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The endocrinology of perimenopause: Need for a paradigm shift

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Perimenopause, rather than a time of declining estrogen, is characterized by three major hormonal changes that may begin in regularly menstruating women in their mid-thirties: erratically higher estradiol levels, decreased progesterone levels (in normally ovulatory, short luteal phase or anovulatory cycles), and disturbed ovarian-pituitary-hypothalamic feedback relationships. Recent data show that approximately a third of all perimenopausal cycles have a major surge in estradiol occurring de novo during the luteal phase. This phenomenon, named "luteal out of phase (LOOP)" event, may explain a large proportion of symptoms and signs for symptomatic perimenopausal women. Large urinary hormone data-sets from women studied yearly over a number of years in the Study of Women Across the Nation (SWAN) and in the Tremin data will eventually provide a more clear prospective understanding of within-woman hormonal changes. Predicting menopause proximity with FSH or Inhibin B levels is documented to be ineffective. Anti-Mullerian hormone levels may prove predictive. Finally, there is an urgent need to change perimenopause understandings, language and therapies used for midlife women's symptoms to reflect these hormonal changes.
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[Frontiers in Bioscience S3, 474-486, January 1, 2011]
474
The endocrinology of perimenopause: need for a paradigm shift
Jerilynn C Prior, Christine L Hitchcock
Endocrinology and Metabolism, Department of Medicine, and Centre for Menstrual Cycle and Ovulation Research (CeMCOR),
University of British Columbia, and Vancouver Coastal Health Research Institute, 2775 Laurel St, 4th floor, Vancouver, British
Columbia, Canada V5Z 1M9
TABLE OF CONTENTS
1. Abstract
2. Purpose, perspective and definitions
3.Ovarian changes of perimenopause
3.1. Estrogen changes-the paradox of perimenopause
3.2. Progesterone, ovulation and luteal phase changes in perimenopause
4. Hypothalamic-pituitary-ovarian feedback changes of perimenopause
4.1. Inhibin and control of perimenopausal follicle stimulating hormone (FSH)
4.2. Feedback loops, ovulation and the luteinizing hormone (LH) peak
5. Additional perimenopause hormonal changes in cortisol and catecholamines
6. Perimenopausal hormonal origins for common experience changes:
6.1. Heavy menstrual flow
6.2. Increased premenstrual symptoms
6.3. Weight gain
6.4. Night sweats/hot flushes
7. Perimenopausal hormonal changes and future health risks:
7.1. Cardiovascular disease
7.2. Breast and endometrial cancer
7.3. Osteoporosis and fracture risks
8. Summary and perspective
9. References
1. ABSTRACT
Perimenopause, rather than a time of declining
estrogen, is characterized by three major hormonal changes
that may begin in regularly menstruating women in their
mid-thirties: erratically higher estradiol levels, decreased
progesterone levels (in normally ovulatory, short luteal
phase or anovulatory cycles), and disturbed ovarian-
pituitary-hypothalamic feedback relationships. Recent data
show that approximately a third of all perimenopausal
cycles have a major surge in estradiol occurring de novo
during the luteal phase. This phenomenon, named “luteal
out of phase (LOOP)” event, may explain a large
proportion of symptoms and signs for symptomatic
perimenopausal women. Large urinary hormone data-sets
from women studied yearly over a number of years in the
Study of Women Across the Nation (SWAN) and in the
Tremin data will eventually provide a more clear
prospective understanding of within-woman hormonal
changes. Predicting menopause proximity with FSH or
Inhibin B levels is documented to be ineffective. Anti-
Mullerian hormone levels may prove predictive. Finally,
there is an urgent need to change perimenopause
understandings, language and therapies used for midlife
women’s symptoms to reflect these hormonal changes.
2. PURPOSE, PERSPECTIVE AND DEFINITIONS
Current care of midlife women is often informed
by outdated knowledge about the nature of perimenopause.
Recent scientific reviews (1-4) have concluded that
perimenopause is characterized by intermittently and
sometimes dramatically high levels of estrogen, lower
progesterone levels and disturbed hormonal feedback
loops. This evidence is in contrast with assumptions of
dropping or lower estrogen levels, and the casual use of the
term “estrogen deficiency” as a synonym for perimenopause.
Although we can easily link perimenopausal heavy flow with
both high estrogen levels and inadequate progesterone-related
endometrial effects (5), today this menorrhagia is commonly
treated with oral contraceptives that make it worse (6), or with
ablative surgeries of the endometrium or the uterus rather than
with effective high dose long-cycle progesterone/progestins
(7). Thus, although the major purpose of this review is to
highlight current new knowledge of the changing
endocrinology of perimenopause, we also want to contribute to
improved clinical care, education and research.
Our perspective is a complex integration of
several points of view—that of scientists studying the
confusing endocrinology of perimenopause and women’s
The endocrinology of perimenopause
475
Figure 1. The Stages of Reproductive Aging Workshop (STRAW) classification of women’s reproductive lives. Reproduced
with permission from (10).
changing daily experiences over time, as investigators
committed to knowledge translation from research into
clinical care, and as educators trying to change concepts
that may be prejudicial for women. One of us has also spent
40 years as a physician attempting to make the data
gathered in a clinical setting speak a scientific language (8).
Taxonomy, or the naming of things, is
fundamental for any field of science (9). We understand
that definitions not only arise from but also create concepts
that may prevent scientific advancement—for example,
with the diagnosis of hysteria, which was formerly thought
caused by the uterus flying throughout the body. There is a
danger in prematurely naming incompletely understood
phenomena, but it is a necessary part of the scientific
process. However, clear definitions are essential for this
paper and for our purpose. Therefore, building on the work
performed by numerous investigators and the Stages of
Reproductive Aging Workshop (STRAW; 10; Figure 1),
we will create and justify definitions that fit with what we
now know (see Table 1).
For the purposes of this review we define
perimenopause as the entire transitional period from
women’s mature reproductive to a non-reproductive state.
Thus, as shown in Figure 2, perimenopause begins when
the estrogen levels have already begun to rise and
progesterone levels have decreased but cycles continue to
be regular (11). We have postulated a clinical definition of
changes in women’s experiences any three of which will
make the diagnosis of perimenopause. It is likely that
perimenstrual cyclic night sweats without daytime
vasomotor symptoms is sufficient unique that it, alone, may
be diagnostic. This clinical diagnostic tool (Table 2) needs
to be validated against the final menstruation prospectively
in a population-based sample. This diagnosis of
perimenopause in women with regular cycles is
controversial because all of the current taxonomies define
the onset of women’s midlife transition by decreases in the
regularity or frequency of menstruation (10; 12; 13) yet by
the onset of irregular cycles, women have usually
experienced several years of hormonal changes typical of
perimenopause and their associated symptoms.
Perimenopause ends, as adopted by STRAW,
one year beyond the final menstrual flow (10). Thus,
perimenopause as defined here encompasses part of the
STRAW “late reproductive stage,” the early and late
menopause transition stages and one year beyond the final
menstrual flow (Figure 2).
The end of perimenopause also defines the onset
of what we prefer to call menopause (rather than
postmenopause, which relies on the use of the word
“menopause” to mean the retrospectively defined literal
final menstrual period). This taxonomy avoids the
inappropriate dual naming of the year following the last
menstrual flow as both “postmenopause” and
“perimenopause” that both the WHO and STRAW schema
preserved (10; 14). Menopause, in our understanding,
although it is also a hormonally complex and an
experientially changing life phase, is the state within which
women achieving it then permanently reside.
3. CHANGES IN OVARIAN STEROIDS DURING
PERIMENOPAUSE
Before discussing the hormonal changes of
perimenopause it is important to state clearly that our
normal referent is the endocrinology of the premenopausal
normally ovulatory cycle (15; 16). Ideally, all studies of
perimenopausal hormonal changes would have a within-
The endocrinology of perimenopause
476
Table 1. Reproductive Life Cycle Definitions
Premenopause – Women’s life phase from the onset of menstruation until
the beginning of perimenopause.
Perimenopause – This term encompasses the entire transitional period of
women’s reproductive aging from the onset of cyclic night sweats or other
characteristic changes (see Table 1) in regularly menstruating women until
one year past final menstruation. Perimenopause includes part of the Late
Reproductive Age (as per Stages of Reproductive Aging Workshop,
STRAW), all of Early and Late Menopausal Transition and the year
following the last menstrual flow.
Menopause – The remainder of a woman’s non-menstruating life, beginning
one year following the last menstruation. (Note that this women’s life phase
is called by some, “postmenopause” to fit with the past use of the term
“menopause” as the final menstrual period.)
Late Reproductive Age – as defined by STRAW, includes older regularly
menstruating women (who in STRAW were required to have elevation of
follicle stimulating hormone [FSH] levels—although these were not
operationalized).
Early Menopausal Transition – as defined by STRAW, women over age
35 with variable menstrual cycle lengths (variability of 7 or more days) but
who have not yet started skipping menstrual periods. The ReStage
Collaboration has further operationalized this definition to having a
difference in consecutive menstrual cycle lengths of at least 7 days, at least
twice within a year.
Late Menopausal Transition – as defined by STRAW, women over age 35
who have skipped a menstrual cycle and have elevation of follicle
stimulating hormone levels—although high FSH levels were not
operationalized in STRAW. With the ReStage Collaboration analysis of
prospective cohort data, a cycle of 60 days or longer is taken as the onset of
the Late Menopausal Transition.
Table 2. Midlife women with regular menstrual cycles may
have a diagnosis of perimenopause if they experience any
three of the following experience changes.
1. New onset heavy and/or longer flow
2. Shorter menstrual cycles (25 days)
3. New sore, swollen or lumpy breasts
4. New mid-sleep wakening
5. Increased cramps
6. Onset of night sweats, in particular premenstrually
7. New or markedly increased migraine headaches
8. New / increased premenstrual mood swings
9. Weight gain without changes in exercise or eating
Reproduced with permission from (11)
center premenopausal control group that is similar in body
mass index, racial mixture and dietary and activity
variables.
3.1. Estradiol changes—the paradox of perimenopause
The word “menopause” is commonly used as
inclusive of both women’s midlife transitional phase and
the stable non-reproductive phase. Because estradiol is
truly low beginning about a year after the final menstrual
flow, it is assumed that during perimenopause levels must
be dropping. Teleologically, the functional requirement in
perimenopause is to rid the ovary of hormonally responsive
follicles that could be stimulated by FSH later in life (17).
Anatomical studies have found an increased rate of
recruitment of small follicles that undergo atresia—this
starts about age 37 (17). At the same time estradiol levels
become, on average, higher. Many of the symptoms of
perimenopause are also associated with unusually high
levels of estradiol. Thus perimenopause is a time during
which estradiol levels become erratic and often high before
eventually becoming lower than in reproductive-aged
women.
Santoro and colleagues were the first to state the
then-radical notion that estradiol levels were higher in
perimenopause (18). This observation was based on a
cross-sectional single cycle, daily urinary hormone study
published in 1996 showing significantly higher levels
especially during the luteal phase (Figure 3). This
observation was confirmed by a meta-analysis comparing
samples from premenopausal women to perimenopausal
women within the same research center; average estradiol
levels were statistically higher in perimenopausal women
(4). Not one of the primary studies from which these data
were extracted had the power to see significant differences
or even noted these higher levels (4). Most remarkably, the
cross-sectional analysis of data from an excellently
designed, population-based study of perimenopausal
women aged 45-55 was summarized as a “decrease in E2. .
.levels” (19), despite abnormally high and hugely variable
follicular phase serum estradiol levels (Figure 4). This
inability to “see” data other than what is expected (20)
appears to persist, especially about the higher estradiol
levels of perimenopause.
The meta-analysis, previously mentioned, of
follicular and premenstrual estradiol levels from studies
published before 1998 showed that perimenopausal mean
serum estradiol levels are 29% higher in the follicular
phase and 22% higher in the premenstruum than in
premenopausal women (4). We now know that estradiol
levels are dramatically higher in some cycles and for some
of the time (21). Although it is hard, yet, to put into a
population perspective, in their prospective observational
study, Hale and colleagues estimate that about a third of all
menopausal transition cycles show evidence of “luteal out
of phase” (LOOP) events, meaning, as shown in Figure 5,
that a second, and usually higher estradiol peak appears
after the normal midcycle estradiol peak (21). It is not yet
known whether LOOP events are the primary explanation
for the erratically higher estradiol levels of perimenopause.
3.2. Progesterone, ovulation and luteal phase changes in
perimenopause
By contrast with the higher levels of estradiol,
lower levels of progesterone characterize perimenopause.
These lower levels arise through three mechanisms: 1)
decreased progesterone production within normal-length
ovulatory cycles; 2) shortened luteal phase lengths within
ovulatory cycles; and 3) more frequently anovulatory
cycles. The evidence about perimenopausal changes in
ovulation and luteal phase lengths are sparser than the now
extensive literature on the higher and erratic estradiol levels
of perimenopause, and none are from population-based
samples (22). Early observers such as Metcalf using
once/week urinary pregnanediol excretions (PdG)
documented that only 37% of irregular perimenopausal
cycles were ovulatory (23). Likewise using classical (non-
quantitative) basal body temperature, Doring showed that
ovulatory cycles only occurred in 50% of cycles in women
ages 46-50 (24), and Vollman by quantitative basal
The endocrinology of perimenopause
477
Figure 2. This figure illustrates women’s reproductive aging and the midlife transition from reproductive to non-reproductive
status, including definitions of perimenopause and menopause used in this review.
Figure 3. Daily urinary hormone data in a cross-sectional single-cycle study showing that urinary estradiol excretions are higher
and progesterone excretions are lower in regularly cycling perimenopausal (open circles) compared with premenopausal (closed
circles) women. Reproduced with permission from (51).
temperature (QBT) (25) noted ovulatory disturbances
(meaning short luteal phases and/or anovulatory cycles)
were significantly increased with increasing gynecological
age over 35 years. Illustrative prospective QBT data that
are valid against PdG, in one woman with regular cycles
documented over more than 10 years showed that, in cycles
that averaged 29r2 days long, only a single cycle out of a
series of 14 had a short luteal phase length (8%) with no
anovulatory cycles when she was in her mid-30s. However,
10 years later her regular cycles were shorter (27r2 d) but
now 86% of cycles showed short luteal phases and 14%
were anovulatory (22).
Several longitudinal studies have monitored
ovulatory characteristics in perimenopause. Hale and
colleagues from Australia (26) used thrice-weekly serum
samples over a single cycle in a convenience sample
comparing four groups: mid reproductive (controls), late
reproductive, early menopausal transition, and late
menopausal transition (26). They found lower progesterone
levels in perimenopausal ovulatory cycles as well as higher
estradiol levels (26). Other studies have used analysis of
urinary hormone metabolites, which are more easily
obtained, but absolute levels must be interpreted with
caution, because of genetic variability in steroid
metabolism (33).
Miro and colleagues presented the results of the
British FREEDOM study (Fertility Recognition
Enabling Early Detection Of Menopause), a convenience
sample using daily first morning urines provided by 103
women prospectively studied over six to 18 months (27).
Results showed that some women with increased urinary
FSH levels but still regular cycles had higher PdG
excretions than did women who were premenopausal,
however, luteal phase lengths are not described (27). In
The endocrinology of perimenopause
478
Figure 4. Serum estradiol levels from a cross-sectional population-based sample of women ages 45-55 organized by categories:
I. no changes in cycle length or flow, II. changes in flow only; III. changes in cycle length only; IV. changes in both flow and
cycle length; and V. those who were three to 12 months since the last menstruation. The figure is adapted from Burger and
colleagues (19). Two added lines indicate the mid-follicular mean of estradiol levels and the mean midcycle peak estradiol levels
as established in the same laboratory in premenopausal women.
Figure 5. Aberrant and extremely high estradiol levels occur during the luteal phase of ovulatory perimenopausal cycles. These
luteal out of phase (LOOP) events appear to occur in about one-third of cycles in the early and late menopausal transition stages
of perimenopause. Reproduced with permission from (21).
general normal-length ovulatory cycles had higher PdG
levels than “delayed” ovulatory cycles in what would be
the early menopause transition by STRAW. In subsequent
reproductive stages PdG decreased as estrogen excretions
(E1G) increased (27).
The Study of Women Across the Nation
(SWAN) prospectively followed a multiethnic cohort of
over 3,000 women ages 42-52 from seven centers in the
USA. Some were invited to join a daily hormone sub-study;
of these, 840 collected daily first morning urines for 50
days/y. The majority of cycles (81%) met criteria for being
ovulatory (28; 30). Women with ovulatory cycles were
further separated into those who were still menstruating
regularly (late reproductive age) and those who had skipped
a menstrual period. Within ovulatory cycles, women in late
menopausal transition had higher excretions of
gonadotrophins, lower PdG and no difference in E1G (30).
Anovulatory cycles were separated into three forms:
normal midcycle peak of estrogen followed by an LH peak
but not by PdG, a normal midcycle estrogen peak not
followed by an LH peak, or no evidence of usual midcycle
events suggesting that anovulation and low progesterone
production were related to various kinds of hypothalamic-
pituitary ovarian feedback disturbances (28). Of women
starting with regular ovulatory cycles, having
oligomenorrhea and anovulation (in data truncated at 50
days) was a strong predictor of being in the late
perimenopause stage. In regular cycles, anovulation
continued at about 10% of all cycles. However, within
The endocrinology of perimenopause
479
Figure 6. Urinary progesterone excretion (PdG) levels over
time by age and years since baseline in the Study of
Women across the Nation. Reproduced with permission
from (29).
ovulatory cycles PdG levels decreased by about seven
percent per year (29; Figure 6). Obesity and greater
education were associated with lower PdG levels (29).
Finally, the Biodemographic Model of
Reproductive Aging (BIMORA) study of the Tremin
longitudinal menstrual cycle data collection in college-
educated Caucasian women asked 156 women to collect
daily first morning urines over six months (January to July)
yearly for five years (31). Assessment of gonadal steroids
primarily focused on reporting estrogen excretions that
were not counterbalanced by PdG—this “unopposed”
estrogen exposure increased during the menopausal
transition because the 95th percentile for estrogen remained
the same while ovulatory cycles and the amount of PdG
were decreasing (32). This perimenopausal increased
estradiol to progesterone ratio is similar to the observations
made earlier by Metcalf and MacKenzie (34).
In summary, in perimenopause both older studies
employing QBT and more recent studies monitoring serum
and urinary hormones have found decreasing levels of
progesterone within ovulatory cycles and a rising incidence
of ovulation disturbances. Ovulatory cycle progesterone
production decreases gradually but continuously with
progress toward menopause. Estrogen production
unopposed by appropriate progesterone production has
been documented in one of the earliest (34) as well as one
of the most recent studies of the endocrinology of
perimenopause (32). In contrast to menopause, when both
estrogen and progesterone are low, in perimenopause the
two primary ovarian steroids are changing in opposite
directions—estradiol levels higher and progesterone levels
lower. These changed ovarian steroid hormone levels and
ratio would be expected to increase women’s risk for both
endometrial (35) and breast cancer (36). It remains to be
seen what contribution these changing steroid ratios make
to women’s midlife experiences and risk factors for
subsequent menopausal health.
4. HYPOTHALAMIC-PITUITARY-OVARIAN
FEEDBACK CHANGES OF PERIMENOPAUSE
Recent research has clarified that the primary hormonal
changes of perimenopause result not only from the “aging
ovary” but also from disruption of the usual positive and
negative hormonal and paracrine feedback networks
controlling the normal ovulatory menstrual cycle. The
evidence for these changes in control mechanisms will now
be briefly discussed.
4.1. Inhibin and control of perimenopausal follicle
stimulating hormone (FSH)
We initially postulated that the higher estradiol
levels in midlife women represented “perimenopausal
endogenous ovarian hyperstimulation” (4). The term
“endogenous” indicates that these changes occur from
within a woman’s reproductive system. The term “ovarian
hyperstimulation” is used by analogy with that of ovulation
induction for in vitro fertilization that can create extreme
estradiol levels and medical emergencies. Higher estradiol
levels normally act to suppress rising FSH levels; in
perimenopause this feedback fails, particularly at the
follicular-luteal transition.
The prime mover in the feedback disruptions that
result in the hormonal changes of perimenopause is now
confirmed to be Inhibin B. At the point at which each ovary
contains fewer than 100 follicles (2), Inhibin B levels,
made by small antral follicles, decline and no longer hold
early cycle FSH level in check. This, in turn, leads to
increased recruitment of follicles, each of which contributes
to the increasing estradiol levels. Important prospective
studies in a few women show decreases in Inhibins A and
B and progesterone levels but maintained estradiol
productions (37). That observation has been confirmed with
sophisticated multiple linear regression studies of FSH and
luteinizing hormone (LH) and their relationships with
Inhibins A and B and their complex relationships with
estradiol and progesterone (37; 38). These studies confirm
the role of declining Inhibin B levels in allowing FSH to
rise in the follicular phase. Elevated FSH, in turn, appears
to stimulate the second estradiol peak called LOOP during
the luteal phase (38). Because normally ovulatory
progesterone levels may prevent a further cohort of follicles
from becoming stimulated enough to cause a second mid-
cycle like estradiol peak, this is further evidence of
hypothalamic-pituitary-ovarian feedback disruption.
Although there are yet no clear feedback roles
for anti-Mullerian hormone (AMH) in the feedback and
control of perimenopausal changes, several studies from the
same Australian group highlight the dropping levels of
AMH across the perimenopausal transition (26; 38). Anti-
Mullerian hormone is produced by granulosa cells from
small follicles and levels are parallel with the number of
remaining ovarian follicles as measured by antral follicle
counts (on transvaginal ultrasound). Research suggests that
AMH is highly reproducible at the same cycle phase (39),
and is basically stable across the menstrual cycle (40). In
addition, AMH levels decline over time in within-woman
studies at ages 36 and 40 (41). It appears clear that lower
The endocrinology of perimenopause
480
AMH levels provide a more reliable biomarker of
approaching menopause than any other known measure
(42). However, at the present moment whether or not AMH
plays a role in the disturbed hormonal feedback loops in
perimenopause is unknown (38).
4.2. Feedback loops, ovulation and the luteinizing
hormone (LH) peak
The just discussed FSH changes relate to the
control of estradiol in both the follicular phase, and also
during the luteal phase in the form of LOOP events.
However, there are additional changes in the control of
ovulation and progesterone production that appear to relate
more to the hypothalamic-pituitary-axis than to ovarian
aging. An elegant description of SWAN daily urinary
hormone data in cycles without evidence of luteal activity
(anovulatory) shows that both estradiol and LH peaks can
be normal but ovulation still not occur (28). One might
speculate, given the strong negative associations between
FSH (controlled for LH) and progesterone shown in the
Australian analysis, that higher FSH levels might interfere
with release of an egg and progesterone production (38).
That phenomenon also can occur in premenopausal cycles
but appears to be more common in perimenopause.
Additional perimenopausal feedback imbalances
leading to anovulation involve disturbances of estradiol’s
positive feedback on LH such that a normal estradiol peak
occurs but an LH peak does not follow (28). Finally, cycles
may have no evidence of either an estradiol or an LH peak
despite high follicular phase estradiol levels—there is also
no ovulation (28). Thus there can be no doubt that the
hypothalamus or pituitary can become insensitive to
estradiol feedback resulting in anovulation.
5. ADDITIONAL PERIMENOPAUSE HORMONAL
CHANGES—CORTISOL AND CATECHOLAMINES
To our knowledge there are no prospective
studies of the autonomic and sympathetic system and
cortisol stress hormone changes across the perimenopause.
It is accepted that perimenopausal women are more likely
than premenopausal women to report “mood swings” and
various symptoms (tachycardia, chest pain, dry mouth,
tingling, panic attacks) that are related to a stress
response—further research should investigate whether
associated hormones such as cortisol or
Adrenocorticotrophic Hormone (ACTH) and/or
sympathetic nervous system responses (such as
norepinephrine) also show increases during perimenopause.
Moreover, the most symptomatic women in
perimenopause even more commonly describe stress-
related symptoms. Given this, it would be surprising if
cortisol and catecholamine levels were not higher in
symptomatic perimenopause, and higher levels of estrogen
may be responsible. In an experimental study, healthy
young men wore either a transdermal estradiol patch or
placebo and 24-48 hours later were subjected to the Trier
Social Stress Test (43). Those men wearing the estradiol
patch experienced greater increases than controls in
cortisol, ACTH and norepinephrine to the social stressors
of the testing (43). Elevated endogenous estradiol is a
potential mechanism to explain the experience women have
of being less able to cope with stress than they were earlier
in their lives. However, further changes in hypothalamic-
pituitary responses may also play a role. Certainly women
with disturbed sleep and vasomotor symptoms may
experience greater stress hormone responses (as discussed
below).
6. PERIMENOPAUSAL HORMONAL ORIGINS FOR
COMMON EXPERIENCE CHANGES
There is a shared hope among physicians and
midlife women that “a test” will tell them whether or not
they are in perimenopause, if they are now menopausal (if
they have had a hysterectomy, for example), or how close
they are to becoming menopausal. Some physicians use the
level of serum FSH level early in the cycle (say cycle day
3) as a test for perimenopause. For an individual woman,
however, FSH is neither sensitive nor specific (44). There
are hopes that the AMH will prove to be useful for deciding
about proximity to menopause but further validation is
needed.
The hypothesis that elevated perimenopausal
estradiol levels were behind perimenopausal experiences
was based on clinical observations of estrogen-associated
experiences (increasingly heavy flow, increased
premenstrual symptoms, mastalgia, fluid retention, weight
gain) in cycles documented with the Daily Perimenopause
Diary (45) and QBT (46). Cycle lengths tend to shorten in
older, regularly menstruating women and the follicular
phase becomes shorter (47). Shortened follicular phase
lengths are associated with higher early cycle serum
estradiol levels (16) and with higher urinary FSH levels in
both follicular and late luteal phases (48).
6.1. Heavy menstrual flow
The best evidence linking symptoms to high
estrogen comes from the analysis of very heavy flow
(menorrhagia) (5). In a clinical study, 28 women over age
40 with heavy and/or heavy irregular flow were age-
matched (r 2 years) with 28 women with regular cyclical
bleeding. Estradiol and FSH levels were measured in a
standardized way in all women showing that, although FSH
levels were not different, estradiol levels were almost
doubled in those with heavy flow (5). Twenty of the
women with heavy flow had endometrial biopsies and 50%
of these showed endometrial hyperplasia, also suggesting
progesterone deficiency may have played a role in the
heavy flow (5).
A recent quantitative study of the amount of flow
during two consecutive menstruations in the Australian
study by Hale and colleagues shows that flow increases in
absolute amount and in variability from mid- to late-
reproductive and across until the late menopausal transition
(49). Flow was over 250 ml/menstrual period in women in
the late perimenopause who experienced an ovulatory cycle
with very high estradiol levels or the unique LOOP
phenomenon (49). Thus two studies strongly associate
The endocrinology of perimenopause
481
Figure 7. Body mass index (BMI) changes in men (left)
and women (right) in the population-based Canadian
Multicentre Osteoporosis Study. Note the gender difference
in the pattern with a marked increase in the ages 45-55
decade for women. Reproduced with permission from (49).
higher estradiol levels with clinically and
absolutely heavy menstrual flow (5; 49).
Although heavy flow in perimenopause is
commonly attributed to fibroids, it is rare for this benign
tumor, originating in the uterine muscle, to impinge on the
endometrium. Rather heavy flow and fibroids co-occur
because both are associated with higher estradiol and lower
progesterone levels.
6.2 Increased premenstrual symptoms
We have previously suggested that the midlife
increase in premenstrual symptoms is a result of the higher
estradiol levels of regularly cycling women in very early
perimenopause (50). Increased premenstrual symptoms also
predict night sweats or hot flushes (51; 52). In healthy
ovulatory young women (mean age 33), we found no
hormonal relationship, however, with premenstrual mood
symptoms (53). Although the exact combined hormonal
and sociocultural etiologies of premenstrual symptoms are
unclear, prospective within-woman data relate them to
cycles with higher estradiol/lower progesterone levels (54)
that are characteristic of the ovarian hormone changes in
perimenopause. However, studies are inconsistent and
contradictory, and the relationship between mood and
hormones is not clear.
6.3. Weight gain
Whether or not the metabolic changes (weight,
body mass index [BMI], waist circumference, blood
pressure and cardiovascular adverse lipid changes) that
increase in midlife women bear any relationship to the
hormonal changes of perimenopause is currently unclear.
The prospective daily urinary hormone study in SWAN
found, however, that estradiol levels were not different in
those with and without a diagnosis of the metabolic
syndrome (29). What is quite clear, however, is that the
BMI increases that occur in the population across ages 25-
50 differ in men and women (55; Figure 7). Using
prospective data from the randomly selected men and
women in the 9243-strong Canadian Multicentre
Osteoporosis Study, men have a gradual BMI increase after
age 25 whereas women’s BMI remains stable until it
increases dramatically between ages 35-44 and ages 45-54.
The majority of women ages 45-54 in the population will
be in perimenopause, given that menopause occurs on
average at age 52 in women without hysterectomy or
ovariectomy (55). This is a strong suggestion that there are
gender differences in the metabolic changes that occur
during the 40s and 50s.
6.4. Night sweats/hot flushes
Although night sweats are often labeled as
“estrogen deficiency symptoms”, they are present in
midlife women who continue to have regular menstrual
cycles (and usually called “premenopausal” in surveys)
(45). The initial large survey of hot flushes in women noted
that seven women volunteered that their night sweats were
cyclic and occurred around flow (56). In an observational
study of Daily Perimenopause Diary¤ data from our
laboratory, we observed not only that night sweats
predominated over daytime hot flushes/flashes (vasomotor
symptoms, VMS) but that they had a cyclic character with
increased prevalence before or during menstruation (45).
Whether night sweats occur in cycles with greater
downward estradiol swings and higher average estradiol
levels, as we postulate, is not currently known—we are
currently performing a daily urine study to explore
hormonal relationships with night sweats in very early
perimenopausal women with regular cycles.
7. PERIMENOPAUSAL HORMONAL CHANGES
AND FUTURE HEALTH RISKS
7.1. Cardiovascular disease
Heart diseases and stroke (together called
cardiovascular disease or CVD) are considered by health
experts to be the leading killer of women in North America
although they don’t enter most perimenopausal women’s
consciousness and predominantly occur for much older
women. However, it is important to ask the question
whether the hormonal changes of perimenopause increase
or decrease the risks for menopausal CVD. If the notion
were correct that estrogen treatment earlier rather than later
The endocrinology of perimenopause
482
in menopause is protective against CVD, one could
postulate that those with the highest perimenopausal
endogenous estradiol levels would have the least
subsequent CVD. Unfortunately, to date, no studies that
have carefully characterized endogenous estradiol levels or
tracked estradiol/estrogen treatment in perimenopause have
subsequently observed the cohort for the development of
CVD.
However, there are new data suggesting that
lower perimenopausal progesterone levels may be related to
subsequent CVD. Before sharing data from that study it is
useful to remember there are mechanisms through which
progesterone may decrease CVD. Intra-arterial progesterone
compared with intra-arterial estradiol has been shown to
equally improve endothelial function in a random-ordered
vehicle-controlled experiment in 28 healthy women who were
recently menopausal (57). Oral micronized progesterone also
lowers blood pressure (58) and appears lipid neutral when
given with estradiol (59). The strongest data relating
progesterone to subsequent CVD are from a nested case
control study from the Netherlands in which menstruating
women of mean age 47 collected first morning urines for
hormone levels on cycle day 22 of three consecutive cycles in
1982-86. All new myocardial infarctions among women in
the same community were observed through 1991 to
determine perimenopausal CVD risks (60). Forty-five
women had acute myocardial infarction and in these versus
controls, estrogen and testosterone excretions and other
reproductive variables did not predict heart attacks over
approximately eight years (60). However, those with lower
progesterone levels and with probable anovulatory cycles
tended to be more likely to have a heart attack during
follow-up (smoking-adjusted odds-ratio: 1.3, 95% CI 0.3-
3.7). With longer follow-up and an increased incidence of
heart attack these data are likely to become stronger.
7.2. Breast and endometrial cancer
In contrast to CVD, midlife women are very
concerned about breast cancer because most women have
known someone who developed it or died from it. Given
that two randomized controlled trials show that breast
topical estradiol treatment stimulates and progesterone
treatment inhibits human breast cell proliferation and cell
division (61; 62), the increased frequency of
perimenopausal days of estradiol unopposed by
progesterone (32; 34) should increase breast cancer risk.
Consistent with those data, higher perimenopausal
progesterone levels in a case-control study were associated
with a lower risk for breast cancer in the European
Prospective Investigation into Nutrition and Cancer study
(odds-ratio: 0.61, 95% CI 0.38, 0.98) (63). Finally, women
in their 40s (mostly perimenopausal) are more likely than
women in their 50s (mostly menopausal) to develop
interval breast cancer between screenings (64; British
Columbia Cancer Agency data). The strongest data
suggesting that the lower progesterone levels of
perimenopause may pose a breast cancer risk are from the
large E3N cohort in which menopausal women treated with
estradiol without progesterone had an increased breast
cancer risk that did not occur when estradiol plus
progesterone was the treatment (36).
Perimenopausal women appear little concerned
about endometrial cancer, perhaps because it is less
prevalent than breast cancer. Unopposed estrogen as a
pharmacological therapy is a well recognized risk factor for
endometrial cancer. Metcalf and MacKenzie (34) and
O’Connor and colleagues (32) found that endogenous
estrogen unopposed by progesterone was common in
perimenopause. In addition, perimenopause has been
identified as a “window of risk” for endometrial cancer
(35). Further research is needed into whether
perimenopausal exposure to high estradiol and low
progesterone levels predicts subsequent risk for
endometrial cancer.
7.3. Osteoporosis and fracture risks
Although the common belief has been, and still
may be, that bone loss and fractures begin in women with
estrogen deficiency who are menopausal, there is
incontrovertible evidence that rapid bone loss begins in
perimenopause (65-68). This is a paradox because of the
higher estradiol levels earlier outlined. However, these
observations fit perfectly with newer understandings of
bone physiology—downward swinging estradiol levels
release cytokines and increase RANKL that causes
increased bone resorption. In a meta-analysis of spinal
bone change observed in perimenopausal versus women
early in menopause we documented a mean rate of bone
loss of –1.8% per year in perimenopause that exceeded the
rate of –1.2 % in early menopausal women (4).
Although it is predominantly bone resorption that
determines bone loss and fracture (69), it has becoming
increasingly clear that endogenous progesterone levels
increase bone formation and contribute with estradiol to
positive premenopausal bone change (70-72). An ongoing
prospective study in Munich is documenting QCT spinal
bone change prospectively (67). This group is now
observing the prevalence of ovulatory cycles in relationship
to bone change and showing greater bone loss in those with
fewer normally ovulatory cycles (73). These data strongly
suggest that the perimenopausal years—with swinging
estradiol levels leading to increased bone resorption and
lower progesterone levels causing less formation—set the
stage for menopausal osteoporosis and fracture.
8. SUMMARY AND PERSPECTIVE
This review has presented evidence that demands
a shift in the paradigm about perimenopausal changes.
Perimenopausal women are not estrogen deficient; rather
they have physiologically high and erratic levels of
estrogen. Many of the clinical presentations of
perimenopause are related to these high levels of estrogen,
particularly heavy menstrual bleeding, breast tenderness
and an increased response to psychological stressors.
Moreover, perimenopausal estrogen is also poorly
suppressible, because of impaired feedback mechanisms.
The second ovarian hormone, progesterone, is largely
ignored in the literature, but is clearly low compared with
what was normal earlier in life. Lower progesterone levels
or the abnormal ratio of estrogen and progesterone also
likely causes many perimenopausal symptoms.
The endocrinology of perimenopause
483
In the absence of relevant perimenopausal
clinical trials, clinicians have extrapolated from studies of
menopausal women to menstruating perimenopausal
women whose hormonal circumstances are very different. The
practice of prescribing estrogen (as menopausal hormone
therapy, or as oral contraceptives) to perimenopausal women
makes little physiological sense, and may cause harm. A few
clinicians (including the first author) have instead prescribed
progesterone as a monotherapy in perimenopause. Clinical
trials have demonstrated that progesterone and progestins are
effective therapies for heavy flow and progesterone improves
sleep fragmentation. In clinical practice progesterone has also
proved effective for many other issues in perimenopause,
especially hot flushes. Clinical trials are needed to address
other therapeutic uses of progesterone as a monotherapy in
perimenopause.
The hormonal changes of perimenopause plus the
onset of the reduced social status associated with aging in
western culture make perimenopause a complex transition.
However, it can also be a time of increased self-awareness and
adaptation that can bring women feelings of improved self-
worth. Should the perimenopausal changes that women notice
not be explained and appropriately named, this can interfere
with potential adaptation and resilience (74). There is urgent
need for controlled trial research into therapies for the
consequences of perimenopausal endocrine changes. A
number of the current medical responses to perimenopausal
symptoms and signs are no longer appropriate. For example,
when a perimenopausal woman is told that she is “too young”
to be having night sweats, or that she must be imagining things
if she becomes symptomatic while she is still regularly
menstruating, when her heavy flow is treated with
hysterectomy rather than proven non-surgical strategies (7),
when she is given therapies such as combined hormonal
contraceptives with additional estrogen that add to her already
erratically high endogenous estrogen, there may well be harm
(6). Even within a purely clinical framework, the use of
ineffective therapies or ones that make women feel worse
have the potential to damage the clinician-patient
relationship going into midlife and thus to decrease the
potential for healthy aging. Within the broader context of
women’s lives and of recent perimenopausal endocrine
research findings, there needs to be a paradigm shift.
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Abbreviations: LH, luteinizing hormone; FSH, follicle
stimulating hormone; QBT, quantitative basal temperature;
QCT, quantitative computed tomography (for bone
density); AMH, anti-Mullerian hormone; ACTH,
adrenocorticotrophic hormone; PdG, pregnanediol
glucuronide; E1G, estrone glucuronide; STRAW, Stages of
Reproductive Aging Workshop; FREEDOM, Fertility
Recognition Enabling Early Detection Of Menopause;
BIMORA, Biodemographic Observations in Reproductive
Aging; LOOP, luteal out of phase; VMS, vasomotor
symptoms (hot flushes/flashes and night sweats); CaMOS,
Canadian Multicentre Osteoporosis Study; BMI, body mass
index = kg/m2
Key Words: Perimenopause, Estradiol, Progesterone,
Inhibin B, LH, FSH, AMH, Menorrhagia, Cyclic VMS,
LOOP, diagnosis, CVD, Breast Cancer, Endothelial
Cancer, Osteoporosis, Menopause, Review
Send correspondence to: Jerilynn C Prior, Endocrinology
and Metabolism, Department of Medicine, and Centre for
Menstrual Cycle and Ovulation Research (CeMCOR),
University of British Columbia, and Vancouver Coastal Health
Research Institute, 2775 Laurel St, 4th floor, Vancouver,
British Columbia, Canada V5Z 1M9, Tel: 604-875-5927, Fax,
604-875-5915, E-mail: jerilynn.prior@vch.ca
http://www.bioscience.org/current/vol3S.htm
... Hormonal dysregulation may cause rodents to exhibit a prolonged acyclic phase prior to frank ovarian failure. During this period, there may also be persistent estrus [8] [9] [10] [11] in which FSH levels are elevated and 17β-estradiol levels are normal, a hormonal milieu similar to human perimenopause [8] [12] [13]. ...
... In addition to menopause or definitive cessation of menstrual cycling, perimenopause is a uniquely human process, but it can be mimicked by experimental models, especially in rodents. According to Prior and Hitchcock, perimenopause, previously seen as a period of hypoestrogenism, can be characterized by three main hormonal changes in women whose menstrual cycle remains regular: 1) normal or erratically high concentrations of estradiol; 2) decline in plasma progesterone concentrations and 3) changes at all levels of the reproductive axis (Prior and Hitchcock, 2011). During perimenopause a high percentage of women manifest typical symptoms of this period, which include: vasomotor changes, variations in menstrual cycle duration, sleep disorders, worsening cognitive functions, behavioral and mood changes (irritability, nervousness, anxiety and depression), in addition to metabolic and physiological changes (Mitchell and Woods, 1996;Brinton et al., 2015;Chalouhi, 2017). ...
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Women are born with an abundant but finite pool of ovarian follicles, which naturally and progressively decreased during their reproductive years until menstrual periods stop permanently (menopause). Perimenopause represents the transition from reproductive to non-reproductive life. It is usually characterized by neuroendocrine, metabolic and behavioral changes, which result from a follicular depletion and reduced number of ovarian follicles. During this period, around 45-50 years old, women are more likely to express mood disorders, anxiety, irritability and vasomotor symptoms. The current animal models of reproductive aging do not successfully replicate human perimenopause and the gradual changes that occur in this phase. While the traditional rat model of menopause involves ovariectomy or surgical menopause consisting of the rapid and definitive removal of the ovaries resulting in a complete loss of all ovarian hormones, natural or transitional menopause is achieved by the selective loss of ovarian follicles (perimenopause period). However, the natural aging rodent (around 18-24 months) model fails to reach very low estrogen concentrations and overlaps the processes of somatic and reproductive aging. The chronic exposure of young rodents to 4-vinylcyclohexene diepoxide (VCD) is a well-established experimental model for perimenopause and menopause studies. VCD induces loss of ovarian small follicles (primary and primordial) in mice and rats by accelerating the natural process of atresia (apoptosis). The VCD, ovary-intact or accelerated ovarian failure (AOF) model is the experimental model that most closely matches natural human progression to menopause mimicking both hormonal and behavioral changes typically manifested by women in perimenopause. Graphical abstract: The female reproductive system is regulated by a series of neuroendocrine events controlled by central and peripheral components. (A). The mechanisms involved in this control are extremely complex and have not yet been fully clarified. In female mammals whose ovulation (the most important event in a reproductive cycle) occurs spontaneously, reproductive success is achieved through the precise functional and temporal integration of the hypothalamus-pituitary-ovary (HPO) axis. (B). In women, loss of fertility appears to be primarily associated with exhaustion of ovarian follicles, and this process occurs progressively until complete follicular exhaustion marked by the final menstrual period (FMP). (C). While in female rodents, reproductive aging seems to begin as a neuroendocrine process, in which changes in hypothalamic/pituitary function appear independently of follicular atresia. The traditional rat model of menopause, ovariectomy or surgical menopause consists of the rapid and definitive removal of the ovaries resulting in a complete loss of all ovarian hormones. (D). The chronic exposure (15-30 days) to the chemical compound 4-vinylcyclehexene diepoxide (VCD) in young rodents accelerates gradual failure of ovarian function by progressive depletion of primordial and primary follicles, but retains residual ovarian tissue before brain alterations that occurs in women in perimenopause. Low doses of VCD cause the selective destruction of the small preantral follicles of the ovary without affecting other peripheral tissues.
... Therefore, it is appropriate to identify a complex period, called perimenopause [2], where some progressive mental and bodily changes could occur [2]. The reduction of female hormones (estradiol and progesterone, and, partly, androgens) may negatively influence female health, by favouring the occurrence of hot flushes (HFs), arthralgia, vaginal dryness, sleep and mood disturbances, bone loss, lean body mass deterioration and increased fat mass [3]. This complex event can accelerate female ageing because of its detrimental consequences on the cardiovascular and musculoskeletal systems [4]. ...
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... During the transition from regular menstruation to its complete absence, there is a gradual decline in ovarian function, which is particularly associated with a decrease in gonadal steroids such as estradiol (E2) and progesterone (P4) (Prior, 2011). As a result, the negative feedback of E2 and P4 on the pituitary is diminished, and concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) significantly increase (Hall, 2015). ...
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... Perimenopause is a period where endocrinology, biological and clinical features of menopause commence and is defined as the period immediately preceding menopause and there is a shift from reproductive state to non-reproductive state (19). This transitory state lasts for about four-five years before reaching menopause (11). ...
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... Menstruation is an important indicator of overall health and quality of life in women: the reproductive endocrine system is associated with sexual and reproductive health, bone and heart health, and cancers [1][2][3][4][5][6][7][8][9] ; it affects fertility 10,11 , menopause [12][13][14] , exercise 15 , and diet 16 . Seminal work on variation of menstrual cycle length throughout the reproductive lifespan 17,18 has concluded that "complete regularity in menstruation through extended time is a myth," and recent empirical studies [19][20][21] have confirmed that variation between cycles, women, and populations is the norm [22][23][24][25][26][27][28][29] . ...
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The SWAN is a multiethnic, community-based, longitudinal cohort study of 3302 women at 7 sites who initially were 42 to 52 years of age. Daily patterns of reproductive hormones have been studied in a subgroup of 848 women. A total of 833 menstrual cycles were evaluated. Urinary levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone conjugate (E1c), and pregnanediol glucuronide (Pdg) were used in algorithms to evaluate menstrual cycles for features of folliculogenesis, ovulation, and corpus luteum function. A significant rise in Pdg was taken as evidence of luteal activity (ELA), which is consistent with ovulation. A 60% decrease in the E1c to Pdg ratio indicated a luteal shift (DLT). Phase-specific lengths of cycles with ELA were estimated using the DLT as day 0, excluding day 0 from both follicular and luteal phase lengths. Hormone levels were summed over the total cycle and over the follicular and luteal phases for cycles with ELA. Participants were 43-53 years of age. Just over one third had smoked, and more than half were either overweight or obese. Just over one fourth of women were premenopausal; the rest were in the early perimenopausal phase. Approximately 81% of cycles had ELA, and these were the ones used in the following comparisons. Hispanic women had more long cycles exceeding 33 days and fewer short ones less than 22 days. Both longer and shorter cycles were most frequent in women aged 49 and older. Women whose body mass index (BMI) exceeded 25 kg/m2 had longer cycles on average than those with lower values. Early perimenopausal women were likelier than premenopausal women to have long cycles. On multivariate analysis, only age was significantly associated with total cycle length. BMI was the strongest predictor of phase lengths, larger women having longer follicular phases and shorter luteal phases. The differences remained significant on multivariate analysis. The follicular phase was significantly longer on average in early perimenopausal than in premenopausal women. Neither age nor smoking status influenced phase lengths. Hispanic women had longer luteal phases than other ethnic groups, but there were no significant ethnic differences after adjusting for BMI. Apart from E1c, daily hormone levels were highest in women whose BMI was 25 kg/m2 or less. Lower BMI correlated with higher total-cycle E1c values. Chinese and Japanese women had higher Pdg and lower E1c levels, largely because of the influence of BMI. Women over age 49 years had higher total-cycle FSH levels but lower total-cycle PdG values than did younger women. Smoking did not predict Pdg on multivariate analysis. Total-cycle FSH was higher in early perimenopausal than in premenopausal women, partly because of age differences. Total-cycle hormone levels were related to BMI in this study, and ethnicity seems to play a role independently of body size. It is not clear whether the observed differences are the result of differing rates of progress through the menopausal transition related to body size or ethnicity, or whether the differences will persist with longer follow up.