Endocrine Reviews 20 (3): 243-248
Copyright © 1999 by The Endocrine Society
Neuroendocrine Influences and Repercussions of the Menopause
Phyllis M. Wise,
Matthew J. Smith,
Dena B. Dubal,
Melinda E. Wilson,
Kristine M. Krajnak and
Katherine L. Rosewell
Department of Physiology, College of Medicine, University of
Kentucky, Lexington, Kentucky 40536-0298
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Abstract
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- I. Introduction
- II. Interplay Between the Ovary and Brain in Reproductive Senescence
- III. Neuroendocrine Contributions to the Menopause
- IV. Neuroendocrine Repercussions of the Menopause
- V. Summary
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I. Introduction
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THE menopause occurs at approximately 51 yr
of age in women and signals the permanent end of fertility. Interests
in understanding the mechanisms that regulate the timing and the
repercussions of this profound "change of life" have increased
greatly during the past 10 yr for several reasons. First, during this
century, the average life span of humans has increased dramatically;
however, the age of the menopause has remained fixed. Thus, an
increasing number and proportion of women will live a larger fraction
of their lives in the postmenopausal state than ever before. Second, a
hallmark of the postmenopausal period is the total exhaustion of
ovarian follicles and the resulting virtual absence of ovarian steroids
and peptides. We now realize that estrogen modulates a far broader
array of functions than was once appreciated. In addition to its
important effects within the reproductive axis, new findings suggest
that this pleiotropic hormone plays novel and important roles in
functions that were considered traditionally as "nonreproductive,"
including modulation of bone and mineral metabolism (1), cardiac and
vascular function (2), and cognition and memory (3, 4) and the risk and
progression of age-related neurodegenerative diseases (5, 6, 7).
Therefore, the repercussions of the profound decrease in ovarian
steroids are likely to be much broader than we imagined. Third, we are
beginning to understand that the transition to acyclicity may not be
triggered simply by decreasing ovarian estrogen, but by an interacting
constellation of ovarian and neuroendocrine events that exacerbates the
rate of loss of the ovarian follicular reserve and leads to decreasing
fertility and fecundity and irregular reproductive cycles. Because such
a long period in a woman’s life is spent in this hypoestrogenic state
and because this impacts on the status of so many physiological
systems, it is critical that we deepen our understanding of the complex
interplay of factors that leads to the transition to the postmenopausal
state; this will enable us to develop the means to treat some of the
repercussions of the declining reproductive system and answer
fundamental questions about the process of aging.
We should point out that many studies on reproductive aging that are
cited in this review have been performed in animal models, particularly
laboratory rodents. By definition, these species do not undergo the
"menopause," since they never experience "menses" during their
reproductive life. Some investigators believe that fundamental
differences exist between primates and rodents in the control of
reproductive cyclicity and infer that aging involves completely
different mechanisms between these species. However, we believe that
important commonalities in the hypothalamic control of ovarian function
exist between primates and rodents. Therefore, we believe that rodents
are excellent experimental models and have provided key insights into
the mechanisms and factors that regulate development of the
reproductive system, puberty, and maintenance of regular cycles in the
adult. We are confident that information gained from studies performed
in these species will allow us to develop concepts that can also be
applied to human reproductive aging.
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II. Interplay Between the Ovary and Brain in Reproductive
Senescence
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For many years, it was accepted that the menopause resulted simply
from exhaustion of ovarian follicles; changes in other components of
the reproductive axis that accompany the menopause were considered
merely consequences of declining ovarian function. More recently,
increasing attention has been paid to the possibility that age-related
changes in the hypothalamus and central nervous system are important
players in the ensemble of events that lead to the menopause:
exhaustion of ovarian follicles may be accelerated as a consequence of
desynchronization of neural signals. We are beginning to appreciate
that before ovarian follicles are exhausted, fertility and fecundity
decrease markedly, reproductive cycles become increasingly irregular in
length, and patterns of gonadotropin secretion are altered. Newer
findings encourage us to reevaluate the simple model of ovarian aging
and to consider the possibility that a more complex series of
simultaneous changes interact with each other, leading to the
menopause. To understand the pacemakers that trigger the cascade of
events leading to the transition to the menopausal state, investigators
have increasingly turned their attention to the period before the
establishment of permanent acyclicity, i.e., the events that
occur during the fourth decade of life in women (8, 9, 10) or the
equivalent stage in experimental animal models (11, 12, 13, 14) (for reviews
see Refs. 15, 16).
The concept that senescence of the ovary is the primary cause of the
menopause results from our knowledge that women are born with a finite,
nonrenewable, postmitotic pool of dormant follicles (17). From the time
that follicles are formed during prenatal development, each day a
number of dormant primordial follicles reawaken and begin to grow and
differentiate. The vast majority of these growing follicles undergo
cell death during development, presumably because the appropriate
hormonal environment does not exist to nurture continued development
and final stages of differentiation. When women reach middle age, the
rate of loss of follicles remaining in the ovary doubles, accelerating
the time of eventual total depletion of the follicular reserve (18, 19). Knowledge about whether or not patterns of hormone secretion
change during the menopause and why they change may help us to
understand the increasing rate of follicular loss that occurs just
before the menopausal transition.
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III. Neuroendocrine Contributions to the Menopause
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The concept that the central nervous system, and the hypothalamus
in particular, regulates the timing of the menopause follows from our
understanding, derived from studies performed largely in animal models,
that during aging the neurochemical and neuroendocrine signals that
dictate the patterns of secretion of the gonadotropins, which, in turn,
govern the development of follicles, become less precise and
synchronized (20, 21). Newer data, primarily from recent studies
performed in women during the perimenopausal period, reveal that
striking parallel changes may occur in humans. Clearly, the methods
that can be used to assess the status of neuroendocrine axis in humans
are more indirect than the experimental approaches that can be used in
laboratory animals. We will discuss first the results of studies
performed in laboratory animals and then those performed in women.
Some of the earliest evidence that the hypothalamus plays a role in
reproductive aging comes from classic studies using two experimental
approaches. First, transplantation of ovaries of old animals to the
kidney capsule of young, regularly cycling, but previously
ovariectomized females hosts, revealed that follicular development and
ovulation occurred under the influence of the young neuroendocrine
environment. This demonstrates that depletion of ovarian oocytes is not
the cause of the acyclic state (21, 22). Later studies that examined
the ability of grafts to restore cyclicity during middle age concluded
that the neuroendocrine axis may contribute predominantly to the
transition from regular cycles to irregular cycles, while the ovary
contributes to the ultimate cessation of cycles (23). Second,
administration of drugs that restore hypothalamic monoaminergic
activity or electrochemical stimulation of the preoptic area of the
hypothalamus of old female rats reinstated LH surges, estrous
cyclicity, and ovulation (24, 25, 26). These results indicate that changing
hypothalamic function contributes to age-related reproductive decline.
More recent studies, which focus attention on the middle age transition
period, suggest that hypothalamic changes, albeit subtle, may
contribute to the onset of irregular cycles that ultimately lead to
acyclicity (for review see Ref. 16).
It would be optimal to measure plasma GnRH secretion to critically test
whether the dynamics of GnRH secretion are altered during or after the
onset of the perimenopausal transition. Unfortunately, at the present
time, GnRH cannot be measured in the peripheral blood of humans because
assays are not sufficiently sensitive. In fact, even in animal models,
where it is possible to measure GnRH in the hypophyseal portal blood
using invasive methods, it is impossible to perform these studies over
several months, which would be required in aging studies. Therefore,
the only alternative is to measure FSH and LH as indirect indices of
GnRH secretion. Numerous reports clearly establish that the patterns of
secretion of both gonadotropins are altered during middle age in rodent
models and are thought to reflect, in large part, changes in the
ability of GnRH neurons to maintain normal patterns of secretion. One
of the earliest signs of the impending transition to irregular
cyclicity is an increase in FSH concentrations, which are particularly
evident during the secondary FSH surge that occurs on estrus (12). This
increase has been attributed to decreased inhibin activity measured in
the ovarian vein. However, we should keep in mind that the patterns of
gonadotropin secretion and the relative amounts of FSH and LH are
driven, in part, by the pattern of secretion of GnRH. In fact, a
selective rise in FSH secretion can be achieved by slowing the
frequency of GnRH pulses (27). Therefore, both the hypothalamus and the
ovary may contribute to the selective rise in FSH levels in middle-aged
rats. Both the preovulatory surge and the pulsatile secretion of LH are
altered during middle age: the preovulatory LH surge is delayed and
attenuated (13, 28, 29), and the interpulse interval and average
duration of individual pulses of LH (11) increase with age (Figs. 1
and 2).
Changes in these two parameters of LH secretion are thought to reflect
more purely changes in the hypothalamic pulse generator and the
accuracy with which it generates discrete, robust signals. Therefore,
these data are particularly provocative and lend credence to the
possibility that subtle changes in the neurochemical inputs and/or the
integrity of the GnRH pulse generator occur early, before the
transition from regular to irregular cycles, and may be a component of
the cascade of events that contribute to reproductive aging.
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Figure 1. Plasma LH concentrations in young and middle-aged
rats on proestrus. The LH surge began later and was attenuated in
amplitude in middle-aged compared with young rats. [Reproduced with
permission from P. M. Wise et al.: Recent Prog
Horm Res 52:279–305, 1997 (16 ). © The Endocrine Society.]
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Figure 2. Pulse amplitude (top panel), interpulse interval
(middle panel), and pulse duration (bottom panel) in young and
middle-aged rats. Age related changes in pulsatile LH secretion precede
the transition to estrous acyclicity and depend upon previous estrous
cycle history. [Reproduced with permission from P. M. Wise
et al.: Recent Prog Horm Res 52:279–305,
1997 (16 ). © The Endocrine Society.]
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An interest in exploring the possibility that neuroendocrine
alterations may play a role in the transition to irregular menstrual
cycles in women has been bolstered by recent reports that estradiol
levels do not decrease but, in fact, increase in middle-aged cycling
women (10) (Fig. 3) and that menstrual
cycles lengthen during the perimenopausal period (30). Since these
changes are similar to those reported in middle-aged rodents, they have
led investigators to reexamine more closely the neuroendocrine
alterations in women as they enter the perimenopausal period. Recent
studies clearly reveal strikingly similar changes in the pattern of FSH
and LH secretion in middle-aged women before any change in menstrual
cycle length. As in rodent models, a selective rise in FSH secretion
heralds the imminent transition to irregular menstrual cycles (8, 31, 32) (Fig. 4). In addition, significant
increases in the interpulse interval and the duration of individual LH
pulses have been reported in regularly cycling middle-aged women during
the mid to late follicular phase of the menstrual cycle when plasma
estradiol levels were normal and FSH concentrations were elevated (9)
(Fig. 5). It is important to note that
some studies report no change or increases in LH pulse frequency (33).
Thus, the ability to detect changes may depend upon the times of the
cycle that were monitored or whether the length of the menstrual cycle
has changed in the women that were included in the study. Furthermore,
the incidence of hot flushes and sleep disturbances, both indirect
indices of hypothalamic function, become evident in women between the
ages of 35–40, at the same time that the rate of follicular loss
accelerates (15). Together, these data suggest that the initial
alterations in the hypothalamic-pituitary axis precede the loss of
regular cyclicity in women, as well as in rodent models.
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Figure 3. Urinary estrone conjugate excretion patterns in
perimenopausal women compared with young controls. Estrogen excretion
was significantly elevated in perimenopausal compared with younger
women. [Derived from Ref. 10.]
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Figure 4. Plasma FSH (top panel) and inhibin B (bottom
panel) levels during the menstrual cycle in young and middle-aged
women. FSH concentrations were elevated and inhibin B concentrations
were suppressed in middle-aged compared with young women. [Adapted
with permission from N. A. Klein et al.:
J Clin Endocrinol Metab 81:2742–2745, 1996 (8 ). ©
The Endocrine Society.]
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Figure 5. LH pulse duration (top panel) and interpulse
interval (bottom panel) in young (clear bars) and middle-aged (black
bars) women obtained from the mid to late follicular phase. Both pulse
duration and interpulse interval increased with age. [Derived from
Ref. 9.]
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Accumulating evidence suggests that deterioration in the coupling of
neurotransmitter signals that regulate GnRH secretion or an uncoupling
of the composite of neurochemical signals from GnRH neurons causes the
initial changes in patterns of gonadotropin secretion. The recurring
and pervasive feature of these initial neurochemical changes is that
their daily rhythmicity is affected far more frequently than their
overall average level of activity or expression (Fig. 6). The finding that the rhythmicity of
so many neurotransmitters change during aging has led to the hypothesis
that deterioration of the "biological clock" or its ability to
communicate with efferents that communicate with GnRH neurons leads to
alterations in the pattern of gonadotropin secretion. In mammals, the
suprachiasmatic nuclei are considered the master circadian pacemaker
because these nuclei not only exhibit 24-h rhythmicity themselves, but
they communicate extensively with many regions of the brain and drive
the timing of multiple outputs. The impact of this is so great that
virtually all physiological functions show a pervasive daily rhythm
(34). The reproductive cycle is fundamentally grounded upon a circadian
foundation. This is most evident in rodents that are maintained in
controlled laboratory conditions. However, even in human populations
where activity, light-dark cycles, and sleep are not rigorously
controlled by experimental protocols, reproductive functions exhibit a
diurnal rhythmicity (35). In animal models, the expression and
rhythmicity of some of the neuropeptides of the suprachiasmatic
nucleus that project to GnRH neurons decrease with age (36), and
the rhythmicity of several neurotransmitters that are driven by the
clock deteriorate with age (16). Thus, a fundamental deterioration in
the neural pacemaker or the coupling to its outputs may initiate the
gradual disintegration of the temporal organization of neurotransmitter
rhythms that are critical for stable, precise, and regular cyclic LH
secretion. This may initiate a cascade that leads to the transition to
irregular cycles and ultimately contributes to acyclicity.
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Figure 6. Diurnal patterns of POMC mRNA levels in young,
middle-aged, and old rats. POMC gene expression exhibited a diurnal
rhythm in young rats; however, no rhythm was detectable in middle-aged
or old rats. [Reproduced with permission from P. M. Wise
et al.: Recent Prog Horm Res 52:279–305,
1997 (16 ). © The Endocrine Society.]
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IV. Neuroendocrine Repercussions of the Menopause
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One of the most exciting areas of research in women’s health over
the past 10 yr involves our growing appreciation that estrogen plays
important neurotrophic and neuroprotective roles during adulthood. This
brings new meaning to the potential impact of the prolonged
postmenopausal, hypoestrogenic state on learning and memory and the
potential increased vulnerability of aging women to brain injury (37)
and neurodegenerative diseases (3, 4, 6, 38, 39).
Studies using animal models reveal that estradiol exerts neurotrophic
actions as measured by induction of neurite outgrowth, dendritic
spines, and synaptogenesis, influence on long-term potentiation and
excitability, and enhancement of gene expression (for review see Ref.
40). These effects can be replicated in in vitro dispersed
neuronal cell cultures (41). Estrogen also exerts neuroprotective
actions in in vivo and in vitro models of brain
injury. Animal models of stroke or cardiac arrest provide convincing
evidence that estradiol is a neuroprotective factor. Females
consistently sustain less brain injury than males, and estrogen
treatment decreases ischemic injury in both sexes (42, 43, 44);
furthermore, replacement with estrogen protects against ischemic injury
in castrated males and females (45, 46, 47) (Fig. 7). In addition, multiple studies have
shown that estrogen can protect against injury induced by a variety of
toxic stimuli (48, 49, 50, 51).
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Figure 7. Effects of low and high physiological levels of
estradiol replacement on the volume of cerebral infarct induced by
middle cerebral artery occlusion. Estradiol pretreatment significantly
reduced the total cortical infarct. [Reproduced with permission from
D. B. Dubal et al.: J Cereb Blood Flow Metab 18:1253–1258
(46 ).]
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Findings suggest that the trophic and protective effects of estrogen
may be mediated via multiple cellular and molecular mechanisms. It may
act via classic genomic mechanisms on a variety of genes including the
neurotrophins and their receptors, cell death proteins and/or
structural proteins that allow maintenance of synapses and neurite
outgrowth. In addition, there is accumulating evidence that estrogen
exerts its effects by novel mechanisms that are different from the well
characterized mechanism involving transactivation, nuclear receptor
dimerization, and binding to consensus estrogen response elements. Many
examples of these alternative pathways exist in peripheral tissues (for
review see Ref. 52). However, examples of these potential mechanisms in
the nervous system have been reported recently with increasing
frequency (50, 53, 54, 55, 56, 57). Estrogen may act through novel mechanisms that
include cross-talk with other second messenger systems, such as cAMP
(54, 58) or mitogen-activated protein kinases (55). Some of
these novel mechanisms of estrogen action may require cross-talk with
the estradiol receptor; however, which receptor subtype (
or ß) is
involved is unclear. Whether ligand-bound receptors must bind to
classic estrogen response elements to evoke protection and growth is
also unclear. Other trophic and protective effects of estrogen occur in
the absence of any known intracellular estrogen receptor (51) and are
detectable within minutes. This strongly suggests that estrogens may
act either on a membrane receptor that has not yet been isolated or
characterized or may act by influencing membrane receptors that are
linked to ion channels (59, 60).
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V. Summary
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In summary, the evidence that both the ovary and the brain are key
pacemakers in the menopause is compelling. Our appreciation that
estrogens are important neurotrophic and neuroprotective factors has
grown rapidly. Future studies will allow us to better understand the
ensemble of factors that interact to maintain regular reproductive
cyclicity and how this precise dynamic balance changes with age.
Furthermore, understanding how estrogen exerts trophic and protective
actions should lead to its use as an important therapeutic agent in the
maintenance of normal neural function during aging and after injury.
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Footnotes
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Address reprint requests to: Phyllis M. Wise, Ph.D., Department of Physiology and Biophysics, University of Kentucky College of Medicine, MS 509 Medical Center, 800 Rose Street, Lexington, Kentucky 40536-0298 USA.
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Top
Abstract
I. Introduction
