compared to soleus. Furthermore, greater proportion of type II brachioradialis muscle fibers was positively related to the blood pressure response and effluent potassium concentration during isometric handgrip exercise (39). Consistent with these findings, effluent concentrations of potassium, in an anesthetized cat model, were lower following static contraction of the soleus compared to the gastrocnemius consistent with the attenuated blood pressure response (38). These findings have important implications in women as previous studies have found sex differences in the proportion of type I muscle fibers (40–42). Specifically, Staron and colleagues found that the percentage area of type I fibers was greater in pre-menopausal women compared to age-matched men (i.e. 44% versus 36%) (41). Although sex differences in metabolite production have not been directly linked to fiber type distribution, the greater proportion of type I muscle fibers in pre-menopausal women likely contribute to the attenuated metabolite concentration and resulting blunted metaboreflex and exercise pressor reflex compared to age-matched men during exercise. An additional mechanism is sex differences in substrate utilization such that men have a greater glycolytic capacity compared to women (43). For example, women have lower pyruvate kinase, phosphofructokinase, and lactate dehydrogenase enzyme activities suggesting a greater reliance on β-oxidation of fatty acids during exercise in women minimizing the increase in metabolite production (43). Taken together, these studies suggest that sex differences exist in skeletal muscle metabolite production and/or clearance resulting in blunted metaboreflex and exercise pressor reflex-induced sympathetic and cardiovascular responses during exercise.

Figure 1:

Figure 1:

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Muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), heart rate (HR), pH, and H2PO4- during isometric handgrip and post-exercise circulatory occlusion in men (closed squares) and women (closed circles). Women compared to men had attenuated increases in MSNA, MAP, and H2PO4- as well as decreases in pH during exercise and with isolated metaboreflex activation. B, baseline; G1 and G2, isometric handgrip exercise minutes 1 and 2, respectively; CA1 and CA2, post exercise circulatory occlusion minutes 1 and 2, respectively; R, recovery. Data from (9) (used by permission).

Sex differences are also present in transduction of sympathetic nerve activity to the vasculature (10, 11, 44, 45). For example, pre-menopausal women have smaller changes in blood pressure with sympathetic ganglionic blockade compared to age-matched men (46) (as well as post-menopausal women (47)) indicating other mechanisms may contribute to these mechanisms. Furthermore, Hogarth and colleagues found that similar increases in muscle sympathetic nerve activity in men and women resulted in less of an increase in limb (i.e. calf) vascular resistance in women (11). Taken together, these data indicate that different mechanisms contribute to peripheral vasoconstriction and blood pressure regulation in pre-menopausal women compared to men. One of the primary mechanisms underlying this sex difference is β-adrenergic receptor vascular sensitivity (10, 13, 44). Specifically, intra-arterial infusion of norepinephrine led to greater increases in limb vascular resistance in men than pre-menopausal women (10) (Figure 2). However, β-adrenergic receptor blockade in pre-menopausal women resulted in similar norepinephrine-induced increases in limb vascular resistance compared to men suggesting that the greater β-adrenergic vasodilation blunts the α-adrenergic vasoconstriction in pre-menopausal women (10). Although currently unclear, estrogen have been suggested as a primary underlying mechanism for the greater β-adrenergic receptor vascular sensitivity in pre-menopausal women (13). For example, estrogen replacement in ovariectomized rats led to improved β-adrenergic vasodilation of the mesenteric arteries (48). Furthermore, estrogen upregulates nitric oxide release (49), which is pertinent as nitric oxide contributes to β-adrenergic vasodilation (50). As such, Briant and colleagues have recently proposed that the fluctuating estrogen levels in pre-menopausal women increase β-adrenergic receptor vascular sensitivity via a nitric oxide-mediating mechanism (13). Taken together, pre-menopausal women exhibit attenuated increases in sympathetic vasomotor outflow with isolated metaboreflex activation (as discussed above) than men, but, importantly, also exhibit less vasoconstriction for the same degree of sympathetic vasomotor outflow significantly contributing to the sex differences in metaboreflex activation and the exercise pressor reflex.

Figure 2:

Figure 2:

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Percent change in forearm vascular conductance (FVC) with increasing doses of noradrenaline (NA) in pre-menopausal women (A), young men (B), and post-menopausal women (C) before (open circles) and during (closed circles) β-blockade (BB). Before BB, increasing doses of noradrenaline resulted in decreases in FVC for young men and post-menopausal women, but not pre-menopausal women. During BB, increasing doses of noradrenaline led to decreases in FVC for pre-menopausal women. Data from (10) (used by permission).

Impact of Sex Hormones on the Exercise Pressor Reflex:

There are a plethora of mechanisms by which menstrual cycle phase can influence the exercise pressor reflex in pre-menopausal women. For example, higher circulatory estrogen levels are associated with increased resting limb blood flow (51), attenuated limb vasoconstriction (52), increased endothelium-dependent flow-mediated dilation and upregulation of nitric oxide (49, 53, 54), enhanced lipid oxidation (55), suppression of α1-adrenergic receptor expression (56), and decreased sympathetic innervation (57). Previous animal studies have indicated that estrogen modulates the exercise pressor reflex (58, 59). Specifically, in female rats, the increases in blood pressure and renal sympathetic nerve activity during static triceps surae muscle contraction (to elicit the exercise pressor reflex) were less during the proestrus (↑ estrogen concentration) than diestrus (↓ estrogen concentration) phases of the ovarian cycle (58). Interestingly, these authors also found that increases in blood pressure and renal sympathetic nerve activity arising from the mechanoreflex (via triceps surae muscle stretch) were also attenuated during the proestrus phase. In stark contrast, previous studies investigating the effects of the menstrual cycle on autonomic and cardiovascular adjustments during exercise in humans have been conflicting with most studies not supporting a role for the menstrual cycle in modulating the exercise blood pressure response or metaboreflex (12, 18, 33, 60, 61).

What are possible explanations for these conflicting findings? First, major differences exist in the estrogen source (i.e. endogenous versus exogenous), concentration, and timing of fluctuations between rats and humans. Second, in the human studies, the early follicular phase has been compared to the late follicular phase (33, 61) or the midluteal phase (12, 60). This may have contributed to the conflicting findings as progesterone is also elevated during the midluteal phase (but not during the late follicular phase). Future studies are required to determine the independent contribution of progesterone to the exercise pressor reflex and isolated metaboreflex activation. Third, it has been suggested that acute fluctuations (albeit large) in hormones between phases may not exert an influence on the exercise pressor reflex because of the chronic elevation of estrogen in pre-menopausal women (12, 20, 25). Support for this latter explanation arises from a recent study in which the blood pressure response during isometric exercise and isolated metaboreflex activation in men, normally menstruating women in the early follicular phase, and women using oral contraception were compared (25). The metaboreflex-induced increases in blood pressure was greater in the women using oral contraception compared to normally menstruating, while not different in age-matched men. While the body of evidence in this area is limited, the currently available evidence suggests that the normal fluctuations in sex hormones across menstrual cycle appear to have a limited role in modulating the exercise pressor reflex in pre-menopausal women. This is possibly due to the chronically elevated hormone levels although additional work in this area is needed.

Effect of Post-menopause on the Exercise Pressor Reflex:

Post-menopause is associated with significant cardiovascular and neural adjustments such as elevated resting blood pressure, peripheral vascular resistance, aortic stiffness and muscle sympathetic nerve activity, as well as lower limb blood flow (10, 14, 19, 51, 62). Furthermore, the blood pressure response during exercise and with isolated metaboreflex activation is greater in post-menopausal women compared to pre-menopausal woman (28, 63–66). In fact, Choi and colleagues found that isometric handgrip exercise resulted in greater blood pressure increases in post- compared to pre-menopausal women which remained elevated when the metaboreflex was isolated with post-exercise circulatory occlusion (63). Interestingly, the mechanisms (although indirectly measured) underlying this blood pressure response were different between pre- and post-menopause during exercise and with metaboreflex activation (Figure 3). Consistent with previous studies (67), pre-menopausal women relied on increasing stroke volume and cardiac output to increase blood pressure. In contrast, post-menopausal women had greater increases in peripheral vascular resistance with minimal change in cardiac output resulting in the elevated blood pressure response with exercise and isolated metaboreflex activation. A recent study found that the intracellular metabolic milieu during plantar flexion exercise was not different between pre- and post-menopausal women despite greater increases in peripheral vascular resistance and blood pressure in post-menopausal women suggesting that the sensitivity of the metabosensitive receptors may be accentuated (65). This increased peripheral vascular resistance with isolated metaboreflex activation is in line with previous studies demonstrating post-menopausal women exhibit greater sympathetically-mediated vasoconstriction (52) and transduction of vasomotor sympathetic outflow to the peripheral vasculature (10). In fact, arterial infusion of norepinephrine in post-menopausal women results in similar increases in limb vascular resistance as men and is unaltered with β-adrenergic blockade suggesting that β-adrenergic vasodilation does not compete with α-adrenergic vasoconstriction post-menopause (10). Collectively, these data suggest that the augmented metaboreflex and exercise pressor reflex contributes to the elevated blood pressure response during exercise in post-menopausal women partially via greater peripheral transduction of sympathetic vasomotor outflow than pre-menopausal women. However, additional mechanisms (e.g., increased metaboreceptor sensitivity and/or increased metaboreceptor density/expression) underlying the metaboreflex remain unclear.

Figure 3:

Figure 3:

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Heart rate (HR), stroke volume (SV), cardiac output (CO), and total vascular conductance (TVC) during isometric handgrip exercise and post-exercise muscular ischemia (PEMI) (i.e. post-exercise circulatory occlusion) in pre-menopausal and post-menopausal women (black square and white square, respectively). During exercise and isolated metaboreflex activation, post-menopausal women had greater increases in blood pressure due to attenuated increases in CO, but augmented decreases in TVC compared to pre-menopausal women. Data from (63) (used by permission).

Significance and Future Directions:

The known sites, discussed in this review, in which sex contributes to altered adjustments in the cardiovascular and autonomic mediated blood pressure response to exercise are highlighted in Figure 4. These sex differences are known to occur in both pre and post-menopausal women as well as during times of hormone fluctuation (varying menstrual cycle phase). A primary mechanism responsible for these alterations is the exercise pressor reflex (and metaboreflex activation). Understanding the key underlying mechanisms (e.g., exercise pressor reflex) responsible for an augmented blood pressure response during exercise is clinically important, as exaggerated increases in blood pressure during exercise are associated with the development of cardiovascular diseases such as hypertension (15, 16). In regards to the topics presented herein, prescribing exercise programs that maximize safety, while optimizing effectiveness is paramount especially pertaining to post-menopausal women. For example, exaggerated blood pressure responses during exercise have been linked to adverse cardiovascular events (68, 69). As such, prescribing exercise programs that limit the exaggerated exercise-induced blood pressure response in post-menopausal women may reduce this risk. However, exercise programs can also result in reductions in resting and exercising blood pressure (70–72). Thus, the prescription of an effective exercise program is important such that the risk of developing cardiovascular diseases may also be reduced.

Figure 4:

Figure 4:

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This summary figure illustrates the sites for sex differences between men and pre-menopausal women in blood pressure control during exercise discussed in this review. Central command and/or the arterial baroreflex may impact blood pressure control during exercise in a sex-dependent manner, however, this has not been clearly defined (75, 76). β2, β2-adrenergic receptor; NO, nitric oxide

To date, studies investigating the components of the exercise pressor reflex in humans have primarily utilized small muscle mass exercise. Much work remains to be performed in this area to further delineate the mechanistic contributions to and consequences of differences in the exercise pressor reflex. Specifically, future studies are necessary to determine if sex differences and menopause status influence the contribution of group III and IV locomotor afferent feedback to neurovascular responses during whole body exercise as done in healthy men and heart failure (73, 74). In addition, it is important to determine if the exercise pressor reflex is also augmented following menopause in patients with cardiovascular-related diseases.

Acknowledgments

Acknowledgements: This work was supported by the National Institutes of Health [HL126638 to TPO] and American Heart Association [18POST3990251 to JRS].

Footnotes

Conflict of interest: The authors have no conflicts of interest to report for this manuscript. The findings of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

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