Disturbances of the Stress Response

The Role of the HPA Axis During Alcohol Withdrawal and Abstinence

Bryon Adinoff, M.D., Ali Iranmanesh, M.D., Johannes Veldhuis, M.D., and Lisa Fisher, Ph.D.

Interactions among the brain, the pituitary gland, and the adrenal glands (i.e., the hypothalamic-pituitary-adrenal [HPA] axis) help regulate the body’s response to stress. The adrenal hormone cortisol plays a key role in stress reduction through its effects on multiple body systems. Excessive cortisol activity during both chronic alcohol administration and withdrawal may underlie some of the clinical complications of alcoholism, including increased risk of infectious diseases; bone, muscle, and reproductive system changes; altered energy metabolism; and disorders of mood and intellect. Despite excessive cortisol levels during intoxication and withdrawal, however, the HPA axis becomes less responsive to stress during abstinence, potentially resulting in an impaired capacity to cope with relapse-inducing stressors. KEY WORDS: AOD withdrawal syndrome; physiological stress; hypothalamic-pituitary axis; pituitary-adrenal axis; cortisol; AOD abstinence; chronic AODE (alcohol and other drug effects); corticotropin RH; arginine; vasopressin; adrenocorticotropic hormone; secretion; metabolic disorder; AODR (alcohol and other drug related) disorder; mood and affect disturbance; personality disorder; infection; drug therapy; literature review

tress is a ubiquitous and unavoid- a wide range of critical physiological secretion occurs during both chronic able experience of daily life whether processes, the activity of cortisol must alcohol consumption and alcohol Sit arises from the external environ- be tightly controlled by the body. withdrawal. This heightened secretion ment (e.g., a job interview or traffic Cortisol secretion is regulated by rate may alter energy metabolism, accident) or from within the body (e.g., interactions among three structures: mental status, the structural integrity an infection or a panic attack). The the hypothalamus, the pituitary gland, of bone and muscle tissue, and the body has powerful mechanisms to cope and the outer layer (i.e., cortex) of each body’s ability to resist infection. In with stress. Among these mechanisms adrenal gland (see figure 1). These three addition, abstinent alcoholics exhibit is a hormone called cortisol, which is structures, collectively known as the a diminished ability of the HPA axis to produced and secreted by the adrenal hypothalamic-pituitary-adrenal (HPA) respond to stress, potentially impairing glands, located atop the kidneys (see axis, provide a regulatory network link- the body’s capacity to cope with stressors figure 1). Without cortisol a human or ing the brain with the body’s behavioral that might induce relapse to drinking. animal cannot respond appropriately to and physiological responses to stress. This article discusses the organization different types of physical or mental Alcohol consumption disrupts this and regulation of the HPA axis, disor- stress. However, because cortisol affects regulatory balance. Excessive cortisol ders associated with impaired HPA

Vol. 22, No. 1, 1998 67 functioning, and the combined effects together to stimulate the release of activation (i.e., a negative feedback of long-term alcohol consumption and adrenocorticotropic hormone (ACTH). system). The hypothalamus and the HPA disturbance on health. ACTH arrives at the adrenal cortex pituitary gland are sensitive to inhibition via the bloodstream, where it stimu- by cortisol. Thus, when activation of lates the secretion of cortisol. Cortisol the stress response produces increases The HPA Axis and Stress then travels through the bloodstream, in CRH and ACTH, the resultant exerting effects on multiple organs elevation in cortisol (after a time delay) and tissues. suppresses further CRH and ACTH Organization and Regulation The HPA axis demonstrates a con- production. of the HPA Axis sistent, daily (i.e., circadian) pattern. These interactions help ensure that In humans, cortisol levels decrease the body’s stress response system does In response to stimulation from the during the late evening hours, reach- not overreact in its response to a stressor brain, the hypothalamus produces ing their lowest point during the early (Munck et al. 1984). This constant corticotropin releasing hormone (CRH) morning hours. Cortisol secretion adjustment and readjustment of hor- and/or arginine vasopressin (AVP)1 begins to increase several hours prior mone levels around a target concen- (Rivier 1996). CRH and AVP are to awakening, and peak levels occur tration has been called the “allostatic then channeled directly to the pitu- in the late morning hours. In addi- load.” Humans or animals with a itary gland situated just beneath the tion, complex short-term fluctuations high allostatic load are in a state of hypothalamus (see figure 1). Within of cortisol levels occur within the day perpetual anxious anticipation. The the pituitary, these two hormones act (Gudmundsson and Carnes 1997; chronic elevation in cortisol induced Johnson and Veldhuis 1995). by a persistent or repetitive allostatic Bryon Adinoff, M.D., is the Distinguished The HPA axis incorporates a sys- load can activate the synthesis of CRH Professor of Alcohol and Drug Abuse tem of controls that dampen its own by the brain, thereby increasing levels Research and associate professor in the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, and medical director of the Substance Abuse Team at the Dallas Hypothalamus Veterans Affairs Medical Center, VA North Texas Health Care System, Dallas, Texas.

ALI IRANMANESH, M.D., is associate professor of endocrinology in the Department of Medicine, University Pituitary gland of Virginia School of Medicine, Charlottesville, Virginia, and is chief of the Endocrine Section and director of the Endocrine Laboratory, Salem VA Medical Center, Salem, Virginia.

JOHANNES VELDHUIS, M.D., is a professor of endocrinology in the Depart- Adrenal gland ment of Medicine and director of the General Clinical Research Center, University of Virginia School of Medicine, Kidney Charlottesville, Virginia.

LISA FISHER, PH.D., is an assistant professor in the Department of Psychiatry, University of Texas Southwestern Medical Center, and a staff psychologist at the Dallas Veterans Affairs Medical Center, VA North Texas Health Care System, Dallas, Texas. Figure 1 Location of the components of the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus is located in the brain, directly above the pituitary gland. The adrenal glands are located in the lower back, one atop each kidney. 1Vasopressin is a hormone with several functions in the body, including regulating water balance.

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of anxiety and fear (McEwen 1994; metabolism, high blood pressure, major Alcohol-Related Schulkin et al. 1994). alterations in mood, impaired mental Disturbances in the functioning, and disturbed sleep. HPA Axis Excess cortisol also impairs the Disorders Associated brain’s ability to metabolize energy, with Disrupted HPA Axis which can leave the brain vulnerable Alcohol Consumption Functioning to low levels of oxygen (such as and Withdrawal following a stroke or heart attack) or A disordered HPA axis response can Investigators have explored the time cause major physiological damage. low blood sugar (i.e., hypoglycemia). course and mechanisms of alcohol- When excess cortisol is produced, Long-term damage to the hippocam- induced HPA axis activation in rodents often because of an ACTH-secreting pus—a brain structure vital to learn- (see Rivier 1996; Eskay et al. 1995). tumor in the pituitary gland (i.e., ing, memory, and the regulation of Although alcohol itself does not Cushing’s syndrome), patients may HPA axis function—appears to occur appear to exert a powerful direct stim- experience symptoms related to in chronic medical and psychiatric ulatory effect on the adrenal cortex, excess levels of the normal physiologi- illnesses associated with persistently increased rates of CRH synthesis, cal activity of cortisol (see textbox). elevated levels of cortisol (Sapolsky coupled with increased secretion of ACTH and cortisol, are generally These symptoms include increased 1996). observed in animals following long- blood sugar, bone weakness, decreased Conversely, a deficiency of cortisol resistance to infection, increased fat term alcohol administration. The can lead to low blood glucose levels effects of short- and long-term alco- and a decreased ability to convert hol consumption in humans are less lipid and protein molecules to glu- clear, although most studies suggest Physiological Effects cose. Symptoms of cortisol deficiency that chronic administration of alcohol of Cortisol include low-grade fever, easy fatigabil- increases cortisol in humans. ity, weakness, weight loss, muscle Both human and animal studies Although the physiological aches, abdominal pain, vomiting, clearly demonstrate an increase in effects of cortisol are well docu- low blood pressure, and personality HPA axis activation with elevated mented, the role of these effects changes such as irritability and restless- cortisol concentrations during alcohol in stress resistance is uncertain. ness. More severe and life-threatening withdrawal (Iranmanesh et al. 1989). Cortisol is one of several steroid consequences, such as cardiovascular In alcoholics with high daily alcohol hormones produced by the outer consumption, cortisol levels return to shell (i.e., cortex) of the adrenal shock, can occur when cortisol- deficient patients are exposed to an normal after 7 days of abstinence glands (see figure 1). Classified (Adinoff et al. 1991). as a glucocorticoid because of episode of severe stress (e.g., surgery) its effect on glucose metabolism, without prior administration of cortisol in simple terms can be cortisol or another glucocorticoid Inhibition of the HPA Axis said to counterbalance the meta- (see textbox).2 in Abstinent Alcoholics bolic effects of insulin. Insulin Alterations in HPA axis function- Studies have shown low CRH con- decreases glucose levels in the ing are associated with a number of centrations and low morning levels bloodstream, whereas cortisol psychiatric disorders and personality of plasma ACTH in abstinent alco- increases glucose levels, break- characteristics. Thus, both over- holics. Additional studies in abstinent ing down fat and protein to activity and underactivity of the HPA alcoholics have revealed decreased supply raw materials for increased axis are associated with depressive hormonal responsiveness at each level glucose synthesis. When corti- mood states, aggression, and lack of of the HPA axis. For example, nalox- sol is produced in excess, the behavioral control (Stansbury and one (see figure 2) induces a blunted breakdown of protein may Gunnar 1994; Yehuda et al. 1993). CRH response by the hypothalamus lead to muscle weakness and in abstinent patients; secretion of decreased bone mass. Cortisol These somewhat disparate findings suggest that HPA axis disturbances ACTH by the pituitary is lessened also suppresses a wide range of following administration of CRH or immune functions. This prop- can be associated with abnormal levels of nervous system excitability insulin; and cortisol secretion is sup- erty forms the basis for the use pressed following exposure to alcohol, on either side of an optimal range of synthetic glucocorticoids insulin, CRH, ACTH, and various (e.g., prednisone) to treat excess (Chrousos 1992). environmental and mental stressors inflammation resulting from (for a review, see Costa et al. 1996). trauma or infection. 2The glucocorticoid corticosterone, also secreted by the adrenal cortex, is of minor importance in Thus, alcohol dependence appears humans compared with cortisol. to be associated with two distinct

Vol. 22, No. 1, 1998 69 patterns of HPA axis disturbances. Implications of HPA Axis response systems would be expected Marked HPA axis activation is present Disturbances in Alcoholism to produce a persistent state of high during chronic alcohol consumption allostatic load. Alternately, cortisol and during alcohol withdrawal, Alcohol-Related Medical Effects levels may remain persistently high whereas a suppression of HPA axis throughout the drinking-withdrawal functioning, particularly in response Daily heavy alcohol consumption cycle, which may be maintained for to various stressors, is observed dur- may induce two putative secretion several months or years. ing abstinence. Accounting for these patterns in the HPA axis. First, high Either of the aforementioned pat- two disparate physiological mecha- levels of cortisol may alternate with terns would be expected to produce nisms is difficult, because decreased normal levels as the patient drinks disturbances associated with high responsiveness of the HPA axis is progressively more alcohol during the concentrations of cortisol. One such evident at each separate level of the day (producing high cortisol levels), condition is pseudo-Cushing’s syn- system (i.e., the hypothalamus, the stops drinking upon the initiation drome, in which alcoholics develop pituitary, and the adrenals each show of sleep (producing normalized levels biochemical and clinical characteris- evidence of blunted responsiveness of cortisol), begins to experience the tics of Cushing’s syndrome (Veldman in abstinent alcohol-dependent early stages of withdrawal upon awak- and Meinders 1996). Additionally, patients). These findings may be the ening (producing high cortisol levels), long-term intermittent or continuous result of genetic influences coupled and then re-initiates the drinking states of high cortisol associated with with multiple physiological attempts cycle (initially lowering cortisol con- alcoholism could contribute to the to compensate for persistent alcohol- centrations as withdrawal subsides). development or increase the severity and withdrawal-induced HPA axis This back-and-forth, “seesaw” activity of loss of bone mass (i.e., osteoporo- activation. of the HPA axis and other stress- sis), diabetes mellitus, muscle wasting,

Figure 2 Regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Almost any type of stress, including trauma, infection, intense heat or cold, or mental Brain effort, is followed within minutes by increased Glutamate (+) secretion of cortisol. The occurrence of stress is Cytokines (+) communicated to the HPA axis by various chemical Opioids (+/ ) messengers. The brain monitors and integrates these CRH (+) communications and, when appropriate, activates GABA ( ) secretion of corticotropin-releasing hormone (CRH) (and arginine vasopressin [AVP]) from the Hypothalamus Naloxone hypothalamus. These hormones stimulate the pituitary gland to secrete adrenocorticotropic CRH (+) hormone (ACTH), which stimulates the adrenal Serotonin AVP (+) cortex to secrete cortisol. Substances that promote CRH secretion include (among others) stimulatory neurotransmitters (e.g., glutamate), mediators of inflammation (i.e., Pituitary cytokines), and CRH itself. CRH secretion is decreased by inhibitory neurotransmitters (e.g., gamma-aminobutyric acid [GABA]); in addition, Serotonin ACTH (+) Insulin endogenous opioids provide continuous (i.e., tonic) background inhibition of CRH secretion. Of the many chemical messengers that influence secretion of ACTH (by the pituitary) and cortisol (by Adrenal Cortex the adrenal cortex), only serotonin is shown because Cortisol ( ) of its modulatory effect on multiple brain functions. In + = stimulates addition, cortisol modulates its own release (i.e., = inhibits feedback inhibition), dampening potentially excessive HPA response. The right of the diagram lists selected substances that can be administered to evaluate the responsivity of the HPA axis at various levels. Naloxone suppresses inhibition of CRH secretion by opioids; insulin administration lowers blood sugar, activating ACTH and cortisol secretion (see textbox).

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high blood pressure, decreased immune in alcoholics are (1) emotional instability References function, low levels of the male repro- (i.e., neuroticism) and (2) lack of ADINOFF, B.; RISHER-FLOWERS, D.; DE JONG, J.; ductive hormone testosterone, and restraint (i.e., behavioral disinhibition) RAVITZ, B.; BONE, G.H.A.; NUTT, D.J.; ROEHRICH, liver damage. (Sher and Trull 1994). High levels of L.; MARTIN, P.R.; AND LINNOILA, M. Disturbances Persistently elevated levels of cortisol, anxiety and mood disturbances also of hypothalamic-pituitary-adrenal axis functioning in combination with certain effects of during ethanol withdrawal in six men. American are commonly reported in alcoholic Journal of Psychiatry 148:1023–1025, 1991. withdrawal, low blood sugar, or defi- patients. The presence of anxiety and ADINOFF, B. The alcohol withdrawal syndrome: ciency of the B vitamin thiamine, may mood disturbances as well as high produce significant neurotoxicity result- Neurobiology of treatment and toxicity. American emotional instability and behavioral Journal of Psychiatry 3:277–288, 1994. ing in hippocampal damage (Adinoff disinhibition are predictive of relapse 1994). Such damage may result in alco- CHROUSOS, G.P. Regulation and dysregulation hol-related symptoms such as person- in abstinent alcoholics (Fisher et al. in of the hypothalamic-pituitary-adrenal axis: The press). As noted previously, decreased corticotropin-releasing hormone perspective. ality changes, memory loss, and depres- Neuroendocrinology 21:833–858, 1992. sion. High levels of CRH and cortisol cortisol concentrations and muted during withdrawal also could contribute HPA axis reactivity are associated COSTA, A.; BONO, G.; MARTIGNONI, E.; MERLO, P.; SANCES, G.; AND NAPPI, G. 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