DDMOD-540; No of Pages 11

Vol. xxx, No. xx 2019

Drug Discovery Today: Disease Models

Editors-in-Chief
Jan Tornell – AstraZeneca, Sweden
DRUG DISCOVERY Andrew McCulloch – University of California, SanDiego, USA
TODAY
DISEASE
MODELS

Paradigm shift in pathophysiology

of vasomotor symptoms: Effects of
estradiol withdrawal and progesterone
therapy
Yubo Fana, Ruiyi Tanga, Jerilynn C. Priorb,c,d, Rong Chena,*
a
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of
Medical Science, Beijing, 100730 People’s Republic of China
b
Centre for Menstrual Cycle and Ovulation Research, Endocrinology and Metabolism, University of British Columbia, Vancouver, BC,
V5Z 1M9, Canada
c
Associate, School for Population and Public Health, University of British Columbia, Vancouver, BC, British Columbia, Canada
d
Women’s Health Research Institute, Vancouver, BC, Canada

Purpose It was previously thought that estrogen defi-
ciency caused hot flushes and night sweats or vasomo-
tor symptoms (VMS). However, VMS also present in
women in the Late Reproductive Transition or ``Very
Early Perimenopause” who still have regular menstrual
cycles and whose estrogen levels have not decreased.
Social emotional stresses increase VMS that, in turn,
increase stress hormones and mood changes. Evidence
suggests that downward swings of estradiol (E2) cause
the dramatic neuroendocrine/cytokine release with
elevated central norepinephrine levels leading to ther-
moneutral zone narrowing and VMS. There are aspects
of the physiology of VMS that resemble ``estrogen
addiction”.
The aim of this review is to integrate scientific and
clinical VMS knowledge in a new paradigm within the
*Corresponding author.
model of balanced estradiol and progesterone levels for
women’s optimal health.
Major sources of information We reviewed studies
focusing on VMS and its risk factors, pathophysiology
and treatment on PubMed, MEDLINE, and EMBASE.
Data synthesis in the context of E2-P4 balance women’s
health model Estrogen withdrawal stimulates release
of a host of cytokines and neurotransmitters most
important of which is increased NE. Downward E2
levels are also associated with anxiety and depression.
Initially premenopausal women made menopausal by
bilateral ovariectomy/chemotherapy with rapid E2 de-
cline are more likely to report severe VMS than those
with natural reproductive aging. When E2 levels drop,
increased central NE neuroendocrine-thermal dysre-
gulation triggers hot flushes/night sweats. Although E2-
based menopausal hormone therapy relieves VMS, its
discontinuation often produces a VMS rebound. P4
relieves VMS in both menopausal and perimenopausal

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Please cite this article in press as: Fan Y, et al. Paradigm shift in pathophysiology of vasomotor symptoms: Effects of estradiol withdrawal and progesterone therapy, Drug Discov Today:
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DDMOD-540; No of Pages 11
Drug Discovery Today: Disease Models |
women likely by decreasing or stabilizing NE. We
hypothesize that the rebound on discontinuing E2 ther-
apy could be prevented by first adding P4 and then
gradually weaning off E2.
This paradigm shift’s clinical and research relevance
The effects—of E2 withdrawal, and high E2 levels to
increase, and of full dose P4 to suppress central NE
levels—need further documentation. Several primate
studies and clinical and controlled trials are needed to
test this new model.
Conclusions High brain E2 exposure followed by E2
withdrawal rather than low estrogen per se is the
underlying cause of VMS; P4 counterbalances the vary-
ing E2 levels in the premenopausal years. P4 therapy in
perimenopause/menopause may effectively decrease
or prevent hot flushes/night sweats without the risk
of withdrawal VMS increases that are related to stop-
ping E2 therapy.
Section editor: Jerilynn C Prior – Department of Medicine,
University of British Columbia, Centre for Menstrual Cycle
and Ovulation Research www.cemcor.ca. BC Women’s
Health Research Institute, Room 4111, 2775 Laurel Street,
Vancouver BC, V5Z 1M9, Canada.
Introduction
Vasomotor symptom (VMS), including hot flushes/flashes
and night sweats, are the most common experiences during
the menopause transition and midlife [1]. Approximately
85% of women experience hot flushes during perimenopause
and early into menopause [2] (that begins one year after the
final menstruation). The prevalence of vasomotor symptoms
in the United States was 79% in perimenopausal women and
65% in postmenopausal women (ages 40–65 years old)
according to a population-based cross-sectional study [1].
A typical hot flush begins as a sudden sensation of intense
heat with or without a variety of disturbing symptoms that
may include sweating, flushing, anxiety and chills, usually
lasting for 1–4 min [3]. The symptoms are characteristic of a
heat-dissipation response and consist of sweating on the face,
neck, and chest, as well as peripheral vasodilation. In this
document we are referring to the comprehensive Prior
‘‘Phases of Perimenopause’’ that incorporate the Stages of
Reproductive Aging Workshop criteria and ‘‘stages’’ [4] using
a revised timeline [5] as shown in Fig. 1. VMS may commence
even before the Early Menopause Transition is diagnosed by
irregular cycles [4] when women still have regular menstrua-
tion in what is now called Very Early Perimenopause [6].
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Vol. xxx, No. xx 2019
Thus, VMS are not limited to the years around the final
menstrual period (FMP) [7,8] as was previously thought.
Several studies document the perimenopausal onset and
long duration of VMS. According to a population-based
cohort study of African American and White women followed
for 13 years, the mean duration of VMS was 10 years, and was
longer in women with an earlier VMS onset during the
earliest years of perimenopause [8,9]. In addition, the Study
of Women’s Health Across the Nation (SWAN), a multicenter,
multiracial convenience cohort from several urban areas in
the United States of America (USA), reported that frequent
VMS lasted more than 7 years during the menopausal transi-
tion for more than half of the women, and they persisted for
4.5 years after the final menstrual period (FMP) through what
has been termed the Late Perimenopause [5] and into the first
3–5 years in menopause [10]. In the prospective observational
Peking Aging Longitudinal Midlife (PALM) study in 189
women 37–53 years old, night sweats and hot flushes were
similarly present and last longer in women whose VMS
started with regular cycling [11]. Thus, VMS become one of
the main symptoms in perimenopausal and menopausal
women and for which they may seek medical advice and
assistance.
The pathophysiological concept for VMS in the past was
that menopausal women are estrogen deficient, and that
‘‘estrogen deficiency’’ caused VMS [12]. However, estrogen
levels often do not differ between women with or without
VMS [13,14]. VMS, usually as night sweats, may also begin in
midlife women whose menstrual cycles remain regular [6]
and who thus cannot be without normal, premenopausal
estradiol (E2) levels. A further confusion is that VMS may
result in emotional distress [15] or be caused by it [16]. Thus,
VMS have a bidirectional association with emotional stress or
duress. In this review, we discuss risk factors for, the patho-
physiology and treatment of VMS, focusing on the model
that current and future life women’s health is optimal with a
premenopausal menstrual cycle balance of E2 and P4. We also
discuss VMS interactions with the sympathetic nervous sys-
tem, situational stresses and glucocorticoid levels related to
the prevalence, experience and the treatment of hot flushes/
flashes and night sweats (VMS).
VMS pathophysiology
As a preliminary aside, we understand that VMS are a physi-
ological phenomenon with measurable changes in galvanic
skin responses, the thermoneutral zone, and responses to
systemic heat [17]. These measurable changes have been
measured in animal models (such as the opioid-addicted
rodent [18]) and in a few primates. However, VMS are pri-
marily a gendered experience best expressed in language; they
extend beyond biology given that they occur within and are
altered by social environments. Therefore, the references and
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Vol. xxx, No. xx 2019 Drug Discovery Today: Disease Models |

PERIMENOPAUSE

Very Early Perimenopause Menopause Transition Late Perimenopause

Early Late

Changes in Irregular Skipped Final MENOPAUSE

Experience periods period menstruation
(cycles vary (starts with
in length by 7 60 days
or more days) without flow)

Time
~2-5 years ~3 years 1 year

Drug Discovery Today: Disease Models

Fig. 1. Phases of Perimenopause from Ref. [5]. In Very Early Perimenopause which may last for 2-5years (called the Late Reproductive Stage by the Stages
of Reproductive Aging Workshop 10+ [4], hormone levels have already changed by the time women with regular cycles become symptomatic. Late
Perimenopause is defined as the year after the last menstruation [5].

the focus of this review are necessarily on clinical or transla-

tional data rather than on basic science.
Since menopausal women with low estrogen (and proges-
terone) levels reported hot flushes and night sweats, it was
previously thought that ‘‘estrogen deficiency’’ caused VMS.
However, estrogen concentrations cannot be solely responsi-
ble for these symptoms because the occurrence and severity
of symptoms varies greatly among women during the meno-
pausal transition [7]. A population-based cross-sectional
study of USA women found more perimenopausal women
(with relatively high estrogen levels [19,20]) had VMS and
severe VMS than did postmenopausal women [1]. Further-
more, VMS in general gradually decease years and stop after
the final menstrual period (FMP), during years when estro-
gens consistently maintain low levels. Children have low E2
levels and no VMS; the same is true for men (unless they have
undergone androgen ablation for prostate cancer).
By contrast to low estradiol levels, per se, estradiol with-
drawal is known to release multiple cytokines [21], hormones
and neurotransmitters including those from the opioid sys-
tem [22–25], many of which are similar to those shown to be
dramatically increased during a hot flush episode. In fact, the
very first placebo-controlled trial of estrogen for VMS treat-
ment, that was a crossover trial, showed increased VMS with
the start of placebo and dropping estradiol levels [26]. Thus,
multiple lines of evidence suggest that it is estradiol withdraw-
al rather than low estrogen levels, per se, that are the cause for
VMS. We put this information together into a new paradigm
describing VMS that incorporates current understanding
(Fig. 2).
The evidence-based current concept is that a high brain
estrogen environment followed by estrogen withdrawal is the
key VMS etiology. This is supported by the huge difficulty
that a quarter of women being treated with estrogen for VMS,
have stopping this therapy since that is followed by VMS that
VMS
Estrogen Stress
Withdrawal hormones
High Brain
Estrogen
Environment
Drug Discovery Today: Disease Models
Fig. 2. Estrogen-withdrawal/Stress model of VMS. Withdrawal from
high brain estrogen exposures causes VMS. Note also, to be discussed
subsequently, that there is a bidirectional association between VMS
and psychosocial stress (anxiety, depression). Not only do VMS
increase stress hormones, stress, in turn, aggravates VMS.
markedly increase [27]. In a prospective study of 75 women
treated with high dose estradiol implants (either 50 mg
estradiol alone or with 100 mg testosterone), both groups
showed that symptoms returned when the plasma estradiol
concentrations start to fall [28]. In another study [29], men-
opausal women were given depot injections of E2 that were
designed to keep E2 levels high for 6 months [29]. However, as
the very high levels declined, they became symptomatic well
before 6 months, presenting with anxiety as well as VMS [29].
They all had levels higher than the midcycle E2 peak at the
time of severe VMS and anxiety symptoms that were due to E2
withdrawal [29].
The prior priming of brain by estrogens seems to also play
an important role in the generation of hot flushes as women
with ovarian dysgenesis develop hot flushes only after they
have been treated with estrogen and it has been withdrawn
[14]. The premenopausal relatively high brain estrogen en-
vironment predisposes some but not other women to develop

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DDMOD-540; No of Pages 11
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VMS. Reasons for these differences could be the previous use
of combined hormonal contraceptives (that expose women
to at least four times higher than physiological estradiol levels
because of the greater potency of ethinyl estradiol versus 17-
beta E2), a genetic variation so estradiol metabolism is slo-
wed, obesity (with increased estrone production from aro-
matization of androgen or androgenic adrenal steroids) or
exposure to environmental estrogen-like chemicals. All of
these are hypotheses that need prospective epidemiological
testing.
This new paradigm of VMS pathophysiology (Fig. 3) incor-
porates concepts of the new model in which the actions of
progesterone within an ideally balanced estradiol and pro-
gesterone Reproductive System. In this new model, estradiol
causes cell proliferation and progesterone decreases prolifer-
ation while causing differentiation/maturation in the cells
and tissues of multiple species [30]. We postulate that the
modern lifestyle of decreased physical activity, increasing
body fat and ubiquitous environmental stimulation (noise
and light pollution, commuting, often women’s multiple
obligations related to childcare, home and work demands)
and more frequent long-term use of combined hormonal
contraceptives, all increase the brain’s exposure to estradiol
and decrease progesterone exposure through subclinical ovu-
latory disturbances [31]. That context sets the stage for estra-
diol withdrawal that increases central norepinephrine (NE)
levels [17]. These high NE levels cause the thermoneutral
zone (TNZ, within which women feel comfortable) to narrow
to zero while it is normally a 0.4-degree Celsius range of basal
temperatures [17]. Estradiol treatment has been shown to
increase the upper bound of temperature comfort [32] in one
study, although without other confirmation to our knowl-
High Brain Estradiol Levels
Estradiol Withdrawal
Progesterone NOREPINEPHRINE
Narrowed
Thermoneutral
Zone
VMS
Drug Discovery Today: Disease Models
Fig. 3. This model of progesterone-estradiol balance and night
sweats and hot flushes shows that an estradiol-dominant brain
environment risks the estradiol withdrawal phenomenon that triggers
vasomotor symptoms (VMS) and elevated central norepinephrine
(NE) levels. Although both progesterone and estradiol widen the
narrowed thermoneutral zone characteristic of VMS, progesterone
suppresses while steady state estradiol stimulates NE. Stimulation
(black) !, Suppression ( ) .
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Vol. xxx, No. xx 2019
edge. Progesterone, in a heating study during the follicular
and the luteal phases of healthy premenopausal women by
Freedman [33] showed that the upper sweating threshold was
similar to that in asymptomatic women, thus documenting
that progesterone raises (or could restore to normal) the TNZ
upper bound [33]. Both progesterone and medroxyprogester-
one [34] raise basal temperature in asymptomatic menopaus-
al women and that may be part of how both progesterone and
MPA treat VMS. Cyclic progesterone therapy versus placebo
also decreased anxiety in a single cross-over randomized
controlled trial (RCT) in premenopausal women with pre-
menstrual symptoms [35].
Although evidence that higher estradiol levels increase NE
levels (also cortisol and ACTH levels) is found primarily in a
study of social stress in healthy young men wearing a 100m
estradiol patch [36], it fits with the generally activating effects
of estradiol in the brain. The evidence that progesterone
suppresses NE fits with its calming and anti-inflammatory
brain actions [37] (Fig. 3).
Although our primary purpose is to describe a paradigm
shift in understanding VMS in the context of the E2-P4
balance women’s health model, there are many ways in
which the hot flush/night sweat experience resemble an
addiction phenomenon related to estrogen [38]:

The brain must first be exposed to high levels of estradiol.

Estrogen withdrawal triggers a massive central nervous
system release of neurotransmitters and causes multisys-
tem discomfort.

Higher and higher levels of estrogen are sometimes needed
to produce effective control of VMS (tachyphylaxis).

Estrogen and other addictions likely act through the
metenkephalin-endorphin-gonadotrophin system in the
brain.

Addictions are improved by GABA actions to suppress brain
activation (as Progesterone does).
Estradiol
VMS are a neuroendocrine phenomenon [39]. Estrogens
modulate a host of cytokines and neurotransmitters, includ-
ing proinflammatory cytokines interleukin (IL)-1, IL-6, tumor
necrosis factor -a, cortisol, adrenocorticotropic hormone,
and luteinizing hormone (LH); the levels of all of these
increase simultaneously with a hot flush [40]. As estradiol
levels decrease in menopause, serotonin levels also decrease
by about 50%, causing an increase of norepinephrine which
disturbs the hypothalamic thermostat [14]. This is conven-
tionally described as narrowing of the TNZ, the core temper-
ature range in which women are comfortable [17]: outside of
TNZ, a heat dissipation response or a hot flush is triggered.
The release of numerous cytokines, neurotransmitters and
hormones during a hot flush or night sweat event causes the
aura (that seems to only occur in Very Early Perimenopause).
DDMOD-540; No of Pages 11
Vol. xxx, No. xx 2019
Other studies also show increases in the opiomelanocortin/
endorphin family of hormones are related to mood changes.
We now know that dropping estradiol levels are a trigger for
depression and anxiety in perimenopausal women [41]. We
hypothesize that these mood changes, and the sleep distur-
bances commonly associated with them, could maintain
elevated central norepinephrine levels, which may be why
VMS continue for years after the swinging estradiol levels of
perimenopause have become low and stable estradiol levels
during menopause. There is also evidence that hormones
such as those regulating gonadotrophin secretions in the
brain may related to VMS [42].
There is increasing evidence that Kisspeptin and related
neurotransmitters are also associated with VMS. Recent stud-
ies found that kisspeptin/neurokinin B/dynorphin signaling
system in the hypothalamus participates in the generation of
VMS, and is sensitive to estrogen withdrawal [43]. Without
suppression by estrogen, the expression of neurokinin B and
kisspeptin increase [44]. There is evidence that neurokinin B
induced hot flushes in healthy premenopausal women [45].
Menopause women who have had surgery-induced meno-
pause caused by bilateral oophorectomy, experience a very
sharp decline in estrogen and progesterone levels and are
more likely to report severe VMS than those with natural
menopause [46]. Women experiencing a later onset of VMS
may have reduced sensitivity of the hypothalamus to estro-
gen withdrawal and thus have reduced symptom perception
[47]. However, this hypothesis has not yet been investigated.
Even prospective epidemiologic studies cannot test the estra-
diol withdrawal hypothesis since perimenopausal changes in
the secretion of several hormonal and metabolic factors could
confound the effects of estradiol withdrawal [41].
Clinical risk factors for VMS
We now understand that night sweats and hot flushes usually
begin during what may be the earliest part of perimenopause
when menstrual cycles are still regular [6]. Because the hor-
monal environment and the clinical situations differ for
perimenopausal and menopausal women, we are discussing
risk factors for VMS in these groups separately.
Perimenopause VMS risks
Multiple factors are associated with the incidence of VMS.
Data from the Australian Longitudinal Study on Women’s
Health (ALSWH) found that women who are heavier, current
smokers, less educated or high-risk drinkers experience more
frequent VMS than those without these characteristics [48].
High body mass index (BMI) increases the risk of VMS in
perimenopausal women [49,50], in part it is related to the
insulating characteristics of subcutaneous fat [51]. In addi-
tion, at least in some cultures, women understand VMS to
mean ‘‘aging’’ which is related to infertility, and socially
undesirable changes in appearance and sexual attraction.
Please cite this article in press as: Fan Y, et al. Paradigm shift in pathophysiology of vasomotor symptoms: Effects of estradiol withdrawal and progesterone therapy, Drug Discov Today:
Dis Model (2020), https://doi.org/10.1016/j.ddmod.2020.11.004
Drug Discovery Today: Disease Models |
Therefore, there are social stresses associated with VMS expe-
rience, especially if women do not understand the distinction
between ‘‘becoming old’’ and the changes that occur during
perimenopause.
Menopausal VMS risk factors
In contrast to the increased VMS risk with higher BMI in
perimenopause [49,50], it was originally thought that thinner
menopausal women (especially those who were very lean)
had the most VMS [52]. However, peripheral fat can convert
androgens into estrogens and thus there might be less dra-
matic ‘‘estrogen withdrawal’’ in heavier women [53]. Besides,
a prospective study of the Peking Union Medical College
Hospital Aging Longitudinal Cohort of Women in Midlife
(PALM) between the ages of 37–53 found that a higher
baseline BMI was correlated with more daytime hot flushes
(p = 0.04), but was not statistically associated with more night
sweats (p = 0.18) [11].
Ethnicity and VMS risk
There also seems to be racial difference in the prevalence of
VMS. In cross-sectional studies, it was previously reported
that approximately 65% of White women experienced VMS,
compared to about 80% of African-American women and
40–50% of Asian women [54,55]. However, PALM found that
85% of Chinese women experienced VMS, but the mean
duration was 5.5 years or seemed to be for a shorter length of
time than has been reported in North American White or
African-American women with a mean duration of about 10
years [11]. The lower prevalence of VMS in Asian women
could potentially be due to shorter durations of VMS expe-
rience; thus, they could be missed by cross-sectional studies.
However, since the SWAN study showed fewer VMS in
Chinese and Japanese American women than in White
women in a prospective longitudinal investigation, the du-
ration issue cannot account for the apparent racial differ-
ences [55]. SWAN also found that fewer Chinese/Japanese
American women had difficulty paying for basics, and also
had higher education than Whites so social and economic
stress may also play a role. Another study, however, has
found that cytochrome P450 3A4 isoforms (CYP3A4) en-
zyme activity in Asian women differed compared with Cau-
casian women [58]. Since Cyp3A4 is responsible for
metabolism of gonadal steroids such as E2, Asian women’s
brains may be exposed to lower E2 levels during the pre-
menopausal years which may account for the apparent racial
difference in VMS [56]. In addition, fewer Japanese women
have used combined hormonal contraception (CHC) than
typical North American women because CHC was not avail-
able in Japan until the 1990s versus the 1960s for American/
Canadian women).
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Cigarette and alcohol use and VMS risk
Current smokers have an over 60% increased occurrence of
VMS [55]. Nicotine is a central sympathetic stimulant and
thus increases central norepinephrine (NE) [57]. As men-
tioned earlier, it is through central NE stimulation that the
thermoneutral zone (TNZ, the core temperature level within
which people normally feel comfortable without either
sweating or shivering [17]) is narrowed leading to increased
risks for VMS. Animal studies show the connection between
increased central NE and the TNZ. Freedman’s research has
clearly documented that those with narrow TNZ are those
who are at most risk for VMS [30].
Alcohol consumption is associated with an increase in
estradiol levels [40] in menopausal women. In perimenopaus-
al women, even a sip of alcohol is reported to trigger hot
flushes but this reaction seems to wane over time (based on
poorly documented clinical reports). However, a number of
studies have documented that alcohol consumption and
VMS have either no or only a modest association [58–60].
Psychosocial, economic and situational stressors and VMS
In contrast to the inconsistent role of alcohol, situational,
economic or other psychosocial stressors, including difficulty
paying for basics [49] are associated with an increased expe-
rience of VMS. There seems to be a ‘vicious cycle’ type
relationship between VMS and stress (Fig. 4). Not only do
VMS cause stress hormone release (as previously discussed),
higher stress hormones increase VMS frequency and result in
longer VMS lifetime durations [10,61,62]. However, the clear-
est association of situational stress (e.g., loud noises, interper-
sonal conflict, frustration, and time pressure) with VMS was
documented in a within-woman controlled laboratory study
Neurotransmitters
ACTH, cortisol stress
GnRH, LH
Endorphins
cytokines
Anxiety
Estradiol
VMS withdrawal
Fig. 4. The two major factors fundamentally responsible for causing hot flushes and night sweats (vasomotor symptoms, VMS) are estradiol withdrawal from
an estrogen-exposed brain and emotional stress. The estradiol withdrawal reason for hot flushes decreases over time while the stress etiology increases
because of a ``vicious circle” in which initial VMS releases stress-related neurotransmitters causing anxiety, depression and sleep disturbances that
perpetuate VMS. In addition, estradiol withdrawal is causal in some anxiety and depression which then increase central norepinephrine and thus the risk for
VMS.
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Vol. xxx, No. xx 2019
[61]. Healthy menopausal women reporting more than eight
VMS/day had objective assessment over two hours (with
galvanic skin response) and self-reported onset of VMS (by
pushing a buzzer) in two different physical and psychosocial
environments a few weeks apart. The laboratory session that
was a quiet and calm environment was associated with few
VMS; the alternate session with unexpected loud noises,
bright lights, violent films they were forced to watch and
other stressors were associated with more VMS [61]. But
decreasing the stress responses, or changing to less stressful
environments, seem to decrease VMS. There is some evidence
that things that decrease central stress (the relaxation re-
sponse, yoga breathing, acupuncture) could decrease VMS
[63,64].
Physical activity and exercise related to VMS
Exercise often raises the heart rate and may slightly increase
the core temperature; both of these changes lead us to expect
an increase in or triggering of VMS. Although a number of
studies have attempted to show that exercise training is
related to decreased VMS, the science is inconclusive at this
point [65].
Diseases related to VMS
Menopausal women with VMS have an increased risk of
coronary heart disease (CHD). A prospective cohort study
of 11,725 women followed for 14 years found a two-fold
increase in CHD in those women who reported having base-
line frequent hot flushes or night sweats compared with
women with mild or without VMS [66]. Another study
showed that VMS was independently associated with multi-
ple indicators of elevated cardiovascular risk and visceral
Depression
Central
Norepinephrine
Drug Discovery Today: Disease Models
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Vol. xxx, No. xx 2019
adiposity [51]. Interestingly, however, daytime VMS and
night sweats were differentially associated with cardiovascu-
lar risk factors in a cross-sectional analysis; night sweats but
not daytime hot flushes were related to higher blood pres-
sures [67]. Bone loss is another common effect of estradiol
withdrawal. Perhaps because VMS are associated with release
of cytokines and glucocorticoids that increase bone resorp-
tion, those menopausal women in the Women’s Health
Initiative observational cohort who had more VMS at base-
line versus those with few/none, adjusting for all differences,
were documented to have almost double the incidence of hip
fracture [68].
VMS could predict the subsequent onset of depressive
symptoms; the association was independent of markedly
changed reproductive hormones [39,69,70]. A SWAN study
found the association worked the other way and that baseline
depressive symptoms were associated with subsequent VMS
[55]. One association with the stress hormones and VMS is
that sleep is disrupted. Disrupted sleep also caused by and
causes increased stress hormones and this is modulated by
progesterone [71]. Furthermore, progesterone improves deep
sleep and decreases sleep latency in several randomized con-
trolled trials in men [71] and women [67,72].
Stress may trigger hot flushes; but women with emotional/
social stress may also be more sensitive to VMS and therefore
more frequently report it. However, the random-ordered
research study by Swartzman et al. (as described above) found
that the association between hot flush experience and stress
was not due to changes in report bias [61]. Women who
reported more depressive symptoms when initially
experiencing VMS, however, had a longer duration of VMS
[10]. A cohort study strongly suggested a link between hot
flushes and anxiety symptoms, and reported hot flushes
increased threefold in women with moderate anxiety and
nearly fivefold in women with high anxiety compared with
women without emotional symptoms [73].The anxiety scores
of women prior to the perimenopause also positively pre-
dicted their subsequent report of hot flushes eight to 12
months later [74]. Interestingly, the association between
VMS and emotional responses has not been clearly shown
for the experience of night sweats, likely because night sweats
are rarely recorded in most studies and by most tools.
Hormone therapy for VMS
Systemic menopausal hormone therapy (MHT), with estro-
gen alone or in combination with a progestin or progester-
one, is the most effective therapy for menopausal VMS [75].
Interestingly, and something rarely mentioned, is that estro-
gen-progestin therapy was statistically more effective than
estrogen-alone [75]. Extended use of MHT brings women
relief from persistent VMS and may also have positive bone
mineral density (BMD) effects and prevent fracture [76]. But
there is also a dramatic drop in BMD with estrogen discon-
Please cite this article in press as: Fan Y, et al. Paradigm shift in pathophysiology of vasomotor symptoms: Effects of estradiol withdrawal and progesterone therapy, Drug Discov Today:
Dis Model (2020), https://doi.org/10.1016/j.ddmod.2020.11.004
Drug Discovery Today: Disease Models |
tinuation [77,78] with an increased risk of fractures [79].
However, based on data from the Women’s Health Initiative
randomized, placebo-controlled hormone trials, discontinu-
ation of estrogen-dominant standard MHT (so the conjugated
estrogen dose was close to physiological but the progestin
dose was approximately a third of physiological, as in 0.625
CEE with 2.5 mg medroxyprogesterone acetate (MPA) or
estrogen alone leads to approximately 50% recurrence risk
of VMS of more intensity than at baseline, independent of age
and duration of use [80]. Women stopping MHT for the
treatment of VMS may experience troublesome withdrawal
symptoms with VMS frequency and intensity worse than
before they were treated [27,81].
Recently, more attention has focused on the potential effect
of progesterone alone on VMS treatment. Progestins have
primarily been used as a supplement for estrogen-alone therapy
to prevent endometrial hyperplasia and endometrial cancer in
women with a uterus. An RCT over one year of oral conjugated
equine estrogen (CEE, 0.6 mg/day) versus the progestin (MPA,
10 mg/day) in women treated immediately following premen-
opausal ovariectomy and hysterectomy for benign disease,
showed no difference in the effectiveness of the two therapies
[82]. Healthy menopausal women (1–10 years since their final
menstruation) with problematic VMS enrolled in an RCT were
also effectively treated by oral micronized progesterone (OMP,
300 mg at bedtime daily over three months) versus identical
placebo [67]. The same therapy, in an RCT in 189 women who
had menstruated within the last year and were thus in peri-
menopause, although underpowered, also showed evidence
OMP also decreased night sweats in perimenopause women
[83]. A post-hoc analysis of the progesterone for menopausal
VMS RCT [67] showed that those women with intense and
frequent VMS of more than 50 moderate to severe/week (called
Severe VMS according to the USA’s Food and Drug Administra-
tion criteria) were even more effectively treated by OMP [84]. In
addition, in contrast to the documented VMS rebound effects
of estradiol withdrawal, there was no rapid increase in VMS
with one months’ stopping OMP versus the increase that
occurred on placebo; women on placebo had VMS that had
increased to baseline levels by one month [84].
Moreover, clinical evidence (Prior, personal communica-
tion http://www.cemcor.ca/search/node/stopping%
20estrogen%20therapy) suggests that the sometimes unbear-
able rebound increases in VMS on stopping estradiol therapy
could be prevented by changing from a progestin to, or
adding, 300 mg of oral micronized progesterone at bedtime
daily, while keeping the estradiol dose the same until all VMS
are gone. Then, if the estradiol therapy dose is lowered by
about 10% every two to four weeks over many months, she
may be able to stop estrogen without VMS rebound. Prior’s
clinical experience is that night sweats are always effectively
treated that way but that stress-related daytime VMS may not
be totally eliminated. That strategy needs testing in a multi-
www.drugdiscoverytoday.com 7
DDMOD-540; No of Pages 11
Drug Discovery Today: Disease Models |
center, well-powered randomized controlled trial, ideally one
in which NE, cortisol and ACTH levels are measured.
According to the E2-withdrawal paradigm of VMS (see Fig. 3
[38]), there is evidence that estrogen increases [85] and proges-
terone may decrease addictions [86]. Because progesterone is a
natural hormone but the oral micronized progesterone (rather
than progestins) has been available for therapy for relatively
few years, there is short-term evidence for its cardiovascular
safety [87,88] but little long-term data. However, vaginal pro-
gesterone is now recommended for threatened miscarriage and
extended use during pregnancy [89]. It is also well documented
that OMP has beneficial effects on sleep without difficulty with
morning neurocognitive performance [72]. An RCT in premen-
opausal women on daily OMP documented it also decreased
anxiety [90]; that may be one way in which progesterone works
to improve VMS [71,72].
Although it remains controversial, since estradiol has been
the center of both concepts about and the treatment of VMS
for over six decades, progesterone may be able to provide
more physiologically safe and durable therapy. We will sum-
marize this paradigm shift in physiological understanding of
hot flushes/flashes and night sweats (VMS) by listing the
several reasons why progesterone may be advantageous over
estradiol as an effective therapy for VMS:

Progesterone can be stopped at any time and does not cause
a withdrawal VMS rebound [82];

Progesterone increases deep sleep [72] and decreases sleep
interruption [90]. It is the only known agent that causes
deep sleep (and anesthesia) without suppressing respira-
tion. As an aside, we believe it should be much more frequently
prescribed for those requiring palliative care.

Progesterone improves intrinsic endothelial function, the
fundamental cardiovascular system regulatory factor, sim-
ilar to, or to a greater degree, than does estradiol [87].

Progesterone does not cause increased arterial or venous
clotting, increased triglycerides or increased risk markers of
cardiovascular disease [88].

Progesterone can be safely given in perimenopause when,
because of already high and relatively non-suppressible
estradiol levels [18], exogenous estrogen therapy may be
risky [83].

Progesterone does not appear to increase the risks for breast
cancer when combined with estradiol based on a large
cohort study [91], human physiological studies [92,93],
and other basic science investigations [94].
Non-hormonal therapies
Non-pharmacological therapies
Mild VMS could be treated by avoiding specific triggers (such
as alcohol, caffeine, warm environments and spicy foods) and
facilitating heat dissipation by good ventilation and dressing
8 www.drugdiscoverytoday.com
Please cite this article in press as: Fan Y, et al. Paradigm shift in pathophysiology of vasomotor symptoms: Effects of estradiol withdrawal and progesterone therapy, Drug Discov Today:
Dis Model (2020), https://doi.org/10.1016/j.ddmod.2020.11.004
Vol. xxx, No. xx 2019
in layers of clothing that can be added or removed [95].
Clinical hypnosis caused a 74.2% reduction of hot flushes
incidence in an RCT of 187 symptomatic menopausal wom-
en, as well showing as improvements in mood and sleep [96].
Based on another RCT study, cognitive behavioral therapy
significantly reduced women’s assessment of VMS as a prob-
lem and also decreased night sweats frequency [97]. Current
evidences do not strongly support definitive beneficial effects
of acupuncture, exercise, yoga, mindfulness, relaxation,
paced respiration or black cohosh for VMS [98] although
these may carry other benefits and are unlikely to cause harm.
Conclusion
A majority of perimenopausal and menopausal women expe-
rience night sweats and hot flushes with many being impor-
tantly bothered by them. We have presented a new paradigm
for the pathophysiology of VMS: VMS result from estrogen-
withdrawal from a brain exposed to higher estradiol levels.
Therefore, those premenopausal women who have mean
higher BMI levels, have extended use of combined hormonal
contraceptives, have slower metabolism/excretion of estradi-
ol or were exposed to estrogen-acting environmental con-
taminants are likely to be at increased risk for VMS. The more
stressful life circumstances and the less emotional/social
resilience a woman has developed, the more likely she is to
experience and be bothered by VMS. The key role of increased
central NE in stimulating the thermal changes putting wom-
en at risk for VMS may relate to progesterone’s ability to
suppress and estradiol’s potential to stimulate NE levels. We
believe that a new and broader understanding of hot flushes
and night sweats must include their bidirectional relation-
ship with social/emotional/situational stress. In this model,
progesterone can effectively treat VMS, improve sleep, cause
no VMS rebound increase if it is stopped, and can aid women
who want to, or for health reasons should, stop estrogen
therapy to avoid the potential estrogen withdrawal rebound
when stopping estrogen-dominant VMS therapy. In conclu-
sion, estrogen withdrawal is the underlying cause for VMS in
this new paradigm based on the model of balanced proges-
terone and estradiol for women’s health. VMS treatments
should be individualized based on whether women are in
perimenopause or menopause and be based on high-quality
evidence to maximize benefits and minimize risks.
Source of funding
None.
Declarations of interest
None.
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