Stress and the Reproductive Cycle
Michel Ferin
Department of Obstetrics and Gynecology and the Center for
Reproductive Sciences, Columbia University College of Physicians and
Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Dr. Michel Ferin, Department of Obstetrics and Gynecology and the Center for Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, New York 10032.
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Introduction
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THE IDEA that by activating the
hypothalamic-pituitary-adrenal (HPA) axis, stress and overt or latent
psychological disturbances have the potential of inhibiting the
hypothalamic-pituitary-gonadal (HPG) axis has been circulated for a
long time (1). It is generally thought that, if severe enough, this
condition may lead to the suppression of the normal menstrual cycle in
a syndrome referred to as functional hypothalamic amenorrhea or
functional hypothalamic chronic anovulation (2). When fully
established, the syndrome is characterized by ovarian quiescence,
amenorrhea, and infertility. Although there appears to be a
relationship between the type and severity of the stress and the
proportion of women who develop amenorrhea (3), in practice it is
difficult if not impossible to identify a threshold at which stress
will interfere with the normal cycle. The probable reason for this is
that in circumstances that are not life threatening the actual stressor
may be less critical in determining the outcome than the individuals
response to it because psychobiological characteristics may heighten
the responsiveness to the stressor (2). This particular problem may
also in part reflect our ignorance of the initial steps by which stress
interferes with normal cyclic events. One may assume that the degree of
hypoestrogenism varies according to the severity of the stress
challenge and that intermittent ovarian function may persist in less
severe stress conditions. Potential differences in the individual
responses to a particular stress paradigm make it difficult in clinical
practice to confirm the independent association of a specific challenge
with the initiation of the functional hypothalamic chronic anovulation
syndrome (2). Furthermore, in many women more than one behavior may, in
fact, be involved. For instance, this clinical syndrome has also been
associated with other life style variables, such as weight loss or
eating disorders, and certain types of excessive exercise (jogging,
athletics) (4, 5, 6). Although it has been speculated that exercise- and
weight-related amenorrhea is more probably caused by disturbances in
the metabolic balance (7), mediators of the HPA axis may also be
activated in these situations.
Most investigators agree that the final neuroendocrine event
responsible for the functional chronic anovulation syndrome is a
decrease in the activity of the hypothalamic GnRH pulse generator.
Reports in women with the established syndrome have usually
demonstrated a significant slowing of LH pulse frequency, probably
reflecting a decreased GnRH pulse activity (8). As proper
folliculogenesis requires an optimal gonadotropin pulse regimen (9), it
would be expected that a decrease in the GnRH-LH pulse frequency would
lead to deficiencies in this process and to an abnormal menstrual
cycle.
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An HPA-HPG link: data in the human
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Notwithstanding the universal recognition of a potential link
between stress, and by implication an activated HPA axis, and an
inhibition of HPG, data confirming this association in the human are
scant and at best indirect. The most revealing data derive from a
careful comparison of circadian cortisol secretion in patients with the
functional chronic anovulation syndrome to that in eumenorrheic women
or in women with other causes of anovulation. Only women with the
functional chronic anovulation syndrome were found to be characterized
by increased cortisol secretion, usually in the form of an amplified,
but phase-intact, circadian excursion (8, 10). Studies in these women
also reveal a blunted cortisol response to exogenous administration of
CRH, suggesting that the increase in cortisol secretion may well
reflect increased endogenous CRH activity (4, 11). Increased cortisol
secretion has also been noticed in eating disorders or after exercise
in many women. Furthermore, elevated levels of CRH in cerebrospinal
fluid have been reported in amenorrheic women with anorexia nervosa
(12), although the precise source of this neurohormone in lumbar CSF
remains to be clarified. The preceding data suggest that in at least
some amenorrheic patients, the endocrine HPA axis has been activated.
Yet, there is presently no direct confirmation of a causal relationship
between this phenomenon, and the suppression of the GnRH pulse
generator and the HPG axis and the induction of the clinical syndrome.
Furthermore, the independent association of stress, exercise, or eating
disorder with the syndrome has up until now been impossible to confirm.
However, it has been reported that although many of the graver stress
situations where high rates of secondary amenorrhea occur are
associated with malnutrition, in general the amenorrhea antedates the
malnutrition (3).
Demonstrating an independent causal association between stress and the
HPG axis is a difficult task ahead. In the established syndrome, it may
be impossible to trace back to the original stress challenge and to
analyze the pathways involved; furthermore, in a chronic situation the
response to stress may vary, and different neuroendocrine elements may
become involved over time. Thus, initial studies should focus on the
identification of relevant and reliable stress paradigms in the human
so that prospective investigations on an HPA-HPG link can be
instigated.
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A direct HPA-HPG link: data in animals
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The concept that physical and emotional stress activates central
and peripheral responses that will preserve homeostasis has been well
studied in animals. Classically, the main actors in this general
adaptational response are believed to be the HPA endocrine axis and the
autonomic nervous system (13). Activation of HPA involves the release
of the neurohormone CRH. Although CRH neurons are scattered throughout
several brain regions, one of the main area in the response to stress
is thought to be located in the parvicellular aspects of the
hypothalamic paraventricular nucleus (14). Central CRH release results
both in the activation of the peripheral components of the HPA axis,
leading to an increase in ACTH and cortisol, and in the activation of
the sympathetic nervous system with increases in glucose release, heart
rate, and blood pressure. Activation by stress of the locus
ceruleus/autonomic system in the brain stem results in the stimulation
of norepinephrine release from several central networks and enhanced
arousal and anxiety. CRH may not be the only HPA neurohormone involved
in the stress response; there is good evidence in the human and in
animals that vasopressin of paraventricular origin is colocalized with
CRH in perikarya and secretory granules and coreleased in stress (15, 16). Vasopressin is known to act synergistically with CRH as an ACTH
secretagogue (17).
The mechanisms that control the activity of the GnRH pulse generator
are still chiefly under study, and only recently has evidence of a link
and cross-talk between the neuroendocrine HPA axis and the GnRH pulse
generator been obtained in the rodent and the nonhuman primate. The
first line of evidence derives from the observation that the
administration of CRH results in an immediate decrease in pulsatile
GnRH and LH release (18, 19). Similar acute inhibitory effects on
gonadotropin secretion after central administration of vasopressin, the
second HPA neurohormone, have also been observed in the ovariectomized
monkey (20). Although CRH administration obviously also activates the
peripheral endocrine HPA axis resulting in ACTH and cortisol release,
the acute inhibition of pulsatile GnRH activity by CRH in the
ovariectomized monkey is clearly the result of a central action of CRH.
Indeed, inhibition of gonadotropin release cannot be reproduced by a
short term ACTH infusion and is still readily observed after CRH
administration to the adrenalectomized monkey (21, 22). Unfortunately,
efforts to demonstrate an inhibitory action of CRH on gonadotropin
release in the human have not been successful (23, 24), except by one
group of investigators (25, 26). The controversy perhaps reflects the
facts that cerebroventricular injection of the neurohormone is not
possible in the human and that at acceptable levels for treatment
insufficient amounts of the compound may reach the proper central area
after peripheral administration. This topic may have to be reassessed,
however, taking into consideration the possibility that the
gonadotropin response to CRH may vary according to the ovarian
endocrine status.
The relevance of CRH or vasopressin injection data in animals is
difficult to interpret, because it is not possible presently to assess
whether injected amounts of these compounds are physiological or
pharmacological. A more direct line of evidence for an HPA-HPG link
would require a demonstration that the neutralization of endogenous HPA
neurohormone activity results in the disruption of the hypothesized
HPA-HPG link. Such evidence has been obtained in the rat, in which the
inhibitory effects of a stressful physical stimulus, such as that
resulting from electrical foot shocks, on GnRH and gonadotropin
secretion is prevented by cotreatment with a CRH antagonist or antibody
(27).
As mentioned above, the difficulty in studies in the primate is to
identify a stress challenge (a stimulus that activates the HPA axis)
that is relevant, quantifiable, and reproducible (i.e. in
which individuality of the response is minimized), so that comparative
experimental protocols can be developed. In initial studies in the
nonhuman primate, our group has investigated the effects of an
infectious-like stress challenge, such as that which follows the
administration of the inflammatory cytokine interleukin-1 (IL-1) or of
endotoxin, which is known to release endogenous cytokines (28). In the
monkey, this challenge reliably produces an acute infectious-like
syndrome and an activation of HPA, as judged by the increases in
central CRH, ACTH, and cortisol release; it also results in the
immediate suppression of pulsatile LH and FSH release (29, 30). A
similar effect of endotoxin has been shown in the sheep (31).
Significantly, in the monkey, but not in the rat, the inhibitory effect
of IL-1 on LH is prevented by the central injection of a CRH antagonist
(30, 32). In accord with the postulated role of paraventricular
vasopressin, an antagonist to this neurohormone is equally effective in
this regard (33). Thus, these data in the primate provide direct
support to the concept that one of the mechanisms by which stress is
inhibitory to the GnRH pulse generator is through the activation and
the central release of neuroendocrine components of the HPA axis.
Whether this conclusion is generally applicable or is limited to this
particular stress challenge remains to be elucidated.
A word of caution is in order here. There are several instances in the
nonhuman primate indicating that an apparent activation of HPA, as
determined by an increase in cortisol, does not necessarily translate
into a suppression of gonadotropin secretion. For example, experimental
data indicate that the increased central CRH activity that follows the
reduced cortisol negative feedback induced by metyrapone does not
result in an acute inhibition of LH secretion (34). Other data show
that although there is frequently a correlation between activation of
HPA and suppression of reproductive hormone secretion in instances of
social stress, this link is not present in all individual animals (35).
In a series of studies, no evidence could be provided that
fasting-induced LH suppression in the male monkey is the result of
the mild HPA activation observed in this instance (36). Clearly,
further research is warranted in both the human and relevant animal
species to fully elucidate what central or peripheral mechanisms are
required to activate the postulated HPA-HPG link. It is also important
to note here that, as expanded upon later in this review, the acute
activation of HPA may, under certain circumstances, elicit an increase
rather than a decrease in LH release, a result that, because
unexpected, may have escaped notice in previous protocols.
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A role for the endogenous opioid peptides: human and animal
studies
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Unfortunately, a direct demonstration of the role of central CRH
on LH secretion has not been possible to date in the human because CRH
antagonists are rapidly degraded when given parentally and probably
require central administration for effectiveness. However, experiments
using µ-opiate receptor antagonists indicate that an increased
endogenous opioid activity may somehow also account for the decreased
pulsatility of the GnRH pulse generator in patients with functional
hypothalamic chronic anovulation. Indeed, studies have shown that the
administration of naloxone or naltrexone acutely restores normal LH
pulse frequency, at least in a subgroup of these patients (37). The
hypothalamic ß-endorphin center, in fact, resides within the
arcuate nucleus of the hypothalamus, which is also the location for the
GnRH pulse generator in the primate. In animals, the acute inhibitory
action of CRH on pulsatile LH release is also clearly prevented by
naloxone or by an antiserum to ß-endorphin (38, 39, 40). [Interestingly,
in the monkey,
MSH, a derivative of the same prohormone giving rise
to ß-endorphin, can also antagonize the inhibitory effects of CRH or
of IL-1 on pulsatile LH secretion (41). This suggests that the
posttranslational processing of POMC may represent a step in the
processes that control the response to stress.] As the animal studies
suggest that increased endogenous opioid activity reflects, among many
possible other causes, enhanced central CRH release and mediates the
endocrine actions of CRH on the HPG axis, the above observation in the
human may be viewed in support, if only indirectly, of the existence of
a HPA-HPG link.
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Ovarian steroids and the response to stress
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After relevant and standardized stress paradigms are devised and
tested for their effect on HPG, one potential complication is that the
varying ovarian endocrine status throughout the menstrual cycle may
modulate the response differentially. Thus, stress challenges should be
tested at various stages of the cycle, and the responses compared. In
this endeavor, investigators may have to be careful not to generalize
data, because each particular stress challenge may well activate HPA
through a different central pathway with its own particular sensitivity
to the ovarian steroids. Experiments in the nonhuman primate serve to
illustrate this aspect. As an example, although small amounts of
estradiol appear to enhance the inhibitory effect of an immobilization
or of a hypoglycemic stress on gonadotropin secretion (42, 43), they
exert a protective action against the effect of an inflammatory-like
stress challenge (44).
In the rodent, there is some evidence that sex steroids may interact
with both central and peripheral substrates of stress, thereby possibly
modifying the HPA response. Such effects may reflect the presence of
estrogen-responsive elements in the CRH gene promoter area and
modulatory actions of estrogen on CRH gene expression (45). Thus, it
may be that reported observations of slight gender differences in
cortisol levels or of a sexual dimorphism in the immune/inflammatory
reaction or in autoimmune disease may reflect direct stimulatory
effects of estrogen on the CRH gene (46, 47). The latter may also
explain the greater activity of CRH at proestrous in the rat (48) or
the enhancement of cortisol release in estrogen-treated ovariectomized
monkeys (49). Yet, it is important to emphasize at this stage that not
all studies demonstrate a positive correlation between estrogen and HPA
activity (50) and in some instances a reverse relationship has been
noted (51, 52). The overwhelming conclusion from a review of the
literature on this subject is the remaining need for systematic
comparative studies of the acute effects of well defined stress
challenges on the HPG axis at various stages of the menstrual cycle. In
this circumstance, it is thus impossible to draw general conclusions
for this article.
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A paradoxical gonadotropin response to stress in an estrogen
environment
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Although the classical HPA-HPG link implies that activation of HPA
will cause a decline in gonadotropin secretion, recent studies in our
laboratory suggest that a reverse outcome is possible under a defined
endocrine condition. Indeed, activation of HPA by IL-1 or endotoxin in
the monkey during the midlate follicular phase (but not the early
follicular phase or the luteal phase) results in an acute release of LH
(52). This observation evidently contrasts with the above-reported
inhibitory effect of the cytokine on pulsatile LH secretion in the
absence of estradiol (30), a result more in tune with the classical
theory. A release of LH after HPA activation can also be produced in
the ovariectomized monkey replaced with mid- to late follicular phase
estradiol levels (53). That such a surprising result is not confined to
the nonhuman primate is suggested by observations in postmenopausal
women receiving estrogen replacement in whom a similar increase in LH
was noted in response to endotoxin administration (Wardlaw, S.,
personal communication). Differences between species may occur because
in the rodent IL-1 exerts an inhibitory effect on gonadotropin release
at all stages of the estrous cycle (54). In the ewe, however, an
increase in LH was also observed after central CRH administration, but
again only in steroid-replaced animals (55). In the monkey, our studies
indicate that the factor that is probably responsible for this acute
stimulatory effect of HPA on LH release may be
progesterone, as this effect is readily prevented by the
administration of a progesterone antagonist (53). We have
speculated that in stress the small but significant increase in adrenal
progesterone that occurs in response to HPA activation,
synergizes with circulating estradiol to enhance LH secretion. In
support of this hypothesis is the observation that the increase in LH
is prevented by the administration of a CRH antagonist, demonstrating
that HPA activation is required for this effect to occur (53). That
such an increase in LH is not observed when the cytokine is given
earlier in the follicular phase probably reflects the fact that at
lower concentrations, estradiol cannot synergize with
progesterone. Lest the reader conclude that an increase in
LH after activation of HPA is an exclusive characteristic of one type
of stress, it should be noted that this phenomenon was also reported in
response to a single bout of exercise in untrained women during the
midfollicular phase (but not the luteal phase) and in eumenorrheic
runners immediately after a race (56, 57).
Are these unexpected observations of a stimulatory effect of the
HPA-HPG link just a curiosity or could these be of any relevance to the
reproductive cycle? It is obviously too premature to tell, but one
could speculate that this response may highlight a cycle stage- or
endocrine-specific recognition of an acute stress reaction and perhaps
represent a mechanism by which an acute stress stimulus, insufficient
to interrupt the reproductive cycle, may nonetheless subtly interfere
with normal cyclic function. Although there are no data in the
literature specifically related to the effects of a stress-induced
premature increase in LH in the mid- to late follicular phase, there
are several reports indicating that elevated LH concentrations at that
stage of the cycle may damage the maturing follicle and/or the oocyte,
desynchronize the ovulatory signal from a timely follicular maturation
process, and/or interfere with fecundity (58, 59, 60, 61).
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On the road to acyclicity and infertility
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Although the long term consequences of chronic stress presumably
include amenorrhea, the initial effects of an activation of HPA on
cyclic events have not been studied. Our initial studies in the monkey
have dealt with the effects of a moderate 5-day infectious-like stress
during the midfollicular phase of the cycle, a stress that produces
mild flu-like symptoms. The results, if confirmed by other studies, are
of potential interest, first because they show that a short term stress
may exert effects on the cycle well past its duration, and second
because it could be argued that this stress challenge, although
inducing endocrine effects too subtle to be readily detected in a
clinical environment and insufficient to interrupt the menstrual cycle,
may, in fact, be substantial enough to potentially interfere with
fertility. Two cyclic disturbances occur in response to this
short-lived stress challenge (62). First, HPA activation at this stage
of the cycle results in a prolongation of the follicular phase that in
a subgroup of monkeys exceeds well over 1 week. Second, the stress
challenge also invariably results in a reduced luteal function in the
form of diminished progesterone secretion during the
luteal phase in the subsequent cycle. These cyclic abnormalities may be
representative of a more universal initial response to HPA activation
and as such be part of the symptomatology accompanying the initial
events in this syndrome. Irregular bleeding patterns, long irregular
cycles, and abnormal luteal phases should indeed be considered part of
the spectrum of symptoms in the functional chronic anovulation syndrome
(2). Although our own preliminary data in the monkey are presently
limited to a single type of stress, there have been observations of a
higher incidence of luteal deficiency in women after the initiation of
an exercise program (63, 64).
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Potential local effects of stress
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Although we have focused this review on neuroendocrine and
endocrine HPA-HPG interactions, autocrine and paracrine regulatory
responses may also have to be considered in future studies. Recent
observations have shown that CRH is present in several peripheral
tissues. In the ovary, immunoreactive CRH and CRH receptors are
identified in thecal cells, stroma, and mature oocytes (65). In some
studies, CRH has been shown to inhibit steroid biosynthesis by human
granulosa-lutein cells in culture through mechanisms that involve the
CRH and IL-1 receptors (66, 67). Human and rat uteri have been shown to
express the CRH gene, and it has been speculated that endometrial CRH
may also participate in physiological events in that organ (68, 69).
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Treatment
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The treatment of patients with functional hypothalamic chronic
anovulation is multifactorial and beyond the scope of this review. It
may include taking care of the behavioral variables, of the
hypoestrogenism relative to the quiescent HPG axis, and of infertility.
With regard to the latter, pulsatile GnRH or gonadotropin therapies are
usually successful (2). Although, as mentioned above, the injection of
an opiate antagonist may acutely reactivate pulsatile gonadotropin
secretion (37), conflicting results have been obtained in regard to a
long term benefit of this treatment. Two studies have reported
successful rates in inducing ovulatory cycles with naltrexone, but
another failed to demonstrate any benefit over placebo treatment in
women with hypothalamic amenorrhea (70, 71, 72).
Hope for a different therapeutic tool may be found in a new class of
nonpeptide CRH antagonists that have been shown to exert a potent and
selective antagonism to CRH (73, 74, 75). These new antagonists may prove
to be more useful therapeutically than those presently available,
because of their ability to be administered parentally. An example of a
specific condition in which a CRH antagonist may be potentially
effective would be to prevent the premature increase in LH in the mid-
to late follicular phase that occurs in a sizable number of
unstimulated cycles (60), if indeed this increase were to reflect an
acute stress response. In this condition, the CRH antagonist may
prevent the small rise in adrenal progesterone that is
probably responsible for the LH increase (see above) and allow for the
normal continuation of folliculogenesis. A CRH antagonist therapy may
also be attempted in patients with the established functional
hypothalamic amenorrhea syndrome to restore GnRH pulsatility, estrogen
secretion, and a normal menstrual cycle. Whether therapy with this
single antagonist would be successful in reversing a well established
chronic condition is difficult to predict. Neuroendocrine aspects in
chronic stress have not yet been investigated in the primate, and
accounts in the rodent suggest that alternative HPA secretagogues may
become prominent in the chronic stress condition. For example, in the
rat it is thought that vasopressin plays a more specific role in
chronic stress by sustaining HPA responsiveness at a time when, at
least in some stress paradigms, the CRH response rapidly desensitizes.
For instance, in cases of repeated restraint stress the proportion of
vasopressin-containing CRH neurons increases significantly, and data
suggest that there may be emergence of an isolated vasopressin response
(76). Vasopressin is very effective in influencing LH secretion in the
primate, as detailed above, but the relative roles of both
neurohormones during chronic stress remains unknown. It may then well
be that a successful treatment may require the addition of
antivasopressin therapy as well.
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Summary
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Although there is general agreement that the functional
hypothalamic amenorrhea syndrome is linked to psychogenic stress and
the resultant suppression of the normal activity of the GnRH pulse
generator, the independent association between stress and the
inhibition of the GnRH pulse generator remains to be demonstrated in
the human. The challenge for the researcher remains to identify
relevant and reliable stress paradigms so that prospective
investigations of an HPA-HPG link can be initiated. Stress affects
multiple sites; behavioral, metabolic, cardiac, and endocrine responses
can be activated (Fig. 1
). Stress
research will be complicated by the probability that different stress
challenges may activate each site to varying degrees and that each site
may be variously sensitized by the presence of each ovarian steroid. In
regard to the neuroendocrine response to stress, we can predict from
animal studies that both HPA neuropeptides, CRH and vasopressin, and
the endogenous opioid peptides will play a role in the inhibition by
stress of the hypothalamic-pituitary-ovarian axis. Both the ability of
CRH and vasopressin to inhibit GnRH and gonadotropin secretion and
their mediation of the effects of several types of stress challenges
have been demonstrated. Initial studies in the nonhuman primate of the
effects of a short term stress episode on the menstrual cycle are of
potential interest to the clinician because they indicate that although
a stress may be insufficient to produce amenorrhea, it may interfere
with the normal cycle in subtle ways and thereby potentially affect
normal fertility. Primate studies have also described a paradoxical
gonadotropin response to a stress challenge in the presence of
estradiol, such as during the mid- to late follicular phase, resulting
in an acute release of LH. The factor most likely responsible for this
stimulatory effect of HPA on LH release, at least in the acute
situation, may be progesterone released by the adrenals in
response to HPA activation (Fig. 2
).
Whether this represents an additional mechanism by which an acute
stress stimulus, again insufficient to interrupt the reproductive
cycle, may interfere with the normal progression of folliculogenesis
and with fertility remains to be determined.

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Figure 1. A simplified representation of the central
response to stress and of its inhibition of the HPG axis.
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Figure 2. A schematic representation of the putative
peripheral mechanism for the paradoxical increase in gonadotropin in
response to stress in the presence of estradiol.
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Acknowledgments
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The author gratefully acknowledges Drs. Rogerio Lobo, Sharon
Wardlaw, and Ennian Xiao for their critical reading of the manuscript
and their helpful suggestions.
Received May 19, 1998.
Revised August 28, 1998.
Accepted September 14, 1998.
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