Stress Induced Anovulation 615

Stress Induced Anovulation

S L Berga and T L Loucks Introduction Emory University School of Medicine, Atlanta, GA, USA A wealth of scientific and clinical evidence supports ã 2007 Elsevier Inc. All rights reserved. the notion that stress causes reproductive compro- mise and increases health burden. Neuroendocrine, Introduction metabolic, and behavioral responses to acute stress Neuroendocrine Mechanisms Linking Cognition, Mood, represent transient homeostatic adaptations that Behavior, and Gonadotropin-Releasing Hormone Drive promote survival in the face of perceived challenge; Pathogenesis of Stress-Induced Anovulation chronic stress elicits allostatic (sustained) adjustments Behavioral, Nutritional, and Metabolic Influences on the that also promote survival but at greater health cost Reproductive Axis (Figure 1). Reproductive compromise impedes popu- Synergism among Stressors lation replenishment and increases acute and chronic Treatment Considerations health burden in women, men, and children due to Summary metabolic dysfunction, obesity, diseases of aging, pre- term delivery, birth defects, costly and risky infertility therapies, and, through epigenetic mechanisms, it Glossary imprints the next generation. Stress is the most com- Allostasis A sustained adjustment that promotes mon and most commonly underappreciated cause survival in response to chronic challenge; of reproductive dysfunction (Table 1). Stress-induced may increase long-term health burden. anovulation (SIA), often termed functional hypotha- Anovulation The cessation of ovulation. lamic amenorrhea (FHA) or functional hypothalamic Cognitive- A form of psychoeducation or talk chronic anovulation, causes infertility and increases behavior therapy that addresses nonadaptive acute and chronic health burden. therapy thoughts, cognitions, attitudes, and Behaviors that chronically activate the limbic- conceptualizations. hypothalamic-pituitary-adrenal (LHPA) axis and/or Eumenorrhea A normal pattern of menstrual bleeding; chronically suppress the hypothalamic-pituitary- can occur in the absence of ovulation. thyroidal (HPT) axis compromise the hypothalamic- Gonadotropin- Decapeptide produced and released in a releasing hor- pulsatile mannner from hypothalamic pituitary-gonadal (HPG) axis in both women and mone (GnRH) neurons; stimulates the release of pitui- men by reducing hypothalamic gonadotropic-releasing tary lutenizing hormone (LH) and folli- hormone (GnRH) drive. Individuals with functional cle stimulating hormone (FSH). (not due to defined organic conditions) forms of Hypothalamic A condition characterized by suppres- hypothalamic hypogonadism typically engage in a hypogonadism sion of GnRH drive and, in turn, pitui- combination of behaviors in response to psychogenic tary LH and FSH, resulting in reduced stress that concomitantly induce intermittent or or absent gonadal steroidogenesis and chronic energy imbalance. Further, chronic adrenal gametogenesis. activation may increase the energetic cost of common Hypothalamic An allostatic adjustment in thyroidal activities such as running. In women, functional hypo- function that conserves energy expendi- hypothalamic hypogonadism exists on a spectrum thyroidism ture and is characterized by relatively nor- that includes polymenorrhea (menstrual interval mal levels of pituitary thyroid stimulating < hormone (TSH) in the presence of sup- 24 days), eumenorrhea with reduced luteal proges- pressed levels of thyroid hormones triio- terone secretion, and anovulatory eumenorrhea, dothyronine (T3) and thyroxine (T4). oligomenorrhea (menstrual interval 735 days), or Limbic- Neuroendocrine circuit that mediates amenorrhea (absence of menstruation for >3–6 hypothalamic- stress perception and stress responses. months). In men, oligoasthenospermia (very low pituitary- sperm count with low motility and abnormal mor- adrenal axis phology) may result, but this is typically not clinically Metabolism Biochemical processes that regulate evident unless fertility is being sought or severe energy expenditure and storage. testosterone deficiency results in muscle wasting or Secondary Cessation of menses in a woman of other phenotypic alterations. amenorrhea reproductive age who was previously eumenorrheic. This article focuses primarily on SIA/FHA in Stress Physical and psychological stimuli that women. SIA/FHA typically results from psychogenic challenge the status quo and elicit homeo- stress coupled with a mild energy imbalance and static or allostatic behavioral responses. represents an allostatic adaptation, that is, a stable 616 Stress Induced Anovulation

Homeostasis Chronic stress Allostasis

Cognitive-behavior therapy Metabolic challenge Psychogenic challenge –Excessive exercise –Performance pressure –Undernutrition –Unrealistic expectations –Nutrient deficiency –Poor coping strategies

Central neuromodulation

Hypothalamic adjustment

Pituitary

Glands Thyroid, parathyroid, gonads, adipocytes, pancreas, adrenal

Figure 1 Conceptualization of synergism between metabolic and psychogenic stress in the pathogenesis of stress-induced anovulation.

Table 1 Common causes of anovulation/amenorrheaa not promote recovery from allostatic endocrine adjustments in the adrenal and thyroidal axes. In- Percentage deed, the rationale for the use of sex steroid replace- Stress-induced anovulation/ functional 34 ment is based on the erroneous assumption that hypothalamic amenorrhea functional forms of hypothalamic hypogonadism rep- Hyperandrogenism/PCOS 29 resent only or primarily a loss of sex steroid exposure Hyperprolactinemia 13 due to reduced GnRH drive. Further, the replacement Premature menopause 12 Asherman’s syndrome 5 of sex hormones masks deficits that accrue from Other 7 chronically altered adrenal and thyroidal functions. a Long-term deleterious consequences of SIA/FHA Based on data presented in Reindollar, R. H., Novak, M., Tho, probably include an increased risk of cardiovascular S. P. T., et al. (1986), Adult-onset amenorrhea: a study of 262 patients, American Journal of Obstetrics and Gynecology 155, disease, osteoporosis, depression, other psychiatric 531–543. PCOS, polycystic ovarian syndrome. conditions, dementia, and neurodevelopmental com- promise in offspring. Although fertility can be restored with exogenous administration of gonado- change in behaviors and secretory patterns that pro- tropins or pulsatile GnRH, fertility management motes acute survival but at some health cost. SIA/FHA alone does not engender adrenal and thyroidal recov- affects roughly 5% of women of reproductive age; less ery. Pregnancy in the face of ongoing psychogenic severe forms of hypothalamic hypogonadism are more stress and metabolic imbalance may increase the like- common and are less clinically evident (Figure 2). lihood of poor obstetrical, fetal, or neonatal out- Stress-induced anovulation is theoretically revers- comes. In contrast, behavioral and psychological ible, but reproductive recovery appears to depend on interventions that address problematic behaviors the restoration of eucortisolemia and at least partial and attitudes have the potential to facilitate repro- recovery from functional hypothalamic hypothyroid- ductive recovery along with adrenal and thyroidal ism. Hormone replacement strategies have limited recovery. In short, full endocrine recovery offers bet- benefit for women with SIA/FHA because they do ter individual, maternal, and child health. Stress Induced Anovulation 617

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LH FSH Estradiol Progesterone

Figure 2 Continuum of ovarian function in women with preserved menstrual cyclicity. a, Ovulatory eumenorrhea; b, luteal insufficiency; c–d, eumenorrheic anovulation. Pituitary gonadotropin (LH and FSH) and ovarian sex steroid (estradiol and progesterone) levels were obtained daily for one cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone. Note that FSH > LH, but FSH < 20 IU/L, thus the cause of hypogonadism is hypothalamic rather than reduced ovarian reserve.

Neuroendocrine Mechanisms Linking The proximate cause of hypothalamic forms of Cognition, Mood, Behavior, and hypogonadism, including SIA/FHA, is reduced hypo- Gonadotropin-Releasing Hormone Drive thalamic GnRH input. Gonadal function depends directly on secretion from the hypothalamus of Our conceptualization of the bidirectional interaction GnRH as pulses. Declines in pulsatile GnRH secre- between behavior and gonadal function has been tion reduce pituitary secretion of luteinizing hormone refined by scientific insights into the mechanisms (LH) and follicle-stimulating hormone (FSH) and mediating neuroendocrine responses to thoughts, wholly or partially compromise folliculogenesis. feelings, and behaviors. 618 Stress Induced Anovulation

Decreased GnRH drive is a common cause of anovu- Table 2 Putative modulators of GnRH drivea lation and amenorrhea. Decrements in central GnRH–LH/FSH drive exist on a continuum, however, CRH Metabolic signals Opioids Sex steroids and may vary from day to day. Because of this poten- Adrenergic Gonadal peptides tial variability in GnRH drive, ovarian compromise GABA Growth factors exists on a spectrum and may present as polymenor- Dopamine Glial cells rhea, eumenorrhea, oligomenorrhea, or amenorrhea. Serotonin GnRH Clinically, the decreased ovarian function can be Immune Other occult or obvious. In men, decreased central GnRH a CRH, corticotropin releasing hormone; GABA, g-aminobutyric drive may cause oligoasthenozoospermia. Typically, acid; GnRH, gonadotropin-releasing hormone. gonadal compromise in men is clinically occult unless fertility is sought and the compromise is sufficiently significant to cause infertility. However, severe hypo- confined to central factors. The brain–gut axis thalamic hypogonadism in men may present as appears to communicate the metabolic status of an decreased libido, diminished muscle mass, or altered individual to the hypothalamic GnRH neurons hair (beard) growth. through multiple mechanisms. A partial list of puta- The most common cause of reduced GnRH drive is tive neuromodulators of GnRH drive is shown in functional; that it, it is not due to identifiable organic Table 2. causes such as hypothalamic tumors or pituitary Progress has been made in quantifying endocrine adenomas. Functional hypothalamic hypogonadism patterns for research purposes. However, in humans, can be defined as a common and theoretically re- GnRH pulsatile secretion can be inferred only from versible form of gonadal compromise in which the pattern of LH secretion in the circulation. Blood psychophysiological responses to life events activate samples must be obtained via an indwelling intrave- central neural networks and thereby alter glandular nous catheter at intervals of 10–15 min for durations secretion and metabolism. of 12–24 h. Even so, inherent limitations exist in The mechanisms mediating the disruption of cen- estimating GnRH secretion from peripheral LH pat- tral GnRH drive are poorly understood and complex. terns. The tedious nature of quantifying central GnRH GnRH neurons are diffusely distributed in the medial drive explains why this is not done routinely during basal hypothalamus. Most, but not all, GnRH axons clinical evaluation. Technical limitations also plague project to the median eminence, allowing pulses of the recognition and quantification of stress and meta- GnRH to be released into the portal vasculature. bolic status. The accuracy of psychometric inventories GnRH neurons communicate with one another via for assessing and quantifying stress, mood, and cogni- synapses. Although GnRH neurons are endogenously tive patterns is inherently constrained by reporting pulsatile, their activity must be synchronized by biases, whereas endocrine or biophysical indices of GnRH-to-GnRH synapses for the GnRH bolus re- stress and metabolic status are technically cumbersome leased into the portal vasculature to be of sufficient and expensive to collect. Neuroimaging techniques magnitude to trigger pituitary release of LH and FSH. have afforded a new window into the neurochemistry GnRH neurons receive synapses from neurons that and neuroanatomy of behaviors and thoughts, but contain GnRH, the endogenous opioid peptide these techniques have not yet been used to under- b-endorphin, neuropeptide Y (NPY), and catechola- stand the pathogenesis of stress-induced reproductive mines. Other factors that modulate the frequency or compromise. activity of the GnRH pulse generator are thought to Although innumerable animal studies have demon- exert their effects indirectly by acting through the strated that activation of the hypothalamic-pituitary- neuronal systems that have direct synaptic connec- adrenal (HPA) axis by a variety of stressful paradigms tions or by interacting with glial cells that interpose induces reproductive compromise, only a few studies between synapses. For instance, progesterone appears have elucidated the mechanisms mediating the disrup- to slow the frequency of pulsatile GnRH release by tion of GnRH drive. Direct evidence exists for corti- increasing hypothalamic opioidergic tone, but it also cotropin releasing hormone (CRH), b-endorphin, may cause glial cells to envelope the GnRH neurons dopamine, and arginine vasopressin. Recently, NPY and to reduce thereby the GnRH-to-GnRH connec- has been implicated as serving a neuromodulatory tions. Peripheral substances may gain access to the link between metabolic deficits induced by diet GnRH neuronal network via specialized neurovascu- and exercise and reduced GnRH drive. A key inhi- lar cells that line the fenestrated blood–brain barrier bitory neurotransmitter system in the brain uses at the level of the hypothalamus and median emi- g-aminobutyric acid (GABA). GABA opens the same nence, so the modulation of GnRH secretion is not potassium channels in neurons of the mediobasal Stress Induced Anovulation 619 hypothalamus as m-opioid receptor agonists such neurotransmission has been chronically altered to as b-endorphin. GABA inhibited GnRH gene expres- forge an allostatic state. The aim of allostatic adjust- sion in rats and suppressed pubertal GnRH increase ments is to allow the individual to cope with chronic in juvenile female rhesus monkeys, but the role as opposed to acute challenge. In this context, then, of GABA in human hypothalamic hypogonadism the hypothalamus links the external environment, the remains unclear. Serotonin neurons may also play a internal milieu, and gonadal function. role in modulating GnRH drive. The process of recovering from the allostatic state of SIA/FHA is also interesting but less well docu- Pathogenesis of Stress-Induced mented. We showed that women in the process of Anovulation recovering from functional hypothalamic hypogo- nadism displayed cortisol levels identical to those The best biochemical evidence supporting the con- of eumenorrheic women before there was complete cept that stress impairs ovarian function in women recovery of GnRH drive. Further, a marked increase is the consistent demonstration that women with in thyrotropin-stimulating hormone (TSH) drive hypogonadotropic hypogonadism not due to defined occurred as a prelude to increases in thyroxine and organic conditions have higher cortisol levels than thyronine. We recently reported that women with eumenorrheic, ovulatory women. There is direct SIA/FHA treated with cognitive-behavior therapy evidence that this relationship holds in women with (CBT) displayed a return of ovarian function and athletic amenorrhea as well. In a study by Loucks ovulation and reduced cortisol levels but had only et al., an inverse relationship was observed between partial recovery from hypothalamic hypothyroidism the degree of ovarian compromise and cortisol levels. and no weight gain. These data, coupled with our When compared with eumenorrheic but sedentary psychometric data showing that women with SIA/ women, eumenorrheic athletes had less luteal proges- FHA differ from eumenorrheic women (EW) in their terone secretion, as evidenced by lower urinary levels attitudes toward eating and desire for thinness, raise of pregnanediol-glucuronide, fewer LH pulses in a the possibility that intermittent or mild energy imbal- day, and higher cortisol levels. Furthermore, amenor- ance may persist after CBT-induced reproductive re- rheic athletes that were anovulatory had the fewest covery. In short, hypothalamic recovery involves a set LH pulses in a day and the highest cortisol levels of interlinked readjustments, including LHPA resto- despite comparable levels of exertion and fitness. An ration, return of GnRH pulsatility, and at least partial inverse relationship holds between adrenal activation remission of hypothalamic hypothyroidism, but the (independent of the life events or behaviors that initi- duration and sequence of recovery is just now begin- ate or sustain this activation) and suppression of the ning to be described and the role of metabolic factors hypothalamic GnRH drive to the ovary, as evidenced as mediators of recovery remains unclear. by marked reduction in LH pulse frequency. The characteristic hypothalamic alterations asso- Other hypothalamic outputs also are altered in ciated with SIA/FHA only become problematic women with SIA/FHA. Given the neuroanatomical when ongoing challenges elicit a chronic rather than integration of the hypothalamus, this is predictable. acute response. The long-term consequences of per- The purpose of the hypothalamus is to generate an sistent HPA activation have been studied in animal endocrine action plan to preserve the organism in the models and hippocampal neuron loss has been face of challenge. Part of the action plan involves documented. Stress appears to increase the risk of metabolic mobilization. However, metabolic mobili- dementia and other neurodegenerative disorders. zation involves more than an increase in cortisol se- Other long-term sequelae of persistent metabolic mo- cretion. In SIA/FHA, the thyroid axis differs from that bilization are largely unknown, but there is no reason of eumenorrheic women in that thyrotropin (TSH) is to assume that such a process is benign. For instance, not increased in response to decrements in thyronine recent data obtained in women with weight-restored and thyroxine, which indicates an altered hypotha- anorexia nervosa who remained amenorrheic indi- lamic set point akin to what is seen in hospitalized cated that exogenous sex steroid replacement was patients who develop what is referred to as sick eu- unable to stimulate appropriate bone accretion. The thyroid syndrome. In athletic women, a similar alter- investigators speculated that the ineffectiveness of ation in the thyroid axis was seen only in those who hormone exposure was due to ongoing metabolic had compromised ovarian function. The secretory derangements such as increased cortisol exposure, patterns of growth hormone, prolactin, and melato- altered growth hormone action, or hypothalamic hy- nin also differed from those of eumenorrheic women. pothyroidism. Because of the concomitant endocrine The constellation of neuroendocrine aberrations that and metabolic disturbances, hypothalamic hypo- accompany SIA/FHA strongly suggests that central gonadism must be regarded as a condition deserving 620 Stress Induced Anovulation clinical attention even when fertility is not an imme- 6 diate goal. * ) 1

The central neuromodulators responsible for the − initiation and maintenance of the disruption of GnRH 4 are difficult to identify in humans. First, the factors that initiate allostasis may differ from those that 2 maintain allostasis. To study initiating factors, we would need to intensely monitor populations at risk Cortisol (ng ml for the development of hypothalamic hypogonadism 0 or try to induce hypothalamic hypogonadism in a (a) EW SIA/FHA nonhuman primate model. Once a chronic hypogo- nadal state had been reached, it theoretically would 50 be possible to identify the agents that maintain this 40 ) disruption by administering antagonists that cross the 1 − brain–blood barrier, by performing lumbar punctures 30 and obtaining cerebrospinal fluid (CSF), or by per- forming neuroimaging studies with an appropriate 20 ligand. To date, efforts to identify these neuromodula- CRH (pg ml 10 tors in humans have yielded inconsistent results. Thus, naloxone, an opioidergic blocker, increased LH pulse 0 frequency or levels in some, but not all, women with (b) EW SIA/FHA SIA/FHA. Also, the infusion of metoclopramide, a Figure 3 Mean Æ SE cerebrospinal fluid hormone levels in dopamine receptor blocker,to women with FHA accel- eumenorrheic women (EW) and women with SIA/FHA, demon- erated LH pulse frequency, whereas that of eumenor- strating allostatic resistance to cortisol feedback suppression of rheic women remained constant. These data suggest CRH. a, Cortisol levels; b, CRH levels. CRH, corticotropin releas- ing hormone; SIA/FHA, stress-induced anovulation/functional that there may be dopaminergic as well as opioidergic hypothalamic amenorrhea. From Brundu, B., Loucks, T. L., Adler, inhibition of GnRH drive. To explore the hypothesis L. J., et al. (2006), Increased cortisol in the cerebrospinal fluid that the reduction in GnRH drive was maintained of women with functional hypothalamic amenorrhea, Journal of by CRH, vasopressin, b-endorphin, or a combination Clinical Endocrinology and Metabolism 91, 1561–1565. of these factors, we performed lumbar punctures to obtain rostral CSF in women with SIA/FHA and those with eumenorrhea. This approach revealed increased CRH in the CSF of women with depression, but we tone was reduced in stress-sensitive as contrasted found that CRH levels were identical in women with with stress-resilient monkeys. Second, serotonergic SIA/FHA and eumenorrhea. Vasopressin levels were neurons, which express leptin receptors, terminate similar, but, surprisingly, b-endorphin levels were on GnRH neurons. Serotonin has satiety effects simi- lower in women with SIA/FHA. Further, we evaluated lar to those of leptin and may modulate the response free cortisol in the CSF of these same women and to orexigenic and anorectic signals. Moenter’s lab found that these levels were approximately 30% higher exposed fasting female mice to saline, leptin, or in those women with stress-induced anovulation. In fluoxetine, a selective serotonin reuptake inhibitor aggregate, these findings (Figure 3) support the notion (SSRI) antidepressant, and followed estrus cycle that the preservation of CSF CRH levels in the presence length. Leptin and fluoxetine prevented fasting- of elevated CSF cortisol reflects chronic stress-induced induced cycle lengthening, whereas the serotonin re- (allostatic) resistance to negative feedback suppression ceptor antagonist metergoline blocked cycle rescue by by cortisol. fluoxetine. Treating leptin-deficient ob/ob and leptin Other putative central neurotransmitters that receptor-deficient db/db mice with fluoxetine did not may contribute to the initiation and maintenance of normalize body weight or rescue estrus cycles. Fur- SIA/FHA are the serotonergic and GABAergic sys- ther, there is abundant evidence of a role for the tems. Several lines of evidence suggest that seroton- serotonergic system in the regulation of stress reactiv- ergic function gates stress reactivity and metabolism. ity and feedback inhibition of the HPA axis by corti- First, we showed in our monkey model of SIA/FHA sol. In addition, variation in transporter-facilitated that stress-sensitive monkeys had larger cortisol uptake of serotonin has been implicated in anxiety elevations and reduced prolactin responses to fen- in humans and in animal models of anxiety and fluramine, a serotonergic agonist. These data were stressfulness. Human serotonin reuptake transporter interpreted as indicating that central serotonergic (SERT) gene transcription is modulated by a common Stress Induced Anovulation 621 polymorphism in its upstream regulatory region. The food restriction and excessive exercise, are often short variant reduces the transcriptional efficiency of initiated to cope with psychogenic stress. However, the SERT gene promoter, resulting in decreased SERT until proven otherwise, the safest assumption is that expression and serotonin reuptake. The short (s) var- stress comes in flavors and that some individuals are iant polymorphism is associated with an increased more sensitive than others to the same stressor or set incidence of affective disorders in humans and of stressors. maladaptive behavior in monkeys coincident with increased HPA responsivity to stress. Further, the Behavioral Influences long/short genotype produces a phenotype similar to A number of behavioral and other psychogenic fac- that of the short/short genotype. In humans, the tors including exercise, low weight and weight loss, SERT polymorphisms moderated the influence of affective and eating disorders, various personality stressful life events on depression in a representative characteristics, drug use, and external and intrapsy- birth cohort. Stress-sensitive monkeys had a lower chic stresses have been associated with functional expression of SERT mRNA and monoamine oxidase hypothalamic hypogonadism. Given individual vari- A (MAO-A) in the caudal region of the dorsal ation in metabolism, autonomic tone, habitus, apti- raphe nucleus, whereas no differences were detected tudes, attitudes, and psychological valences, what is between stress-sensitive and stress-resilient monkeys stressful to one person may be more or less so to in the mRNA for the serotonin 1A autoreceptor or another. Therefore, it is not surprising to find behav- MAO-B. The determinants of stressfulness in women ioral heterogeneity in the pathogenesis of SIA/FHA. with SIA/FHA are incompletely understood, and this Any given stressor, when the dose is large enough, can is certainly one of the variables that warrants further probably activate the central neural pathways leading investigation. to the disruption of GnRH. In clinical research, the Judd et al. reported that a single 2 mg dose of trend has been to study single stressors and to parti- alprazolam, a GABA receptor agonist, decreased cor- tion as separate populations women with exercise tisol levels and increased LH pulse frequency from amenorrhea, anorexia nervosa, and idiopathic amen- 0.8 to 2.0 pulses/8 h in women with stress-related orrhea. Populations studied in clinical research set- anovulation, whereas its administration decreased tings may not be entirely representative of all women LH pulse frequency in eumenorrheic women in the with SIA/FHA because research subjects must meet follicular phase. These data also suggest a possible relatively strict inclusion and exclusion criteria. In indirect role for GABA neurons in the stress-induced general, women with SIA/FHA do not report or do neuromodulation of GnRH pulsatility. Not surpris- not have an easily identified solitary stressor. Typical- ingly, the neurochemistry of stress and SIA/FHA is far ly, there are multiple, seemingly minor, stressors, such from simple, and firm mechanistic conclusions are as a combination of job or school pressures, poor not possible at present. eating habits, and increased energy expenditure through activity or exercise. Behavioral, Nutritional, and Metabolic To understand the role of psychological variables, Influences on the Reproductive Axis such as attitudes and expectations, in the pathogene- sis of SIA/FHA, we compared three groups of women: Identification of factors that activate the adrenal axis those with eumenorrhea and demonstrable luteal and suppress the thyroidal and ovarian axes can adequacy; those with SIA/FHA unrelated to excessive be challenging. It has been suggested that different exercise, weight loss, an eating disorder, drug use, or stressors and behaviors activate somewhat different an affective disorder; and those with anovulation due central mechanisms, such that the signals that alter to an identifiable organic cause. Being amenorrheic, hypothalamic function are specific to the type of regardless of cause, was associated with a compro- stressor. Indeed, this variability may well explain in mised sense of psychological equilibrium as reported part why the neurochemistry of stress is so complex. on psychometric inventories, but, as a group, only Psychosocial dilemmas are seen as activating those women with SIA/FHA differed from the other groups central pathways subserving perception, whereas ex- on scales that measured unrealistic expectations and ercise and weight loss are generally viewed as disturb- dysfunctional attitudes (defined as attitudes likely ing metabolic regulation. Although it seems logical to impair coping responses). For instance, women that specificity in the neural or peripheral cascades with SIA/FHA were both highly perfectionistic and mediating responses to specific stressors exist, we sociotrophic (having a high need for social approval). currently have no method for clearly delineating psy- Because perfectionism interferes with social approval chogenic from metabolic stress. Psychogenic stress or acceptance, one interpretation is that the concomi- has a metabolic cost and metabolic stressors, such as tant high drive for perfectionism and sociotrophy 622 Stress Induced Anovulation creates an intrapsychic conflict that women with SIA/ having been given to the secondary consequences of FHA may not possess the appropriate coping skills to obesity on endometrial development and central hy- resolve. Another interpretation is that the expectation pothalamic drive. Few studies have characterized the of simultaneously being perfect and garnering social role of nutritional signals in the modulation of approval is an unrealistic expectation of self and reproductive function in men, but available evidence others. Our earlier study suggested that women with suggests that undernutrition is as deleterious to repro- SIA/FHA had trouble relaxing and having fun, attri- ductive competency in men as it is in women. butes that may further predispose them to value per- Metabolic imbalance occurs when energy expendi- formance at the expense of psychological needs. ture exceeds energy intake (negative energy balance). Although women with SIA/FHA do not typically The brain is the most metabolically active tissue in the meet the criteria for an eating disorder, they display body, requiring 16 times more energy per unit mass many attitudes and behaviors similar to women with than muscle tissue. Because humans have much big- eating disorders, such as a drive for thinness and ger brains relative to body size than do other primates disordered eating. What appears to separate women or other species, they use more of their daily energy with undifferentiated SIA/FHA from those with an intake than any other species to supply their brain; eating disorder is the degree of disturbance, including humans are estimated to use 25%, monkeys 8%, and the degree of food restriction, weight loss, binging, rodents 5%. Indeed, as a species, humans may be and perfectionism. However, direct comparisons have uniquely sensitive to energy imbalance. Metabolism not been conducted for any of these psychological reflects the interactions of the neuroendocrine system attributes, so these interpretations are based on (e.g., HPA and HPT axes), body composition (adipo- impressions from extant literature. The bottom line kines), and the enteric system (insulin, ghrelin, etc.). is that attitudes and expectations engender behaviors Given the multitude of redundant metabolic and such as aberrant food intake and excessive exercise nutritional signals communicating energy status to that further challenge the hypothalamus to maintain the brain, it is difficult to specify the independent homeostasis. Whether the identifiable behavior is per- role of any one factor or signal. Signals reflecting formance pressure, exercise, or irregular food intake, energy stores, recent nutritional information, and the end result is the same, that is, the disruption of the specific classes of nutrients are integrated in the cen- GnRH pulse generator to the extent that anovulation tral nervous system, particularly the hypothalamus, occurs. It stands to reason, then, that the key to to coordinate energy intake and expenditure. Chronic recovery is to change both the behaviors and attitudes energy deficiency alters thyroidal function to slow that have initiated and now sustain reduced GnRH metabolism and correct negative energy balance. drive. Once the hypothalamic GnRH pulse generator Food intake is influenced by availability, emotional has been disrupted, it may take a prolonged duration state, social cues, and learned behaviors. Although of energy balance and improved psychological equi- peripheral signals convey information about energy librium for the hypothalamic allostasis to reverse and stores and immediate energy availability to the hypo- for ovulatory function to return. thalamus, particularly the arcuate nucleus, these two The available data suggest that any behavior or categories of signals are not exclusive. For instance, expectation that concomitantly activates to a suffi- leptin and insulin, which are actively transported cient degree the HPA and HPT axes has the potential across the blood–brain barrier, potentiate satiety sig- to disrupt the GnRH pulse generator. Thus, the list of nals. Thus, the level of any one signal per se may be behaviors and attitudes associated with the develop- less important than the action of that hormone, and ment of SIA/FHA is expected to be diverse and exten- the action is likely to be gated by the constellation of sive. Generally, a mix of multiple, seemingly minor other metabolic signals. Putative orexigenic signals psychogenic and metabolic stressors appears to be include ghrelin, NPY, orexins A and B, melanin- more deleterious to reproductive function than a concentrating hormone (MCH), and agouti-related solitary stressor. peptide. Putative anorectic and satiety signals include (but are not limited to) cortisol, CRH, insulin, glu- Nutritional and Metabolic Influences cose, resistin, leptin, proopiomelanocortin (POMC), Nutritional and metabolic signals play critical roles cocaine- and amphetamine-regulated transcript in the elaboration of homeostatic and allostatic (CART) peptide, peptide YY (PYY), and glucagon- responses to ongoing challenges and can influence like peptide (GLP)-1. Adipokines (adipocyte-derived the reproductive system at many levels. Research on hormones) implicated in energy regulation include lep- overnutrition has focused primarily on specifying its tin, adiponectin, and resistin. Leptin is the dominant effects on gonadal function, with some attention long-term energy signal informing the brain of adipose Stress Induced Anovulation 623 energy reserves; it also functions as a satiety signal. appetite and a reduction in food intake so as to Adiponectin acts as an insulin-sensitizing agent by shift attention away from maintenance/sustenance reducing hepatic glucose production and is reduced in needs and toward coping responses. Chronic reduc- obesity. Resistin is linked to insulin tolerance and tions of appetite and energy intake in the face of an decreases glucose uptake by adipocytes. Ghrelin, a increase in energy demand probably represent appetite 28-amino-acid acylated hormone that is also a growth or metabolic allostasis; because of ensuing hypotha- hormone secretagogue, is produced by the gastrointes- lamic hypothyroidism, undernutrition may develop tinal tract, especially the fundus of the stomach. Plasma without weight loss. The exact mechanisms subserving ghrelin levels rise during fasting and immediately be- the multiple associations between reproduction and fore anticipated mealtimes and then fall within an hour nutrition and the applicability of animal studies to of food intake, suggesting that ghrelin is important for human syndromes remain to be determined. Given meal initiation. Given the plethora of nutritional and the considerations outlined here, including the high metabolic signals, specifying their independent effects metabolic demands of the human brain, energetic is challenging, particularly in humans. imbalance may have more serious reproductive con- Relevant human studies on the role of these factors in sequences for humans than for other animals. reproduction are few. Depression, like stress, involves Psychological states generate metabolic demands. LHPA axis dysregulation and is associated with loss of Psychological states recognized as stressors activate appetite; resistin levels correlated with free cortisol the LHPA axis. When this activation is acute and levels and adiponectin correlated with insulin sensi- limited, the adrenal releases a bolus of cortisol, a tivity in a study of depressed humans. In a rodent hormone with multiple metabolic properties. If the model, the central LHPA axis challenge of hypoxia stressor is chronic and mild to moderate, then there is and the LHPA axis feedback challenge of dexametha- modest activation of the LHPA such that cortisol is sone independently decreased body weight and mildly elevated but the circadian pattern of cortisol increased adiponectin levels, whereas dexametha- is preserved. With extreme unremitting stress, cortisol sone, but not hypoxia, increased resistin. In women, secretion is elevated and there is loss of the circadian ghrelin levels were reported to be increased in anorex- pattern. Conditions that chronically activate the ia nervosa and exercise amenorrhea. However, Troisi LHPA axis have been associated with a spectrum of et al. observed lower ghrelin in women with anorexia reproductive impairment. or bulimia that correlated with serum cortisol levels. In summary, there is a plethora of metabolic signals In these studies, subjects and controls differed mark- that reflect the acute and chronic nutritional state of edly with regard to body weight and leptin levels, a given individual. These signals convey information food intake was not assessed, and the diurnal pattern to important tissues and organs and thereby engender of ghrelin was not determined; for instance, De Souza homeostatic and allostatic responses. A key target et al. and Tanaka et al. obtained only a single mor- tissue is the brain. Both undernutrition and over- ning’s blood sample after an overnight fast and Misra nutrition impact reproductive processes. Given the et al. determined ghrelin levels only overnight. Of energetic demands of reproductive processes, how- note, Miljec et al. reported ghrelin insensitivity ever, undernutrition has the potential to induce in response to an infusion of ghrelin in women more significant reproductive compromise. with anorexia nervosa compared to eumenorrheic women, but appetite was measured only by self- Synergism among Stressors report and not by food intake. Women with SIA/ FHA are more active than most eumenorrheic women The notion that stress comes in neurochemical flavors and tend to consume less fat and more carbohydrates, is supported by animal studies suggesting that there but reproductive recovery from SIA/FHA did not re- are subtle but distinct differences in the neuroendo- quire weight gain and was not associated with a change crine responses to different stress paradigms. Further, in standard metabolic variables such as leptin. neuroendocrine and metabolic responses to acute A balance between energy intake and expenditure exercise were greater in men whose HPA axis did is critical to survival. Every action, even thinking, has not suppress when they were given dexamethasone an energetic cost. Given the fundamental nature of before the exercise challenge. These data indicate that metabolism, it is not surprising that organisms have the degree of HPA activation potentiates the neuro- evolved a complex and redundant signaling system endocrine and metabolic responses to subsequent to gate appetite, food-seeking behavior, and fuel challenge. Conversely, Altemus et al. showed that storage. Although stress increases energetic demand, lactating women are hyporesponsive to exercise the acute behavioral response is often a blunting of challenge. Taken together, these data buttress the 624 Stress Induced Anovulation notion that responses to a given stressor are gated not availability of 10 kcal/kg of LBM (75% deficit), the only by the stressor type but also by host factors, mean 24-h cortisol was increased by approximately including hormonal and metabolic states. Thus, 30%, which is the amount of increase typically seen some individuals are clearly more reactive to similar in women with SIA/FHA. Much like stress-sensitive stressors than others. Obviously, emotional valence monkeys, women whose luteal phase progesterone and expectations also determine the extent to which levels were lowest at the initiation of the energy re- psychosocial variables serve as a psychogenic stressors. striction showed the greatest response to the imposed Our preliminary investigations in women who devel- metabolic challenge. In most real-life situations, ex- oped SIA/FHA unrelated to weight loss, exercise, and cept for extreme circumstances such as war or fam- definable psychiatric disorders indicated that a prima- ine, metabolic deficits are not imposed but, rather, ry factor that distinguished women with SIA/FHA initiated by individuals in response to self-imposed from those with definable causes of anovulation and expectations including drive for thinness. Most those who were ovulatory was the presence of unreal- women with SIA/FHA, when carefully evaluated, dis- istic expectations. Fioroni also found that women with play more than one trait, state, or behavior capable SIA/FHA, compared to eumenorrheic women or those of activating stress response cascades or inducing a with other causes of anovulation, held more negative mild metabolic deficit, but most do not have a pro- attributions about recent life events. Kirschbaum found metabolic deficit that alone would explain the found that men who did not habituate when exposed reduction in central GnRH drive. Many of the beha- to repeated psychogenic challenge viewed themselves viors, such as exercise, that independently suppress cen- as less attractive, had lower self-esteem, and reported tral reproductive drive but only at more extreme levels, being in a depressed mood more often. Apparently, may be initiated as coping responses to psychosocial unachievable ambitions or other cognitive distortions dilemmas. Because of the synergism between meta- create vulnerability to life’s inevitable challenges and bolic and psychogenic stressors, a combination of probably heighten responsivity to metabolic stressors multiple, small magnitude, mixed stressors may be such as exercise or food restriction. Potentially, the potentially more disruptive of reproductive function converse is true. Energetic imbalance may augment than a single large stressor limited to one category. reactivity to psychogenic stressors. To better understand how a combination of seem- There can be no doubt that weight loss and exercise ingly minor psychogenic and metabolic stressors serve as metabolic stressors. In monkeys trained to might synergistically disrupt GnRH drive as demon- run, it was shown that caloric supplementation re- strated in our monkey model, we compared endo- versed the anovulation induced by training. Interest- crine responses to submaximal exercise in women ingly, the monkeys did not spontaneously develop a with SIA/FHA to those in eumenorrhea. Women with compensatory increase in appetite and had to be SIA/FHA displayed a larger increase in cortisol bribed with colorful candy to consume more calories. than ovulatory eumenorrheic women in response to On the other hand, modest dietary restriction accom- exercise. Further, glucose responses between the two panied by small amounts of exercise greatly increased groups were divergent in that women with SIA/FHA the proportion of monkeys who become anovulatory showed a 10% decrease in glucose whereas eumenor- when presented with social stress. A prospective rheic women had a modest 3% increase in glucose, study of unselected women demonstrated that exer- presumably to cope with the energetic demand of cise and weight loss caused anovulation. It is likely exercise. Interestingly, these two groups did not differ that sufficient exercise and weight loss, independent at baseline with regard to cortisol or glucose levels. of psychogenic stress, can alter metabolism to the The decrement in glucose seen in SIA/FHA but not point that GnRH pulsatility is disrupted. Loucks eumenorrheic women suggests latent metabolic com- and Thurma quantified the amount of energy res- promise and indicates that SIA/FHA women are un- triction needed to impact GnRH drive by studying able to meet energetic demands of ongoing activities. eumenorrheic women in the follicular phase. Energy Further, it is likely that the drop in glucose activates balance was achieved by providing 45 kcal/kg of lean the HPA axis and is at least partly responsible for body mass (LBM)/day. Graded daily energy deficits the sustained hypercortisolemia characteristic of of 10, 25, and 35 kcal/kg were then experimentally SIA/FHA. Because metabolic signals modulate induced for 5 days. An energy deficit of 33% had no GnRH pulsatility, exercise-induced metabolic imbal- impact on LH pulse frequency, whereas an energy ance also probably contributes to ongoing repro- deficit of approximately 75% induced a decline in ductive suppression. These results also reveal why LH pulse frequency of approximately 40%. The the endocrine effects of a stressor, such as exercise, induction of an energy deficit resulted in a graded depend on the preexisting neuroendocrine and increase in the 24-h cortisol level. At an energy metabolic state of the individual. Stress Induced Anovulation 625

Treatment Considerations of preterm delivery. It is not known if the endocrine concomitants associated with SIA/FHA pose a similar SIA may not be recognized unless the menstrual inter- risk, but this is clearly a potential hazard if ovulation val is markedly short, long, irregularly irregular, or induction is undertaken before amelioration of the absent. Likewise, luteal phase insufficiency due to allostatic changes in the adrenal and thyroidal axes. decreased hypothalamic drive may not be noted un- A popular approach to a woman with SIA/FHA less infertility results. Even then, luteal insufficiency is who is not seeking immediately to become pregnant notoriously difficult to document unless it is recur- is to offer her hormone replacement. This approach is rent. Based on the foregoing concepts, we speculate based on the presumption that sex steroid deprivation that the more clinically evident the ovarian compro- is the primary therapeutic issue. There are inherent mise, the greater is the hypothalamic challenge and limitations with this approach, however. First, data the more profound are the associated adrenal and indicate that exogenous sex steroid exposure does not thyroidal derangements and sex steroid deprivation. fully promote bone accretion or cardioprotection in If a woman with functional hypothalamic hypo- the presence of ongoing metabolic derangements. gonadism is seeking to become pregnant, ovulation Second, the ongoing insults to the brain from chronic induction can be accomplished technically with the amplification of stress cascades go unchecked. Fur- exogenous administration of pulsatile GnRH therapy ther, estrogen therapy does not correct hypothalamic or gonadotropins. The administration of exogenous hypothyroidism. In short, hormone therapy may GnRH therapy is advantageous insofar as it di- mask potentially deleterious processes that are un- minishes the risk of ovarian hyperstimulation and likely to be ameliorated by hormone exposure alone. multiple gestation associated with gonadotropins. It is critical to remember that SIA/FHA is more than a Clominphene citrate is an option, but it may be less disorder of reduced GnRH secretion. effective because of its hypothalamic site of action Hormone therapy per se is unlikely to be harmful, and the hypothalamus of women with SIA/FHA is but more than hormone administration is needed – already not responding to decreased sex steroid the stress process needs to be interrupted. Although secretion. Concerns have been raised that ovulation psychopharmacological approaches have not been induction may place women with SIA/FHA at increa- well studied, they probably could be used on an inter- sed risk for premature labor and intrauterine growth im basis in special circumstances. The study by Judd restriction. The parenting skills of women with suggested that a short course of alprazolam might SIA/FHA may be impaired because they are already be effective in reducing HPA activation and permit- overwhelmed and stressed prior to pregnancy and ting hypothalamic-pituitary-ovarian (HPO) recovery. delivery and their psychological precariousness may However, this approach is not recommended for a place their children at risk for poor psychosocial woman hoping to conceive. The optimal intervention development. Further, a recent study showed that is to reverse the stress process so that the hypotha- children born to mothers with clinically occult lamus recovers and gonadal function resumes. An hypothyroidism due to autoimmune thyroiditis had integral goal of the treatment plan for women with a mean full-scale intelligence quotient that was seven functional hypothalamic hypogonadism is to help points lower than the control population. The women them identify and ameliorate the sources of psycho- with clinically silent hypothyroidism had a 30% genic and metabolic stress and to provide emotional reduction in thyroxine, which is roughly what is ob- support while they learn coping mechanisms other served in women with SIA/FHA. Of critical impor- than dieting or exercising. Nonpharmacological tance is the fact that maternal thyroxine is the only interventions such as stress management, relaxation source of fetal thyroxine in the first trimester and the training, or psychoeducation empower individuals by predominant fetal source in the second and third fostering self-care and competency. In this regard, trimesters. Because the fetal brain requires an appro- nonpharmacological therapies have the potential to priate amount of thyroxine for neurogenesis, even produce long-term benefits on psychological and, small deficits in thyroxine may induce neurodevelop- thereby, physical health. Behavioral therapies ac- mental deficits. Increased maternal cortisol may also knowledge the wisdom of the body and understand have independent effects on fetal neurodevelopment that SIA/FHA represents an endocrine adaptation and organogenesis. Recent evidence showed that se- that can be reversed with appropriate psychogenic vere stress, such as that associated with the unexpect- and behavioral modifications. ed death of a child, increased the risk of congenital Given these considerations, we recently studied anomalies of the cranial neural crest eightfold. Fur- whether CBT aimed at ameliorating problematic atti- ther, stress and its endocrine concomitants and even tudes and behaviors facilitated ovarian recovery in brief undernutrition have been implicated as a cause 626 Stress Induced Anovulation normal weight women with SIA/FHA. Women with ovulation, whereas only 25% of those in the obser- SIA/FHA were randomly assigned to observation vation group did. Figure 4 illustrates the recovery of versus CBT groups. CBT consisted of 16 visits with a sex steroid secretion in a woman in the CBT group physician, therapist, or nutritionist during 20 weeks. who showed ovarian recovery and in a woman in The two groups were followed for return of menses the observation group who did not have recovery for up to 8 weeks following the intervention. Regard- of ovarian function. Interestingly, when it occurred, less of menstrual pattern, estradiol and progesterone ovarian recovery was not associated with significant levels were monitored at weekly intervals for 4 weeks weight gain. This does not mean that subjects did not before and after observation or CBT. Approximately alter food intake or energy expenditure, however. 88% of those who underwent CBT had evidence of Improved nutrition generally restores the thyroidal

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Figure 4 Serum estradiol and progesterone levels and menstrual bleeding in women with SIA/FHA. a, A patient who was observed and did not recover; b, a patient who was treated with cognitive-behavior therapy and recovered. CBT, cognitive-behavior therapy; SIA/FHA, stress-induced anovulation/functional hypothalamic amenorrhea. From Berga, S. L., Marcus, M. D., Loucks, T. L., et al. (2003), Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy, Fertility and Sterility 80, 976–981. Stress Induced Anovulation 627 axis, thereby leading to an increased basal metabolic See Also the Following Article rate and a need for more calories. Our earlier studies Allostasis and Allostatic Load. showed that women who experienced a spontaneous recovery from SIA/FHA were eucortisolemic, had increased but not fully restored LH pulsatility, and Further Reading markedly increased TSH levels in the face of persis- Altemus, M., Deuster, P. A., Galliven, E., et al. (1985). tent reductions in T3 and T4 levels. We recently com- Suppression of hypothalamic-pituitary-adrenal axis pared metabolic variables in women who did and responses to stress in lactating women. Journal of Clini- who did not recover from SIA/FHA after CBT inter- cal Endocrinology and Metabolism 80, 2954–2959. vention and observed that ovarian recovery was asso- Alvero, R., Kimzey, L., Sebring, N., et al. (1998). Effects of ciated with a decline in cortisol and increase in TSH fasting on neuroendocrine function and follicle develop- but that thyroidal hormones and leptin levels were ment in lean women. Journal of Clinical Endocrinology comparable between recovered and unrecovered and Metabolism 83, 76–80. women. Taken together, these findings suggest that Ariyasu, H., Takaya, K., Tagami, T., et al. (2001). Stomach is major source of circulating ghrelin and feeding state the thyroidal axis, which gates metabolic tone, determines plasma ghrelin-like immunoreactivity levels remains restrained by an as yet uncharacterized fac- in humans. Journal of Clinical Endocrinology and tor(s) after HPA and HPO recovery or recovers more Metabolism 86, 4753–4758. slowly than the HPA and HPO axes, similar to the Badman, M. K. and Flier, J. S. (2005). The gut and energy recovery timeline related to acute illness. Ultimately, balance: visceral allies in the obesity wars. Science 307, behavioral and psychological interventions that ad- 1909–1914. dress problematic behaviors and attitudes permit the Barr, C. S., Newman, T. K., Schwandt, M., et al. (2004). resumption of ovarian function along with recovery Sexual dichotomy of an interaction between early adver- of the LHPA and HPT axes. In short, full endocrine sity and the serotonin transporter gene promoter variant recovery offers better individual, maternal, and child in rhesus macaques. Proceedings of the National Acade- health. my of Sciences USA 101, 12358–12363. Barr, C. S., Newman, T. K., Shannon, C., et al. (2004). Rearing condition and rh5-HTTLPR interact to influence Summary limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biological Psychiatry 55, Stress is one of the most common and most commonly 733–738. underappreciated causes of infertility and reproductive Becker, A. E., Grinspoon, S. K., Klibanski, A., et al. (1999). compromise in men and women. Stress-induced hypo- Eating disorders. New England Journal of Medicine 340, thalamic hypogonadism increases the acute and chron- 1092–1098. ic health burden for individuals and their offspring. Bennett, A. J., Lesch, K. P., Heils, A., et al. (2002). Early Our findings regarding the pathogenesis of SIA/FHA experience and serotonin transporter gene variation reveal a powerful synergism between metabolic imbal- interact to influence primate CNS function. Molecular ance and psychogenic challenge and underscore that Psychiatry 7, 118–122. Berga, S. L. (2002). Disorders of gonadotropin secretion. seemingly mundane psychological issues evoke not In: Wass, J. & Shlet, S. M. (eds.) Oxford textbook of only reproductive compromise but also concomitant e&ocrinology and diabetes, pp. 1119–1129. Oxford neuroendocrine and metabolic allostasis. These mech- University Press. anistic pathobiological insights have been harnessed to Berga, S. L. and Daniels, T. L. (1991). Use of the laboratory develop therapeutic options aimed at ameliorating the in disorders of reproductive neuroendocrinology. Journal sustaining cognitive and behavioral variables. By of Clinical Immunoassay 14, 23–28. showing that CBT reverses SIA/FHA, we can appreci- Berga, S. L., Daniels, T. L. and Giles, D. E. (1997). Women ate the inherent neural plasticity that forms the ratio- with functional hypothalamic amenorrhea but not other nale for coupling mindfulness approaches with the forms of anovulation display amplified cortisol concen- judicious use of psychopharmacological and technical trations. Fertility and Sterility 67, 1024–1030. interventions. Berga, S. L., Loucks, A. B., Rossmanith, W. G., et al. (1991). Acceleration of LH pulse frequency in functional hypothalamic amenorrhea by dopaminergic blockade. Acknowledgments Journal of Clinical Endocrinology and Metabolism 72, 151–156. Portions of the work presented herein were funded Berga, S. L., Loucks, T. L. and Cameron, J. L. (2001). by grants from the National Institutes of Health Endocrine and chronobiological effects of fasting in (R01-MH50748 to SLB and RR-00046 to the women. Fertility and Sterility 75, 926–932. General Clinical Research Center at the University Berga, S. L., Loucks-Daniels, T. L., Adler, L. J., et al. (2000). of Pittsburgh). Cerebrospinal fluid levels of corticotropin-releasing 628 Stress Induced Anovulation

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Stress Management and Cardiovascular Disease

D Lane Glossary Sandwell and West Birmingham Hospitals NHS Trust, Angina Chest pains, often radiating to the arms, Birmingham, UK pectoris shoulders, and jaw, arising from reduced D Carroll blood flow to the heart as a result of University of Birmingham, Birmingham, UK coronary atherosclerosis. ã 2007 Elsevier Inc. All rights reserved. Angiography A technique for measuring the extent of coronary atherosclerosis. This article is a revision of the previous edition Atherosclerosis An accumulation of fatty deposits article by D Lane and D Carroll, volume 3, pp 527–531, causing hardening and narrowing of ã 2000, Elsevier Inc. the arteries. Cardiac A combination of lifestyle education, rehabilitation exercise, and, increasingly, stress man- Stress Management Training agement training directed at patients Essential Hypertension suffering from coronary heart disease. Angina Pectoris The aim of cardiac rehabilitation is to Myocardial Infarction facilitate physical, psychological, social, Conclusions and emotional recovery.