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1 Noll Physiological Research Center and 2 Statistical Consulting Center, Pennsylvania State University, University Park, Pennsylvania 16802
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Brooks, E. M., A. L. Morgan, J. M. Pierzga, S. L. Wladkowski, J. T. O'Gorman, J. A. Derr, and W. L. Kenney. Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women. J. Appl.
Physiol. 83(2): 477-484, 1997.
This investigation
examined effects of chronic (
2 yr) hormone replacement therapy (HRT),
both estrogen replacement therapy (ERT) and estrogen plus progesterone
therapy (E+P), on core temperature and skin blood flow responses of
postmenopausal women. Twenty-five postmenopausal women [9 not on
HRT (NO), 8 on ERT, 8 on E+P] exercised on a cycle ergometer for
1 h at an ambient temperature of 36°C. Cutaneous vascular
conductance (CVC) was monitored by laser-Doppler flowmetry, and forearm
vascular conductance (FVC) was measured by using venous occlusion
plethysmography. Iontophoresis of bretylium tosylate was performed
before exercise to block local vasoconstrictor (VC) activity at one
skin site on the forearm. Rectal temperature (Tre) was ~0.5°C lower for
the ERT group (P < 0.01) compared
with E+P and NO groups at rest and throughout exercise. FVC: mean body temperature (Tb) and CVC:
Tb curves were shifted
~0.5°C leftward for the ERT group
(P < 0.0001). Baseline CVC was
significantly higher in the ERT group
(P < 0.05), but there was no
interaction between bretylium treatment and groups once exercise was
initiated. These results suggest that
1) chronic ERT likely acts centrally to decrease Tre,
2) ERT lowers the
Tre at which heat-loss effector mechanisms are initiated, primarily by actions on active cutaneous vasodilation, and 3) addition of
exogenous progestins in HRT effectively blocks these effects.
skin blood flow; vasodilation; temperature regulation; core
temperature; reproductive hormones; estrogen; progesterone
INTRODUCTION IN HUMANS, skin blood flow (SkBF) is controlled by a
noradrenergic vasoconstrictor (VC) system and an active vasodilator
(VD) system. At rest in a thermoneutral environment, SkBF is primarily under the influence of tonic VC tone. However, during heat stress, human SkBF increases to effectively transfer heat from core to skin by
an initial withdrawal of VC and a progressive activation of VD.
Vasomotor control of the cutaneous circulation is important in
maintaining core temperature
(Tc) homeostasis in humans at rest as well as during thermal challenges.
There is substantial evidence that female reproductive hormones may
directly or indirectly influence SkBF and thermoregulation. In young
women, differential patterns in SkBF and thermoregulatory responses to
heat stress and exercise occur during a normal menstrual cycle (14,
34). Compared with the follicular phase, the luteal phase of the
menstrual cycle is associated with an elevation in body
Tc of ~0.5°C coupled with an
increased Tc threshold for the onset of heat-loss-effector function, including skin vasodilation (4,
14, 34). These patterns of blood flow and thermoregulatory responses
have been attributed to elevated circulating progesterone (P4) or the increased
P4/estrogen
(E2) ratio that characterizes the luteal phase of the menstrual cycle (16).
While the preceding observations have suggested a role for endogenous
P4 in vasomotor and
thermoregulatory control, acute (14-23 days) exogenous estrogen
replacement therapy (ERT) in postmenopausal women caused a leftward
shift in the curve relating cutaneous blood flow and
Tc during exercise in the heat
(36). Tc was decreased at baseline
and throughout exercise after acute ERT. Results from animal studies
are consistent with the preceding observations in women (1, 25). For
example, when Baker and co-workers (1) administered
E2 to ovariectomized (OVX) rats, a
lowered Tc and a reduced
Tc threshold for heat loss (e.g.,
evaporative water loss through saliva spreading) resulted. In a more
recent study, E2 administration to
OVX rats decreased basal Tc and
increased thermotolerance within 8-12 days of ERT administration
(25). Thus it appears that E2
enhances thermotolerance through a decreased Tc threshold for skin vasodilation
and a lower regulated Tc, whereas P4 is associated with increased
metabolic heat production and an elevated
Tc (14). There is evidence of
reproductive hormones acting at both central and peripheral levels (8,
26, 33). However, the precise mechanism(s) through which reproductive
hormones alter thermoregulatory responses to heat stress and exercise
is not clear.
Although previous studies have examined SkBF and thermoregulatory
changes in response to heat stress and exercise in premenopausal women
during the menstrual cycle (4, 14, 34) and in postmenopausal women on
acute ERT (36), the effects of chronic (functionally defined here as
continuous therapy of Therefore, the primary purpose of this study was to examine the
influence of chronic ERT and E+P on thermoregulation and control of
SkBF during exercise in the heat in three groups of women [no hormone therapy (NO), ERT, and E+P]. We hypothesized that chronic ERT would result in a lowered Tc
and a reduced Tc threshold at which heat-loss-effector mechanisms would be regulated and that E+P
would attenuate these changes. A second goal of this study was to
determine the efferent mechanism through which chronic ERT and E+P act
to alter cutaneous vasomotor control. By selectively blocking skin VC
through local iontophoresis of bretylium tosylate at one site in the
forearm, it was possible to examine and identify the peripheral
sympathetic pathway(s) (VC vs. VD) through which E2 and
P4 may act to alter the pattern of
SkBF control during heat stress and exercise.
METHODS
2 yr) ERT and estrogen plus progesterone
therapy (E+P) have not been investigated. Acute administration of ERT
may result in an expansion of plasma volume (PV), which can potentially
impact thermoregulatory function and SkBF patterns (10, 11, 36). Thus
thermoregulatory alterations with acute ERT could be due to changes in
PV rather than to direct effects of
E2 on the central nervous system
or on cutaneous vessels. We theorized that acute increases in PV
previously observed with ERT (36) would return to baseline levels by 2 yr, thus allowing for a comparison of direct effects of hormone
replacement therapy (HRT) on thermoregulatory function.
1 year after a history of eumenorrhea,
2) hysterectomy and oophrectomy, or
3) 2-wk repeat serum
E2 concentration
([E2]) 
30 pg/ml.
Women who participated were no longer experiencing symptoms (hot
flashes, insomnia, and so forth) normally associated with the
perimenopausal period. Chronic HRT was functionally defined as
continuous therapy for 2 years. All but five women on HRT received
0.625 mg of Premarin (Wyeth-Ayerst Laboratories, Philadelphia, PA) on a
daily basis. The five exceptions included three women who received
0.625 mg of Premarin on the first 25 days of the month; a fourth woman
who received 0.625 mg of Premarin on Monday, Wednesday, and Friday; and
a fifth woman who received 0.625 mg of Premarin on all odd days and
1.25 mg of Premarin on even days. One of these women also used a
vaginal estrogen cream. P4 dosages ranged from 2.5 to 10 mg, and like
E2, the pill cycle varied among women. Progesterone agents included Provera (Upjohn,
Kalamazoo, MI) and Cycrin (Esi Lederle, Philadelphia, PA), both of
which contain medroxyprogesterone acetate. One woman in the E+P group received daily E2 but received 400 mg of P4 per day
(medroxyprogesterone acetate, Paddock Laboratories, Philadelphia, PA)
for 14 days every third month.
O2 peak), subjects performed a graded exercise test on a modified cycle ergometer during
which heart rate (HR) was recorded by an electrocardiogram, and blood
pressure was measured by brachial auscultation. Body surface area
(Ad) was
calculated from height and weight (7), and physical activity level was
estimated by using a validated questionnaire (6). Venous blood samples
collected 5 min before exercise on the day of the experimental trial
were assayed for estradiol-17
and
P4. Subject characteristics are
presented in Table 1, and serum hormone
concentrations are presented in Table 2.
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· cm) water (NANOpure, Barnstead, Dubuque, IA)
and iontophoresed for 40 min over a
3-cm2 area of skin by using
alternating current (Lectro Patch, General Medical, Los Angeles, CA).
Doubly distilled water was iontophoresed over a third site on the right
forearm (3-cm2 area) to serve as a
control. After this procedure, each subject drank 5 ml water/kg body
weight to ensure adequate hydration before exercise.
Approximately 1 h later, blockade of VC at bretylium-treated (BT) sites
was verified by using whole body cooling as a stimulus for reflex skin
VC. The subject inserted a rectal thermistor, provided a urine sample,
dressed in exercise clothing (shorts and sports bra), and was fitted
with a water-perfused suit (Diving Unlimited, San Diego, CA) covering
the entire body except for the hands, feet, and head. After stable
baseline measurements of HR, laser-Doppler flux (LDF) at control and BT
sites, and rectal temperature
(Tre) were established,
whole-body cooling was performed for 3 min. Blockade of VC was
considered complete if LDF either increased or remained stable at the
BT site but decreased at the control site. If blockade was incomplete,
the alternative BT site was tested in a similar manner. The experiment
proceeded only if full blockade of VC by bretylium iontophoresis was
achieved.
After verification of VC blockade, the water-perfused suit was removed
and the subject rested on the cycle ergometer while additional probes
and monitors were attached. The environmental chamber was warmed
to dry-bulb temperature = 36°C and wet-bulb temperature = 24°C (relative humidity = 40%). After ~5 min were allowed for stabilization, baseline measurements were collected for 10 min. Mean arterial pressure (MAP), HR,
Tre, mean skin temperature (Tsk), and LDF were monitored
continuously throughout this 10-min baseline and the exercise period
that followed. Forearm blood flow (FBF) was recorded at 2-min intervals
during baseline and exercise (described below).
After the baseline period, subjects exercised for 30 min at 40%
O2 peak, then 30 min
at 60% O2 peak. Each
subject initially cycled at 60 revolutions/min at a resistance of 30 W,
and resistance was increased by 30 W every 2 min until the target
intensity was reached. After subjects completed 1 h of exercise,
resistance was decreased, and subjects cycled slowly to maintain blood
pressure. By using thermostatically heated probe holders, local
Tsk at the laser-Doppler probe
sites was then increased to 42.5-43.0°C and maintained for
~40 min to obtain a site-specific maximal LDF. Maximal LDF was
verified by performing a postocclusion reactive hyperemia maneuver
(18).
Measurements.
Tre was measured
by using a series 400 Yellow Springs Instruments rectal
thermistor inserted 10 cm past the anal sphincter. Tsk was calculated as the weighted
average of temperatures recorded by thermocouples (type T; Omega
Engineering, Stamford, CT) affixed to four uncovered skin sites: chest,
upper arm, thigh, and calf (29). Mean body temperature
(Tb) was calculated as
Tb = 0.8 Tre + 0.2 Tsk (35). MAP and HR were
continuously monitored from a Finapres cuff (Finapres blood pressure
monitor, model 2300; Ohmeda, Louisville, CO) attached to the middle
finger of the right hand.
FBF was measured on the left forearm by venous occlusion
plethysmography with the use of a mercury-in-Silastic strain gauge (EC4
Plethysmograph; Hokanson, Bellevue, WA) (38). During heating and
dynamic leg exercise, increases in FBF are confined to the forearm skin
rather than the underlying muscle (5, 19). An occlusion cuff (Hokanson)
around the wrist was inflated to suprasystolic (200 mmHg) pressures to
occlude hand blood flow, while an upper arm cuff cycled between 10 s of
inflation (40-60 mmHg) and 5 s of deflation during measurement
cycles (E20 Rapid Cuff Inflator, Hokanson). The FBF at each time point
comprised the mean of a series of four readings initiated at 2-min
intervals. Forearm vascular conductance (FVC = FBF/MAP) was reported in
units of milliliters per 100 milliliters per minute per 100 millimeters mercury and later was plotted as FVC:
Tb.
As described above, changes in SkBF were also examined using
laser-Doppler flowmetry (model DRT4 laser blood flow monitor; Moor Instruments, Devon, UK). LDF was recorded at a BT and
a control site from probes attached to the right forearm by using the
aforementioned thermostatically controlled holders. Cutaneous vascular
conductance (CVC) was calculated as LDF/MAP. Because LDF is highly
variable between skin sites within the same individual as well as
between different individuals (2), CVC at each skin site was
standardized by expressing CVC as a percentage of the maximal CVC at
that skin site (%CVCmax)
obtained during local heating of the site to 42.5-43.0°C (37).
Tre, individual
Tsk, MAP, and HR data were each
collected at a rate of 5 data points/s, averaged over 1-min intervals
by using a SuperScope II (GW Instruments, Somerville, MA)
data-acquisition system, and stored on a dedicated computer (Macintosh
Quadra 650, Apple Computer, Cupertino, CA). Similarly, LDF data were
recorded at a rate of 1 data point/s, and a mean was calculated for
1-min intervals.
A nude body weight was recorded for each subject before and after
completion of each session. An estimate of sweating rate (in
g · h
1 · m2)
was calculated from the change in body weight, corrected for urine
volume production but not for respiratory water loss (assumed to be
negligible).
Venous blood samples were collected (SST Vacutainer; Becton-Dickinson,
Rutherford, New Jersey) ~5 min before exercise during the
experimental trial, stored in ice, and centrifuged. Serum was frozen
and later assayed in duplicate. Estradiol-17 concentration was
measured from serum aliquots with an
I125-labeled double-antibody
radioimmunoassay (RIA) procedure (ICN Biomedicals, Costa Mesa, CA). The
sensitivity of the assay was 9 pg/ml, and inter- and intra-assay
precision coefficients of variation were <12 and <11%,
respectively, for an estradiol range of 28-38 pg/ml. Progesterone
concentrations were measured at the Milton S. Hershey Medical Center
Core Endocrine Laboratory by RIA with the use of an antibody-coated
tube methodology. Assay sensitivity was 0.10 ng/ml, and inter- and
intra-assay precision coefficients of variation were both <10% for a
P4 range of 0.7-1.0 ng/ml.
Three to six days after the exercise protocol, subjects returned to the
laboratory for measurement of resting PV by Evans blue dye dilution.
Subjects arrived early at the laboratory after a 12-h overnight fast.
Subjects rested in a seated position for at least 15 min at
normothermia, then a 20-ml control blood sample was obtained through a
heparinized butterfly needle. Approximately 3.0 g of dye were injected,
then blood was collected at 10-, 20-, and 30-min postinjection. Plasma
samples were later analyzed spectrophotometrically at a wavelength of
620 nm (Spectronic 21D, Milton Roy, Rochester, NY). Reported values
(Table 1) are based on the peak absorbance reading, which occurred at
10 min for all subjects.
Analysis of data.
Data are presented as means ± SE. Descriptive plots of
Tsk, HR, change in
Tre,
Tre, MAP, and
Tb vs. exercise time were analyzed as follows. The independent variable (exercise time) was partitioned into seven regularly spaced bins of 4-min width and with a gap of 6 min
between bins. Within each subject, the dependent variables were
averaged within the range of each bin for time, and a repeated-measures analysis of variance model was fit to the data. "Group" was the between-subjects factor, and "binned time" was the
within-subjects factor.
The descriptive plots of %CVCmax
vs. Tb showed a general sigmoid
shape, as previously described (21). A set of four-parameter sigmoid
curves was fitted to the data by using a nonlinear mixed-effects model
that permits estimation of separate parameters for each individual and
condition (22). The four-parameter model has the form
![%CVC<SUB>max <IT>i</IT></SUB> = (A<SUB><IT>i</IT></SUB> − D<SUB><IT>i</IT></SUB>) ⋅ [1 + (T<SUB>b <IT>i</IT></SUB>/C<SUB><IT>i</IT></SUB>)B<SUB><IT>i</IT></SUB>]<SUP>−1</SUP> + D<SUB><IT>i</IT></SUB>](/content/vol83/issue2/fulltext/477/img001.gif)
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of 0.05 was used as the criterion for
statistical significance of factors and their interactions. Follow-up tests with a Bonferroni correction were used to evaluate the
significance of specific pairwise comparisons.
RESULTS
As illustrated in Fig. 1,
Tre was significantly lower in the
ERT group compared with E+P and NO groups at rest and throughout exercise (P < 0.05). Once exercise
was initiated, the rate and magnitude of increase in
Tre during exercise were not
significantly different among the three groups. A similar relationship
existed for Tb (Table
3), i.e., the
Tb of the ERT group was
significantly lower than that for NO and E+P groups
(P = 0.0001) during exercise.
O2 peak) and 60%
O2 peak in an ambient temperature of 36°C. Baseline period consists of 
10 to 0 min. Exercise began at 0 min and was completed at 60 min.
Tre of estrogen replacement
therapy (ERT) group was significantly lower than estrogen plus
progesterone therapy (E+P) and no hormone replacement therapy (NO)
groups at baseline and throughout exercise
(P < 0.05);
n, no. of subjects. Bars represent 1 SE.
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Table 3 also presents the HR, MAP, and Tsk responses at rest and at the end of 30 min at each exercise intensity. HR and Tsk were not different among the three groups at rest or during exercise.
The curve relating FVC to Tb was
shifted to the left for the ERT women compared with the remaining
groups, but the slope and plateau of the FVC:
Tb curve was not
significantly different among groups (Fig.
2). The
Tb threshold for the onset of
cutaneous vasodilation in women taking ERT (36.5 ± 0.1°C) was
significantly (P < 0.05) lower than
that for the NO group (Tb = 36.9 ± 0.1°C). Baseline FVC was not significantly different
among the three groups of women (8.1 ± 1.0, 7.1 ± 0.8, and 8.3 ± 9 ml · 100 ml1 · min1 · 100 mmHg1 for ERT, NO, and E+P
groups, respectively; P < 0.05).
Therefore, during the early rise phase of FVC, FVC was higher in the
ERT group than in NO and E+P groups because of a shift in the
Tb threshold.
Table 4 presents the parameter estimates for the sigmoid model of %CVCmax: Tb at both control and BT skin sites for each group, and this relationship is plotted in Fig. 3 for control skin sites. Baseline %CVCmax was not significantly different among groups at BT sites. However, at control sites, baseline %CVCmax in ERT was significantly higher (P < 0.05) than that of the NO group. As in FVC: Tb, there was a leftward shift in the %CVCmax: Tb curve in the ERT group. This observation is supported by a significantly lower ET50 at both BT and control skin sites for the ERT group compared with that of the E+P and NO groups (P < 0.05). The slope of %CVCmax: Tb did not differ among the three groups, nor was it affected by BT treatment. In all groups, CVC reached a similar percentage of the site-specific maximum (59-68%) at high Tc regardless of BT treatment. As presented in Table 4, BT significantly affected the ET50 by shifting it slightly to the right within each group. Therefore, although BT affected baseline %CVCmax in ERT, there was no interaction between group and treatment once exercise began.
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DISCUSSION
The present investigation provided insight into the influence of chronic HRT (ERT and E+P) on thermoregulatory function and cutaneous vasomotor control in postmenopausal women. The primary finding was that chronic ERT significantly reduces the regulated baseline Tc by altering vasomotor function, but the addition of progestins to HRT blocks this thermoregulatory effect (Figs. 1, 2, 3). The similar resting PV values (Table 1) among the groups verify our premise that acute increases in PV with ERT (36) are no longer evident after 2 yr, and the PV values effectively rule out hypervolemia as a primary mechanism. This finding suggests that the thermoregulatory adjustments observed are more likely caused by direct effects of reproductive hormones on the thermoregulatory centers in the preoptic area anterior hypothalamus (PO/AH), the vasculature, or both. Although the modifications in thermoregulatory function and SkBF observed in the present study are more likely central in nature, the differential effect of BT on baseline %CVCmax in ERT suggests that peripheral actions by reproductive steroid hormones on the vasculature also may occur (Table 4). Finally, the similarity of the slope of the %CVCmax: Tb curve and the plateau in %CVCmax curve between BT and control skin sites in all three groups suggests that VD sensitivity is not altered by exogenous reproductive hormones.
Tc regulation. Heat balance is achieved by equivalent rates of heat production and heat loss. At neutral (24-25°C) ambient temperatures at rest, human Tc is regulated by alterations in SkBF rather than by changing metabolism appreciably or evaporative cooling (13, 32). Tre is maintained at ~37°C, while Tsk may vary from ~33 to 35°C (13) in this so-called "vasomotor" zone. SkBF in this zone is regulated by adjustments in VC tone, such that SkBF ranges from 2 to 6 ml blood · min1 · 100 ml skin1.
Although these changes in SkBF are rather small, they can have rather
profound effects on heat transfer, and therefore, on resting Tc (17).
As mentioned previously, control of thermoregulatory SkBF at rest and
during exercise is altered in eumenorrheic women during the menstrual
cycle (4, 14, 34). A recurrent observation is a significant elevation
in resting Tc and in the
Tc threshold (by ~0.5°C) for
the initiation of cutaneous vasodilation and sweating during the luteal
phase of the menstrual cycle, a time when the P4-to-E2
ratio is significantly increased. It is generally believed that
P4 is thermogenic (14) and alters
the control of heat loss effectors to increase
Tc, and that
E2 unopposed by
P4 decreases Tc (16). For example,
Tre in premenopausal women at rest
and throughout exercise is lowest immediately before ovulation,
intermediate during menses, and highest during the midluteal phase (4). Thus, the ratio of the concentrations of the reproductive hormones is
an important determinant of the level at which
Tc is regulated.
Our laboratory previously investigated the effects of acute
(~2-3 wk) ERT on thermoregulatory and SkBF responses to exercise in the heat in postmenopausal women (36). We found a significant decrease in Tre and esophageal
temperature (Tes) at rest and
during exercise after ERT. Furthermore, in that study, the
Tes threshold for the onset of
vasodilation was reduced. Like acute ERT, chronic ERT significantly
increased serum [E2]
in postmenopausal women compared with the NO group
(P < 0.05, Table 2), significantly reduced Tre and
Tb at rest and throughout
exercise, and produced a leftward shift in the curves relating SkBF to
Tb. The reduced level at which
Tc is regulated in the ERT group
throughout exercise is likely caused by vasomotor adjustments rather
than changes in sensible or insensible heat loss, because exercise
sweating rate was not significantly different among groups (Table 1). The combination of these two studies suggests that the thermoregulatory advantages associated with ERT are achieved within 2-3 wk and are
maintained throughout the duration of continuous ERT administration. However, it is unknown how quickly these benefits are lost if ERT is
discontinued.
In the present study, serum
[E2] was significantly
higher in E+P than in NO (P < 0.05, Table 2). Although the addition of progesterone to HRT attenuated the
thermoregulatory effects of ERT, it did not cause
Tc to increase beyond that
observed for NO. Because a minimal quantity of
P4 (2.5-10 mg) is
incorporated into commercial HRT, the serum
P4 concentration
([P4]) resulting from
E+P therapy is low. In fact, there was no difference in serum [P4] among the three
groups of women. We attribute these results to the time of venous blood
collection (~6 h after pill ingestion), clearance rates of
P4, the low cross-reactivity
between the assay and medroxyprogesterone acetate (oral progestin), and
potential individual differences in the metabolism and adrenal
production of steroid hormones. It is possible that increasing doses of
P4 could further increase
Tc and the level at which
Tc is regulated (31).
The lower regulated Tc and the
leftward shift in the Tb threshold
for cutaneous vasodilation in the ERT group, along with the inhibition
of these thermoregulatory responses with the addition of progestins in
HRT, are consistent with an alteration of thermoregulatory function by
reproductive hormones via a central mechanism. Estradiol stimulates
warmth-sensitive neurons in PO/AH tissue slices of the rat (33).
Additionally, Nakayama and Suzuki (26) examined the effects of
intravenous P4 administration on
the activity of thermosensitive neurons in the hypothalamus of the
rabbit and noted that P4 increased
the firing rate of cold-sensitive neurons while concurrently decreasing
the firing rate of warmth-sensitive neurons. However, in that study
(26), because P4 was not directly applied to thermosensitive neurons, it was unclear whether
P4 directly stimulated the neurons
or if P4 activated an additional cellular mediator that then acted on thermosensitive neurons in the
hypothalamus.
Reproductive steroid hormones could act centrally by crossing the
blood-brain barrier and directly stimulating thermosensitive neurons in
the PO/AH. Androgen, E2, and
P4 receptors have been characterized and mapped within the rat brain (24). However, it is also
possible that these steroids act indirectly by stimulating a secondary
mediator or pathway. E2 and
P4 have been shown to differentially stimulate cytokine and prostaglandin secretion in a
dose-dependent manner (3, 9). For example, Flynn (9) noted that lower
doses of E2 and
P4
(~109 M and
~107 M, respectively)
stimulated interleukin-1 (IL-1) production from monocytes, but higher
doses (108 M and
106 M, respectively)
inhibited production. Similarly, Polan and coworkers (28) more recently noted biphasic dose-response curves
for IL-1 activity by E2 and
P4.
Cannon and Dinarello (3) noted that, during the luteal phase of the
menstrual cycle in healthy premenopausal women, a profound increase
occurred in the plasma activity of IL-1, a mediator of fever. The
luteal phase of the menstrual cycle is similar to fever in that
Tc is regulated about a higher
temperature. The measurement of the agonist-to-antagonist ratio is
important for determining the effective response of cytokines. For
example, the ratio of IL-1 to IL-1 receptor antagonist (IL-1Ra) was
found to be elevated in women during the luteal phase of the menstrual
cycle compared with men or with women in the follicular phase (23). In
postmenopausal women, cytokine production is inconsistent. Pacifici et
al. (27) observed elevated cytokine bioactivity in the circulation,
including IL-1 and IL-6, after menopause, and a reduction in these
cytokines after the initiation of E+P. However, not all investigators
have reported similar findings (15). Inconsistent results could be due
to the dosage of E2 or
P4, time past the onset of
menopause, health of the subject, and methodology. In summary,
thermoregulatory alterations by reproductive steroids could be due to
direct actions by these hormones at the PO/AH, indirect effects by
other cellular mediators, such as cytokines, or both.
SkBF.
At rest in thermoneutral environments,
Tc is regulated by vasomotor
adjustments rather than metabolic changes. However, beyond thermoneutrality, vasomotor alterations along with other
thermoregulatory effectors (e.g., shivering and sweating) are
initiated. During exercise and heat stress, heat storage requires that
SkBF be significantly increased by withdrawal of VC and activation of
the VD system to convect heat from the core to the skin for
dissipation. Reflex increases in SkBF are driven by increases in both
Tc and
Tsk. In the present study,
Tb was calculated to account for
the contributions of both thermal drives on heatloss-effector
function, including SkBF (35). Thus, the SkBF responses were plotted as
a function of Tb rather than
Tre.
That control of SkBF is altered by hormonal status is clearly
illustrated by the leftward shift in SkBF:
Tb curves in the ERT group (Figs.
2 and 3) compared with NO and E+P groups
(P < 0.05, Table 4). Based on
previous studies (1, 33), these observations are likely caused by a
central alteration in the regulated level of
Tc. Because the slopes of the
%CVCmax:
Tb curves at BT and control skin
sites were not significantly different within or between groups (Table
4), nor was the rate of rise in FVC:
Tb curve different among groups,
end-organ sensitivity to VD does not seem to be altered by reproductive
hormones once exercise is initiated. Finally, CVC reached a similar
percentage of the site-specific maximal conductance at both BT and
control skin sites in all three groups. Because VC activity was blocked by BT, the plateau in CVC during exercise must be due to a limit in VD
that appears not to be dependent on hormonal status.
An interesting and unexpected finding in the present investigation was
the significant ERT group and treatment interaction for
%CVCmax at baseline (Table 4).
One would expect CVC at rest to be greater at a site where basal VC
activity had been blocked, especially because it is assumed that only
the VC system is activated at thermoneutral resting conditions.
However, baseline %CVCmax at
control sites in the ERT group was significantly higher than that in
the other groups, and higher than the
%CVCmax at BT sites within the
ERT group. This phenomenon could have a major effect on resting
Tc for reasons initially discussed
in Tc
regulation and may help explain the
lower resting Tc in the ERT group.
Because %CVCmax is a function of
absolute CVC and the site-specific
CVCmax, the combination of ERT and
BT could potentially alter either of these parameters. Intra-arterial
infusion of estradiol-17 has been shown to potentiate
endothelium-dependent vasodilation (12) and to increase basal coronary
flow in postmenopausal women (30). However, it is unknown whether HRT
administration in postmenopausal women similarly alters maximal
cutaneous flow. A decrease in
CVCmax seems unlikely, given the
vasodilatory nature of E2. The
second alternative to explain the higher resting
%CVCmax at control skin sites in
the ERT group is consistent with the idea that
E2 is sympathoinhibitory at a
central level, i.e., a central thermoregulatory action. In this case,
the reduced %CVCmax at BT skin
sites in the ERT group may be due to an inhibitory effect by BT on a
vasodilatory factor or pathway that is stimulated by
E2 at rest. The convergence of
%CVCmax:
Tb curves at the BT and control
skin sites in the ERT group suggests that this hypothetical
vasodilatory factor or pathway plays an insignificant role once VD is
activated. Potential vasodilatory mechanisms by estradiol include
increased production or activity of nitric oxide, increased
prostaglandin production, stimulation of potassium channels, inhibition
of calcium channels, or blockade of vasoconstrictor agents such as
endothelin (8). The mechanism(s) through which BT interacts with ERT is
unknown at present.
Another effect of BT iontophoresis was a small but consistent rightward
shift in ET50 within each group.
There was no group-by-treatment interaction, because
ET50 at BT sites was consistently
shifted to the right in each of the three groups. Possible explanations for this finding are 1) the onset of
active vasodilation may be delayed by BT or
2) VC withdrawal may play a role at
the onset of vasodilation, but this effect can only be seen during slow heating of an individual. This finding raises questions about additional cellular actions of bretylium tosylate.
In conclusion, chronic ERT in postmenopausal women reduced the
regulated Tc at rest and during
exercise. The addition of progestins to HRT attenuated the
thermoregulatory effects of E2,
such that the E+P group responded to exercise in the heat as did the NO group. There may be an interactive effect of BT and ERT, such that the
average resting %CVCmax is
significantly higher at control skin sites in the ERT group than at BT
sites in the ERT group or at either site in the other two groups.
However, during exercise, this differential effect is overcome by an
equivalent sensitivity to increasing VD activity in the three groups
along with achievement of a similar
%CVCmax.
ACKNOWLEDGEMENTS
We thank the group of subjects who gave their time and effort to make this study possible. In addition, we thank Rebecca Eckman, William Farquhar, Dr. Anthony Cardell, the General Clinical Research Center nursing staff, Marlin Druckenmiller, Doug Johnson, and Fred Weyandt for medical and technical support; and we thank Dr. Joseph G. Cannon for editorial expertise. This research was supported by National Institutes of Health Grants R01-AG07004-07 and M01-RR10732-01.
FOOTNOTES
Address for reprint requests: W. L. Kenney, Noll Physiological Reserach Center, Pennsylvania State University, University Park, PA 16802 (E-mail: w7k{at}psu.edu).
Received 15 January 1997; accepted in final form 15 April 1997.
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