endocrine withdrawal syndromesas

Endocrine Withdrawal Syndromes

ZEEV HOCHBERG, KAREL PACAK, AND GEORGE P. CHROUSOS

Division of Endocrinology (Z.H.), Meyer Childrens Hospital, Haifa 31096, Israel; and Pediatric and ReproductiveEndocrinology Branch (Z.H., K.P., G.P.C.), National Institute of Child Health and Human Development, National Institutesof Health, Bethesda, Maryland 20892

Hypersecretion of endogenous hormones or chronic admin-istration of high doses of the same hormones induces varyingdegrees of tolerance and dependence. Elimination of hormonehypersecretion or discontinuation of hormone therapy mayresult in a mixed picture of two syndromes: a typical hormonedeficiency syndrome and a generic withdrawal syndrome.Thus, hormones with completely different physiological ef-fects may produce similar withdrawal syndromes, with symp-toms and signs reminiscent of those observed with drugs ofabuse, suggesting shared mechanisms. This review postulatesa unified endocrine withdrawal syndrome, with changes inthe hypothalamic-pituitary-adrenal axis and the central opi-oid peptide, in which noradrenergic and dopaminergic sys-

tems of the brain act as common links in its pathogenesis.Long-term adaptations to hormones may involve relativelypersistent changes in molecular switches, including commonintracellular signaling systems, from membrane receptors totranscription factors. The goals of therapy are to ease with-drawal symptoms and to expedite weaning of the patient fromthe hormonal excess state. Clinicians should resort to the fun-damentals of tapering hormones down over time, even in thecase of abrupt removal of a hormone-producing tumor. Inaddition, the prevention of stress and concurrent administra-tion of antidepressants may ameliorate symptoms and signs ofan endocrine withdrawal syndrome. (Endocrine Reviews 24:523538, 2003)

I. Introduction

II. GlucocorticoidsA. Withdrawal syndrome after discontinuation of glu-

cocorticoid therapyB. Withdrawal syndrome after correction of hypercorti-

solism in Cushings syndromeC. Possible mechanisms of the glucocorticoid withdrawal

syndromeD. Therapeutic approaches to glucocorticoid withdrawal

III. Estrogens and ProgestinsA. Postpartum as a withdrawal syndromeB. Menopause as a withdrawal syndromeC. Withdrawal syndrome after interruption of hormone

replacement therapyD. Premenstrual syndrome as a withdrawal phenomenonE. Possible mechanisms of the estrogen withdrawal

syndromesF. Therapeutic approaches to estrogen withdrawal

IV. AndrogensA. Withdrawal syndrome after discontinuation of replace-

ment therapyB. Withdrawal syndrome in athletes abusing androgensC. Withdrawal from physiological androgen levelsD. Possible mechanisms of the androgen withdrawal

syndromeE. Therapeutic approaches to androgen withdrawal

V. GHA. Withdrawal syndrome after discontinuation of GH

therapyB. Withdrawal syndrome after correction of hypersoma-

totropism in acromegalyC. Possible mechanisms of the GH withdrawal syndromeD. Therapeutic approaches to GH withdrawal

VI. ConclusionsA. Possible pathways for a unified endocrine withdrawal

syndromeB. Therapeutic approaches to endocrine withdrawal

I. Introduction

DEPENDENCE, OFTEN ASSOCIATED with drugs ofabuse, is a biological phenomenon with both psycho-logical and physiological components. During the period ofaddictive substance use, the body adjusts to a new level ofpathological homeostasis, or allostasis. When the drug isabruptly discontinued, this equilibrium is disturbed and theorganism reacts both behaviorally and physiologically witha constellation of manifestations collectively called a with-drawal syndrome. Dependence is preceded by a phase oftolerance, which signifies a progressively decreased re-sponse to the effect of a drug, necessitating ever-larger dosesto achieve the same effect. Tolerance is largely due to com-pensatory responses of the organism, which attempt to mit-igate the drugs pharmacological actions. Tolerance may re-sult from the functional adjustments of target tissue signaltransduction systems and/or from metabolic adjustment as-sociated with increased catabolism and disposition of thedrug of abuse taken chronically. The term addiction im-plies both psychological and physiological dependence, withclear adverse behavioral and social consequences, and hasbeen used mainly with regard to drugs of abuse. The severityof a withdrawal syndrome depends on the genetics anddevelopmental history of a patient, on his/her environment,and on the phase the patient has reached (Fig. 1).

Abbreviations: CNS, Central nervous system; GABA, -aminobutyricacid; HPA, hypothalamic-pituitary-adrenal; LC, locus ceruleus; NE,norepinephrine; PMDD, premenstrual dysphoric disorder; POMC,proopiomelanocortin.

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This present review suggests that hypersecretion of someendogenous hormones or chronic administration of highdoses of the same hormones may induce many of the featuresof dependence, tolerance, and withdrawal observed withdrugs of abuse and might occasionally cause frank addictivesyndromes.

Endocrine withdrawal syndromes have often been misin-terpreted as symptoms and signs of specific hormonedeficiency, after removal of an endocrine gland or after dis-continuation of hormonal therapy. However, critical exam-ination of the symptoms and signs during this period fre-quently shows a mixed picture of two different syndromesthat can be differentiated into a typical hormonal deficiencysyndrome and a generic withdrawal syndrome. Thus, themania, hypomania, and depression attributed to the with-drawal of anabolic steroid abuse in athletes has little to dowith the symptoms and signs of testicular failure, becausethese symptoms occur in some patients with hypogonadism.Similarly, the syndrome that follows discontinuation of high-dose glucocorticoids or correction of hypercortisolism inCushings syndrome bears similar but not identical symp-toms and signs of adrenal insufficiency.

Interestingly, hormones with completely different physi-ological effects can produce similar withdrawal syndromes,whereas some of the clinical manifestations that are due tothe chronic presence of high hormone levels or withdrawalsyndromes are also observed with drugs of abuse. This re-view postulates that changes of the hypothalamic-pituitary-adrenal (HPA) axis and the central opioid peptide, norad-renergic and dopaminergic systems act as shared features inthe pathogenesis of several endocrine withdrawal syn-dromes. The molecular and cellular bases of endocrine ordrug-related addiction and withdrawal syndromes, how-ever, are poorly understood. The best established molecularand cellular mechanisms of short- and long-term adaptationto hormones or allostasis induced by drugs of abuse is po-tentiation of G protein receptor coupling, up-regulation ofcAMP, increased activities of protein kinases, and changes inthe expression and activities of several transcription factors.

The withdrawal syndrome after glucocorticoid discontin-uation has drawn a great deal of attention over the years andhas been studied extensively. We suggest that the symptomsand signs that occur after cessation of administration of sev-eral other hormones may also comprise a similar withdrawalsyndrome. These other hormones have not been studied asthoroughly as the glucocorticoids, and the following discus-sion refers primarily to animal studies and clinical inferencesfrom such studies. Whereas some of the observations andsuggestions are scientifically evident and valid, based onsolid data in both animals and humans, other annotations aretentative or speculative, lacking evidence from well-designed clinical studies. Further clinical research needs totake place before these suggestions are implemented.

II. Glucocorticoids

A. Withdrawal syndrome after discontinuation ofglucocorticoid therapy

Glucocorticoids are widely used in clinical practice to con-trol the activity of autoimmune, inflammatory, and allergicdiseases, neoplasms of the hematopoietic system, and othernosological entities. High therapeutic doses of glucocorti-coids, when used to control the activity of these diseases,suppress the HPA axis and exert numerous central nervoussystem (CNS) effects, including anxiety, insomnia, impair-ment of cognition, and mood changes ranging from euphoriato hypomania, mania, depression, and psychosis (1). Some ofthese symptoms have been attributed to the suppression ofhypothalamic CRH and proopiomelanocortin (POMC)-derived peptides such as -endorphin, stimulation of theamygdala, and initial stimulation followed by tolerance andinhibition of the dopaminergic mesocorticolimbic system.

Four aspects of drug withdrawal after cessation of phar-macological high-dose glucocorticoid therapy deserve spe-cial attention (2). First, the illness treated by steroids mayrelapse. Second, the HPA axis and POMC-derived peptidesecretion may remain suppressed for a long time. Third, anonspecific withdrawal syndrome may develop even whilepatients are receiving physiological replacement doses ofglucocorticoids. Fourth, psychological dependence to thesehormones often develops. Thus, after abrupt discontinuation

FIG. 1. Phases in the development of hormonal withdrawal syn-dromes. Similar to the phases after the consumption of drugs of abuse,chronic hormonal excess production or administration may lead totolerance for the respective hormone. This may be followed by de-pendence and, rarely, addiction. Correction of the chronic hormoneexcess syndrome at each of these phases may lead to withdrawalsyndromes. The severity of the withdrawal syndrome depends on thephase and degree of dependence.

524 Endocrine Reviews, August 2003, 24(4):523538 Hochberg et al. Endocrine Withdrawal Syndromes


of glucocorticoid therapy, patients may develop anorexia,nausea, emesis and weight loss, fatigue, myalgias, arthralgiasand headache, abdominal pain, lethargy and postural hy-potension, fever, and skin desquamation (Table 1). Interest-ingly, the syndrome may occur during weaning from phar-macological high-dose therapy, while the patient is onadequate glucocorticoid replacement. This may also happenafter the response of the HPA axis to stimuli has returned tonormal (3, 4), indicating that long-term tolerance to glucocor-ticoids has developed and hormone substitution is inade-quate to allow the central nervous system or other organs tofunction properly.

B. Withdrawal syndrome after correction ofhypercortisolism in Cushings syndrome

Successful surgery of Cushings disease or cortisol-secret-ing adrenal tumors often makes patients feel worse. Post-operatively, during the first days after surgical correction ofCushings disease and before replacement therapy is insti-tuted, patients experience a flu-like syndrome characterizedby anorexia, nausea, fatigue, somnolence, arthralgias myal-gias, and fever (5). In the long run, and while patients are stillon glucocorticoid replacement, an atypical depressive dis-order develops in over half of postoperative Cushings dis-ease patients, which persists in a quarter of the patients forup to a year (6). Biochemical evidence that may be related toa withdrawal syndrome after glucocorticoid discontinuationincludes hypercalcemia (7) and hyperphosphatemia (8), mir-roring the loss of the suppressive effects of glucocorticoids oncalcium absorption. Recovery from the withdrawal syn-drome that develops after pituitary adenomectomy or bilat-eral adrenalectomy may take as long as a year or more.

C. Possible mechanisms of the glucocorticoidwithdrawal syndrome

The withdrawal syndrome, which patients experience af-ter either discontinuation of glucocorticoid therapy or cor-rection of hypercortisolism in Cushings syndrome, has beenconsidered a withdrawal reaction due to established physicaldependence on supraphysiological glucocorticoid levels.Several mediators may be considered, and include CRH,vasopressin, POMC, central noradrenergic and dopaminer-gic systems, cytokines, and prostaglandins (Table 1).

Chronic hypercortisolemia decreases CRH mRNA expres-sion in the rat hypothalamus while increasing it in the centralnucleus of the amygdala (9). Acute withdrawal after chronicglucocorticoid administration decreases rat hypothalamicCRH for a further 7 d or more (10), and CRH neurons are thelast part of the HPA axis to normalize. This is supported bydata on humans, showing that patients with Cushings dis-ease show markedly decreased CRH levels in cerebrospinalfluid, suggesting that some central CRH neurons secretinginto or spilling CRH into the cerebrospinal fluid have beenrestrained by long-standing hypercortisolism (11).

CRH in the brain not only activates the HPA axis but alsomediates stress-related behavioral effects. Intracerebroven-tricular administration of high doses of CRH in the rat ormonkey enhances fear-related behaviors, decreases explora-tion, and inhibits sleep, feeding, and sexual activity (12).Similarly, the origin of hypercortisolism in human melan-cholia has been suggested to have a central origin, predom-inantly reflecting hypersecretion of central CRH (12, 13).Glucocorticoid-induced hyperactivity of CRH neurons in theamygdala induces arousal, fear response, and anxiety (14).Moreover, an intact CRH system in the brain seems necessaryfor adequate mesolimbic dopaminergic function. Thus, cen-tral CRH hyposecretion in the period of acute glucocorticoidwithdrawal may further contribute to anxiety and depres-sion via inadequate stimulation of dopaminergic neuronsterminating in the nucleus accumbens.

With regard to suppressed CRH, some investigators feelthat hyposecretion of central CRH plays an important role inthe pathogenesis of atypical depression. Thus, abrupt glu-cocorticoid withdrawal in patients with Cushings syndromeis associated with profound psychopathology (6), which maybe attributed to long-standing hypoactivity of central CRHneurons (6, 1113). Because several recent lines of evidencein man and experimental animals suggest that fatigue, hy-persomnia, lethargy, and hyperphagia are associated withhyposecretion of hypothalamic CRH (5, 12, 15), symptomsand signs of acute glucocorticoid withdrawal may reflecthypoactivity of central CRH neurons.

Elevated plasma vasopressin levels, accompanied by im-proved water excretion, are observed in patients with adre-nal insufficiency and can be normalized by glucocorticoidreplacement (16, 17). In contrast, chronic glucocorticoid ad-ministration in man increases water diuresis due to directrenal tubular effect, but also due to central inhibition ofvasopressin release, and escape from this inhibition is de-fined by vasopressin secretion (18). Clinical findings of in-creased frequency of urination in patients with Cushingssyndrome and recent experiments showing glucocorticoid-induced suppression of vasopressin expression in humanhypothalamic neurons further support these conclusions(19). The number of vasopressin-immunoreactive neurons inthe parvocellular paraventricular nucleus of patients withdepression is significantly increased (20). Some clinical stud-ies have shown improvement in short- and long-term mem-ory processes, mood, and concentration of depressed pa-tients after vasopressin administration (21, 22). In contrast,oxytocin was found to impair memory performance (23, 24).Behavioral and other changes may occur via a direct effect ofvasopressin on central neuronal processes or via potentiation

TABLE 1. Symptoms, signs, and mechanisms of glucocorticoidwithdrawal

Symptoms and signs Mechanisms

Relapse of primary illnessSuppressed HPA axis s CRH

Addisonian crisis s GlucocorticoidHypercalcemia,

hyperphosphatemiaa Vasopressin

Nonspecific withdrawalsyndrome

s Central noradrenergicsystem

Anorexia, nausea, emesis,weight loss

s Central dopaminergicsystem

Myalgias, arthralgias, fever,headache

s POMC-related peptides

Somnolence, lethargy a CytokinesSkin desquamation a Prostaglandins

Hochberg et al. Endocrine Withdrawal Syndromes Endocrine Reviews, August 2003, 24(4):523538 525


of the central CRH effects. The activation of oxytocin neuronsmediates CRH-induced depression in experimental animals(25). One may, therefore, speculate that in humans, glucocor-ticoid withdrawal symptoms, such as anorexia, nausea, de-creased motivation, anxiety, and depression, may also reflectchronic glucocorticoid-induced disturbances of vasopressinand oxytocin neurons.

Substantial clinical and animal evidence supports the viewthat hypercortisolism can produce depression. In particular,about two thirds of patients with hypercortisolism due toCushings syndrome are clinically depressed, and correctionof their hypercortisolism, such as by surgery or medicaltherapy, usually ameliorates the depression (6, 12, 13, 26, 27).Conversely, a substantial proportion of patients with majordepression have abnormalities of the HPA axis, such as anincreased apparent frequency of ACTH secretory episodes,elevated urinary free cortisol excretion, elevated CRH levelsin cerebrospinal fluid, and relative insensitivity of the HPAaxis to the suppressive effect of dexamethasone (12, 27, 28).Recently, the central noradrenergic and dopaminergic sys-tems were considered to play important roles in the patho-genesis of cortisol-induced mood disorders (2934).

Evidence from preclinical investigations indicates distur-bances of mesocortical and mesolimbic dopaminergic func-tion in anxiety, anhedonia and, depression (31, 32, 3539).Genetically selected Flinders Sensitive Line rats that exhibitbehavioral features characteristic of anxiety and depressionhave markedly decreased dopamine release in the nucleusaccumbens (40). Dopamine depletion in the nucleus accum-bens and caudate nucleus occurs in rats with learned help-lessness, and treatment with dopamine agonists preventsdevelopment of this syndrome in this animal model of de-pression (41, 42). This is supported by human studies, show-ing that enhanced dopamine release in the nucleus accum-bens correlates with reward-related activities, increasedpsychomotor activation, and decreased anxiety (43, 44). In-creases in dopamine release after acute glucocorticoid treat-ment have been demonstrated in the nucleus accumbens (33),and this could be associated with the euphoric (hypomanic)states seen acutely with high doses of steroids. Blunted re-sponses of dopamine to palatable food have been proposedto serve as a marker of anhedonia (45).

Acute stress-induced dopamine release in the human me-solimbic system associated with marked activation of theHPA axis promotes behavioral activation and results in de-fensive responses toward the stressful stimulus (30). In con-trast, prolonged exposure to stress leads to inhibition of themesolimbic dopaminergic system, associated with copingfailure and cessation of defensive attempts, with subsequentdevelopment of depressive signs (30). Similarly, chronic hy-percortisolemia inhibits dopaminergic activity in the nucleusaccumbens but not in the prefrontal cortex (46, 47). Thus,region-specific glucocorticoid-induced alterations in dopa-minergic activity may be an important factor underlyingpathophysiological mechanisms of depressive symptoms inchronic hypercortisolemia.

In clinical studies, patients with endogenous depressionhave decreased levels of dopamine metabolites in cerebro-spinal fluid and low values for indices of brain dopamineturnover (32, 48), consistent with an association between

depression and inhibition of central dopaminergic systems.After clinical improvement, brain dopamine turnover in-creases (32). The magnitude of increase in dopamine-2 re-ceptor binding in the striatum and anterior cingulate gyrus,assessed by single-photon emission tomography, correlateswith clinical recovery from depression (49, 50). Drugs suchas reserpine, methyl dihydroxyphenylalanine (DOPA), andneuroleptic agents that block dopamine receptors can causedepression. This may occur via effects on central dopami-nergic systems (32). In contrast, dopamine receptor agonists,such as bromocriptine, pergolide, and roxindole, have anti-depressant efficacy similar to tricyclic antidepressants (29,51, 52). Dopamine antagonists block euphoria induced byamphetamine, which promotes release of dopamine and in-hibits its uptake (32).

The interplay between central noradrenergic systems andglucocorticoids in the pathogenesis of mood changes, espe-cially depression and withdrawal syndrome, remains un-clear. Both increased and decreased central noradrenergicactivity has been described in depression (for reviews, seeRefs. 53 and 54). Similarly, antidepressant responses havebeen linked to increased (53, 55) as well as decreased (54, 56,57) central noradrenergic function.

As discussed earlier in this review, based on results fromanimal and human studies, there is enough evidence that, inmajor melancholic depression, there is marked activation ofthe central CRH systems that leads to persistent activation ofcentral noradrenergic systems, especially in the locus cer-uleus (LC) (5860). In contrast, in animals exposed to chronichypercortisolemia, the activity of the central noradrenergicsystems (e.g., those originating in the brainstem or the LC andterminating in the hypothalamic paraventricular nucleus), aswell as the CRH system in the paraventricular nucleus, areinhibited, whereas the activity of the CRH system in theamygdala is increased (47, 61, 62). In contrast, adrenalectomyincreases norepinephrine (NE) release and turnover in dif-ferent brain regions, as well as in periphery, and cortisolreplacement blunts these changes (63, 64). Furthermore,CRH-knockout mice show decreased adrenomedullary ac-tivity and increased sympathetic nervous activity (65).

Chronic hypercortisolemia in patients with Cushings syn-drome or exogenous administration of glucocorticoids innormal volunteers inhibits peripheral sympathoadrenal ac-tivity (6668). Furthermore, functional imaging using[18F]fluorodeoxyglucose as a positron-emitting agent showsthat patients with Cushings syndrome have decreased ce-rebral uptake rates for glucose in all brain regions except thestriatum, whereas patients with major depression have in-creased activity in the amygdala and the ventral prefrontalcortex and decreased activity in the dorsal prefrontal cortex,regions that have abundant noradrenergic innervation (69).Lack of proper glucocorticoid replacement in the postoper-ative period in patients with Cushings syndrome is associ-ated with increased incidence in panic behavior (6) togetherwith increased sympathoadrenal activity, which returns tonear-normal preoperative levels after appropriate glucocor-ticoid replacement. These data suggest that acute glucocor-ticoid withdrawal characterized by anxiety and panic symp-tomatology in patients with Cushings syndrome may bepartly due to lack of glucocorticoid restraint characterized by



markedly increased central noradrenergic activity. When thefunctions of CRH and noradrenergic neurons recover, symp-toms of anxiety and panic subside.

Thus, whereas patients with major depression can be de-scribed as hyperadrenergic and hypercortisolemic, patientswith depression due to Cushings syndrome can be describedas hypoadrenergic and hypercortisolemic and patients afterglucocorticoid withdrawal as hypernoradrenergic andhypocortisolemic.

ACTH is synthesized as part of the 241-amino-acid pre-cursor POMC, which is also cleaved to generate the NH2-terminal peptide, the joining peptide, lipotropin, melanocytestimulating hormone, and -endorphin. CRH and vasopres-sin stimulate serum levels of all of these peptides (70), andglucocorticoids suppress pituitary and hypothalamic POMCexpression (71). Hence, some of the symptoms of Cushingssyndrome may be related to deficiency of these peptides.Furthermore, recovery of the HPA axis is associated withparallel recovery of POMC-derived peptide secretion (72). Itis not surprising, therefore, that some of the CNS symptomsof glucocorticoid dependence and withdrawal are related tothose of opiate withdrawal. Brain neurons, neurotransmit-ters, and their receptors, as well as peripheral signal trans-duction machinery, adapt to POMC deficiency in the courseof Cushings syndrome.

During the acute phase of glucocorticoid withdrawal andthe flu-like syndrome that characterizes it, plasma IL-6 levelsrise markedly and TNF and IL-1 levels increase. Exoge-nous administration of IL-6 induces similar manifestations,and a role for this cytokine in the pathogenesis of the flu-likesyndrome in adrenal insufficiency was suggested (5). Thisreaction might also involve the suppression by glucocorti-coids of prostanoid and platelet activating factor production,and a sudden increase in their production upon withdrawalof steroid hormones. Indeed, prostaglandins E2 and I2 alsoinduce many of the features of the flu-like syndrome (73).

Interestingly, a dose-dependent increase in plasma cortisollevels is found in habitual smokers after smoking two cig-arettes, and complete cessation of smoking is followed by afall in plasma cortisol levels that is associated with the with-drawal of the nicotine stimulus (74). Many of the nicotinewithdrawal symptoms of smokers who try to quit seem to berelated to the bodys response to changes in CRH and/orcortisol levels, along with the downstream mesocorticolim-bic and POMC-peptide effects. As part of a comprehensivesmoking cessation program, one or two im injections ofACTH gel have been shown to help smokers stop and con-tinue to abstain from smoking (74).

D. Therapeutic approaches to glucocorticoid withdrawal

Gradual tapering of high-dose glucocorticoid therapy hasbecome the standard of practice. However, the glucocorti-coid withdrawal syndrome, which develops after correctionof endogenous hypercortisolism, is largely ignored or con-sidered as a separate entity. In attempting to minimize post-operative withdrawal symptoms and signs, the clinician isfaced with two options: the first is to normalize cortisolsecretion before surgery, employing medical suppression ofsteroidogenesis. This has to be done gradually, or else with-

drawal symptoms might ensue. The second option is to re-institute high-dose glucocorticoid replacement therapy aftersurgery and taper it off gradually. It sounds reasonable,although untested, to resume a dose that would result inpretreatment urinary free cortisol levels as the basis for ta-pering off. The disadvantage of this therapy is the very likelyprolongation of Cushings symptoms and signs, as well asadrenal suppression. These preventive options await well-designed clinical studies. With a decrease in CRH and thecentral dopaminergic and POMC-peptide systems, the ra-tionale is there for correcting these derangements graduallyin cases of severe withdrawal syndrome.

III. Estrogens and Progestins

Estrogens are potent stimuli to the HPA axis and theLC/NE system. Postpartum, menopause, and the premen-strual syndrome are all associated with decreasing estrogenand withdrawal syndrome-like manifestations (75, 76) (Table2). These may include hot flushes and autonomic hyperac-tivity, but also fatigue, irritability, anxiety and depression,and even psychosis. Withdrawal symptoms and signs do notresemble those of estrogen hormonal deficiency, as theymanifest in young women with Turner syndrome or hy-pogonadotropic hypogonadism.

A. Postpartum as a withdrawal syndrome

Pregnancy is a complex endocrine condition, associatedwith high levels of cortisol, estrogen, progesterone, CRH, GHvariant, human placental lactogen, and other placental prod-ucts. These hormones have metabolic and/or CNS activities.After long exposure to such high hormone levels duringpregnancy, parturition constitutes a sudden withdrawal ofall these factors (77).

The withdrawal syndrome that follows labor and deliveryhas much more to it than a reaction to the birth process. Blochet al. (78) investigated the possible role of changes in gonadalsteroid levels in postpartum blues, or depression, by simu-lating two hormonal conditions related to pregnancy andparturition in euthymic women. The supraphysiological go-nadal steroid levels of pregnancy and withdrawal from thesehigh levels to a hypogonadal state were simulated in womenwith or without a history of postpartum depression. Hypo-gonadism was induced with a GnRH agonist, adding backsupraphysiological doses of estradiol and progesterone for 8wk, and then withdrawing both steroids under double-blindconditions. Five of eight women with a history of postpartum

TABLE 2. Symptoms, signs, and mechanisms of estrogen andprogesterone withdrawal


Hot flushes, autonomichyperactivity

s CRH,

Fatigue s POMC-related peptidesIrritability, anxiety,

depressions Vasopressin

s Seizure threshold s Central noradrenergic systems Central dopaminergic systems Central serotoninergic systems GABA



depression (62.5%), but none of eight women in the com-parison group, developed significant mood symptoms dur-ing the withdrawal period. These investigations suggestedthat women with a history of postpartum depression aredifferentially sensitive to mood-destabilizing effects of go-nadal steroids. Mild depression, or the blues, occurs in asmany as 60% of women, whereas an additional 13% developfull-fledged depression (79). When women with histories ofpuerperal psychosis or major depression were treated withhigh-dose oral estrogen immediately after delivery, they re-mained healthy and required no treatment with psycho-tropic medications during the 1-yr follow-up period as com-pared with an expected 3560% recurrence rate (80).

Changes in levels of endorphins may be involved in thepathophysiology of psychiatric postpartum estrogen with-drawal syndrome (81). Studies of various endorphins indi-cate a possible relation between levels of endorphins anddepressive symptoms. In addition, some studies employingnaloxone suggested a relation between a blockade in theaction of endorphins and the development of a syndrome ofdysphoric symptoms similar to the depressive features man-ifested premenstrually and in the postpartum. Estrogen andendorphin levels have been shown to covary. During thepostpartum and the premenstrual periods, levels of bothchange rapidly and substantially.

B. Menopause as a withdrawal syndrome

Women who suffer hot flushes soon after menopause havelower estrogen levels than those who do not have hot flushes(82), indicating that this may be a symptom of estrogendeficiency or withdrawal, and, indeed, it can be amelioratedby estrogen replacement therapy. Several lines of evidencesupport a possible withdrawal syndrome. For example, somepostmenopausal symptoms are self-limited and distinct fromthose of pure estrogen deficiency. The more severe with-drawal symptoms of autonomic hyperactivity, hot flushes,and hyperemic coronary flow occur when menopause isinstituted abruptly by surgery or antiestrogens, such as clo-miphene citrate or tamoxifen (83, 84), but not in congenitalforms of hypogonadism and less so in slowly progressingpremature ovarian failure, when the signs and symptoms ofestrogen deficiency include amenorrhea, endometrial andbreast atrophy, and osteoporosis.

Another important symptom of menopause is climactericdepression; however, no convincing evidence has linked de-pression with menopause yet (85). Its duration and charac-teristics are reminiscent of those seen after correction of hy-percortisolism in Cushings syndrome, and we propose thatit reflects an estrogen and CRH withdrawal syndrome. Inboth cases, recovery with hormonal replacement therapy isnot instantaneously beneficial.

C. Withdrawal syndrome after interruption of hormonereplacement therapy

Hormone replacement therapy has been widely pre-scribed only in the past two decades, and the indications fortreatment and the risk/benefit ratio are still disputed. Es-trogens are psychoactive: they cause mood changes, and

their use has powerful psychological effects. Reports ofwomen with supraphysiological estradiol concentrationsmay represent tolerance and withdrawal (85). Menopausal-like symptoms sometimes evolve despite high serum levelsof estradiol, perhaps as tolerance to estrogen. Hormone re-placement therapy is often withdrawn abruptly for a varietyof clinical indications, but little attention is given to symp-toms and signs of withdrawal. In addition to physiologicaldependence, hormone replacement therapy promotes feel-ings of well-being, which may contribute to psychologicaldependence (85). A dramatic case report described a 51-yr-old woman with no previous psychiatric history who am-putated her hand in a psychotiform state after discontin-uation of her contraceptive medication. The patientstabilized under a combined therapy with estrogen-proges-tin substitution (86).

D. Premenstrual syndrome as a withdrawal phenomenon

On a smaller scale, each menstrual cycle is terminated witha miniature withdrawal syndrome during the late lutealphase. Premenstrual irritability, fatigue, and mood changesare common. The syndrome, called also late luteal or pre-menstrual dysphoric disorder (PMDD), is associated withthe cyclically recurring increase and decrease in levels ofestrogen and progesterone. The key characteristics of PMDD,with clear onset and offset of symptoms closely linked to themenstrual cycle and the prominence of symptoms of anger,irritability, and internal tension, were contrasted with thoseof known mood and anxiety disorders (87). PMDD displaysa distinct clinical picture that, in the absence of treatment, isremarkably stable from cycle to cycle and over time. Normalor near-normal functioning of the HPA axis, biological char-acteristics generally related to the serotonin system, and agenetic component unrelated to major depression are furtherfeatures of PMDD that separate it from other mood disorders(87, 88). These symptoms are often abrogated after eliminat-ing cyclic hormone levels by administering estrogen andprogesterone daily (89). Women who suffer a premenstrualwithdrawal syndrome are more likely to develop late preg-nancy depression and anxiety, as well as postpartum bluesand depression (90). This would suggest a common mech-anism for the various facets of estrogen and progesteronewithdrawal syndromes.

The concept of PMDD as a withdrawal syndrome wasrecently challenged (91). These authors suggested that thelink between the decline in hormonal levels and the symp-toms of PMDD was much more like that of a menstrualzeitgeber or synchronizer than a hormonal withdrawal state,because extending or truncating the luteal phase did notimmediately affect the course of symptoms. The concept ofSchmidt et al. (91), however, is compatible with the idea thatwomen with a history of postpartum depression are differ-entially sensitive to mood-destabilizing effects of gonadalsteroids.

E. Possible mechanisms of the estrogen withdrawalsyndromes

Sex hormones have long been known to exert powerfuleffects on brain functions including mood, behavior, and



neuroendocrine regulation (92, 93). Postpartum estrogenwithdrawal occurs in the first week after parturition whenthere is a substantial fall in plasma estrogen levels along withmany a decrease in other hormones (75, 94). Numerous clin-ical studies support the notion that cyclic patterns of epilepticseizures and mood disturbances may also result from rapidlychanging sex hormone levels, as seen during specific phasesof the menstrual cycle (9597).

Several mechanisms may explain the pathogenesis of es-trogen withdrawal syndrome. From numerous animal stud-ies, it has been postulated that some of the antidepressanteffects of estrogens and progesterone reflect their action oncentral CRH, opioid peptidergic, catecholaminergic, and se-rotoninergic neurons (75, 98100). Ovarian steroids alsomodulate the activity of the central dopaminergic system inrats (101). A case of postpartum psychosis with abnormalmovements was shown to result from dopamine hypersen-sitivity that was unmasked by withdrawal of endogenousestrogens (102).

In terms of dopamine synthesis, chronic administration ofestrogen inhibits tyrosine hydroxylase in various dopami-nergic brain areas of hypophysectomized rats (99). The in-hibitory effect of estradiol on dopamine synthesis is consis-tent with other observations that chronic treatment withestrogens causes a decrease in the limbic content of dopa-mine in rats (101103). Mesolimbic dopaminergic activity, ascharacterized by dopamine release and reuptake, fluctuateswith alterations in endogenous gonadal steroid levels. In ratproestrus, nucleus accumbens dopaminergic activity is sig-nificantly decreased (104, 105). Estrogens, on the other hand,significantly increase the density of 5-hydroxytryptamine 2Abinding sites in the rat anterior frontal, cingulate and primaryolfactory cortex, and in the nucleus accumbens, all of whichare areas of the brain involved in the control of emotion,cognition, and behavior (93). Furthermore, elevated estrogenlevels at the estrous phase of the rat cycle significantly de-crease extracellular hypothalamic serotonin levels (14).Whether similar mechanisms operate in humans remains tobe determined. However, the response of patients withPMDD to selective serotonin reuptake inhibitors (87) sug-gests a role for serotonin in its pathophysiological mecha-nism (Table 2).

Following earlier evidence that hot flushes are triggeredwithin the hypothalamus by 2-adrenergic receptors on nor-adrenergic neurons (106), it has been shown that clonidine,an 2-agonist, is sometimes effective in reducing autonomichyperfunction during menopause (107).

POMC-related peptides are increased within several min-utes of subjective menopausal flushes (108), but, on the otherhand, sex steroids are able to increase -endorphin and -lipotropin secretion in postmenopausal women, with a con-comitant relief of climacteric symptoms (109). Another al-ternative common pathway for various steroid withdrawalsyndromes is vasopressin. Within 24 h of parturition, rodentvasopressin mRNA levels increase (110). Should human ex-periments support a similar effect, exposure and then with-drawal of estrogen and testosterone could mimic thisincrease.

Abrupt discontinuation of progesterone in the rat, or itsdecline after chronic administration or pregnancy termina-

tion, increases anxiety and sensitivity for convulsions (111,112). This is supported by human data, as both anxiety andseizures are part of the premenstrual and postpartum syn-dromes, for which the role of progesterone withdrawal hasbeen repeatedly discussed (111113). This might be mediatedby progesterones -aminobutyric acid (GABA)A-modulatormetabolite 3-OH-5-pregnan-20-one, which is abruptly de-creased after progesterone withdrawal in the rat (111114).Manipulation of GABAA receptor by altered progesteronelevels may also affect cross-tolerance with sedative drugswhose abrupt withdrawal may also cause premenstrual-likesymptoms (112).

From the studies described above, it can be concluded thatacutely altered central opioid peptide, catecholamine, andserotonin levels due to ovarian steroid manipulations mightbe an important contribution to the symptoms of ovariansteroid withdrawal syndromes.

F. Therapeutic approaches to estrogen withdrawal

The currently recommended treatment for postpartumand climacteric depression is antidepressants. Also, inPMDD, at least 60% of patients respond to selective serotoninreuptake inhibitors (87). Recognizing the possible mecha-nism of hormone withdrawal may lead to a different ratio-nale and approach. Lower-dose hormone replacement ther-apy could diminish dependence. Postpartum administrationof high-dose estrogen and tapering off minimize the psy-chiatric estrogen withdrawal syndrome (80). The autonomicsyndrome of hot flushes in postmenopause responds partlyto hormone replacement therapy and also to androgens, thussuggesting a common mechanism with the androgen with-drawal syndrome. The latter may in fact be mediated byaromatization of androgen to estrogen. Initiation of hormonereplacement therapy immediately after oophorectomy mayprevent the withdrawal syndrome that would otherwise fol-low surgery. An alternative therapeutic approach would beto use drugs with CNS effects, such as some of the selectiveantidepressants, to modify the neurotransmitter abnormal-ities postulated to be associated with the withdrawalsymptoms.

IV. Androgens

A. Withdrawal syndrome after discontinuation ofreplacement therapy

Traditionally, replacement therapy in patients with testic-ular failure of any etiology utilizes long-acting preparations,the most common of which is testosterone enanthate. Thepharmacokinetics of a dose given every 34 wk is such thatit provides supraphysiological serum levels over the initialweek and subphysiological levels on wk 34 (115). A fewdays before each injection, emotional lability and moodswings may occur (116, 117). This cyclic withdrawal syn-drome is easily prevented by administration of lower dosesof testosterone enanthate every 1 or 2 wk or continuousadministration with skin patches or gels, which eliminates amajor fluctuation in testosterone serum levels (118, 119). Inthis respect, the androgen withdrawal syndrome and its ther-



apy are analogous to the premenstrual syndrome and itsmanagement.

B. Withdrawal syndrome in athletes abusing androgens

The abuse of anabolic steroids by athletes and body build-ers is, for obvious reasons, poorly documented (120). Gen-erally, doses of abused steroids may be up to 100 timesgreater than therapeutic replacement doses. Both psycho-logical and physical dependence occur, and withdrawalsymptoms are seen frequently. The analogy of androgenwithdrawal syndrome with that of drugs of abuse was madeover a decade ago (121). Taken in large doses, these com-pounds have severe psychological and behavioral side ef-fects, including aggressive and violent behavior (122). Prob-lems with drug withdrawal and dependence may result indecreased sexual drive, but also in a flu-like syndrome thatmimics in many ways the glucocorticoid withdrawal syn-drome (123). Fatigue, muscle and joint pain, headache, andinsomnia are followed by a second phase of depression (124),a condition that appears to be more common than previouslyrealized (125). As many as 23% of users reported major moodsyndromes: mania, hypomania, and depression probably oc-cur as a result of the episodic nature of use and discontin-uation of anabolic steroids (117). Androgen withdrawal isoften associated with the desire to resume steroid consump-tion (craving) (124). These symptoms and signs are obvi-ously unrelated to specific symptoms and signs of androgendeficiency, as they manifest in patients with hyper- or hy-pogonadotrophic hypogonadism.

C. Withdrawal from physiological androgen levels

Orchiectomy or GnRH analog therapy, such as that givento patients with prostate cancer, often result in hot flushesthat resemble the postmenopausal syndrome (126). Thesymptoms are alleviated by either androgen or estrogen ther-apy (127), suggesting a role for androgen-derived estrogen.

D. Possible mechanisms of the androgen withdrawalsyndrome

Depending on their structure, endogenous androgens andandrogenic compounds may be reduced to dihydrotestos-terone or aromatized to estrogen in target tissues, includingthe human brain (128). During androgen abuse, estrogenlevels in target tissues may approach those of ovulatingfemales, with gonadotropins suppressed via a negative feed-back mechanism by both androgen and estrogen effects at thehypothalamic-pituitary level (129). Symptoms and signs ofandrogen overdose and withdrawal may be partly accountedfor by the relative conversion to these derivatives. In the rat,a further metabolic pathway has been suggested: the con-version of testosterone to 3-androstanediol has been shownto mediate brain effects of androgen, decreasing GABA-stim-ulated chloride influx in cortical synapto-neurosomes andmuscimol binding in the hippocampus (130).

Effects of androgenic steroids on central aminergic sys-tems (Table 3) may explain some of the withdrawal symp-toms. In rats, an increase of noradrenergic activity in certainbrain areas has been observed immediately after castration

(131, 132), whereas testosterone administration decreases hy-pothalamic NE turnover (133). Bilateral implants of testos-terone or dihydrotestosterone in the preoptic area (supra-chiasmatic nucleus) of orchidectomized rats decreaseddopamine turnover without influencing NE turnover (134).An acute hypernoradrenergic state could at least partiallyexplain some of the anabolic-androgenic steroid withdrawalsymptoms, but relevant clinical studies are not available. Inhumans, elevated plasma levels of NE correlate positivelywith insomnia, anorexia, and depressed mood, whereas inrats, abnormalities in the monoamines, along with their co-transmitters, may cause many forms of eating disorders (135,136). In contrast, castrated animals have increased basal andamphetamine-stimulated dopamine release in the mesolim-bic dopaminergic system (137). In humans, we can only hy-pothesize that acute anabolic-androgenic steroid withdrawalmay be associated with decreased central dopaminergic ac-tivity, reflected by frequent occurrence of depressivesymptoms.

Some of the key players involved in the glucocorticoid andestrogen brain effects and withdrawal syndromes may alsoplay a role in the androgen withdrawal syndrome. Sequentialexposure of female rats to estrogen and testosterone andsubsequent withdrawal of testosterone increases the level ofarginine vasopressin mRNA in the hypothalamic paraven-tricular nucleus (135). Comparison of V1a receptor ligandbinding and mRNA in intact, castrated, and castrated tes-tosterone-treated animals reveals that V1a receptors in themedial preoptic nucleus are regulated by androgen, mostlikely by an up-regulation of V1a receptor gene expression ina cluster of neurons concentrated in the ventromedial part ofthis nucleus (138). In castrated hamsters, testosterone exertedan inhibitory effect on the number of POMC mRNA-positivecells, and more POMC mRNA-labeled cells were found in thearcuate nucleus of long-term than short-term castratestreated with testosterone (139). This effect does not involvearomatization into estrogen and seems to be mediated by theandrogen receptor. CRH is another brain target for androgenaction. Long-term castration increases hypothalamic CRHcontent and CRH-immunoreactive cell numbers in the para-ventricular nucleus, possibly by removal of an androgen-dependent repression function. Androgen treatment begin-ning at the time of gonadectomy prevented this increase(140).

Male hot flushes may reflect an effect of aromatized an-drogen deficiency with a similar mechanism to those of es-trogen withdrawal syndromes. The severity and frequency

TABLE 3. Symptoms, signs, and mechanisms of androgenwithdrawal


Myalgia, arthralgia, headache s Central dopaminergic systemFatigue, insomnia a Central noradrenergic systemEmotional lability, irritability,

depressions GABA-stimulated chloride influx

Autonomic hyperactivity,anorexia

a V1a vasopressin receptor

as POMC-related peptidesMetabolism into estrogen, DHT,

and 3-androstanediol



of sweating was reduced with naloxone, as can be seen infemale climacteric flushing. Injection of testosterone signif-icantly reduced the frequency and severity of the attacks,which, however, were unexpectedly unaltered by estrogentreatment (141, 142).

E. Therapeutic approaches to androgen withdrawal

The anabolic steroid withdrawal syndrome is preventableby refraining from any abuse of androgens. Yet, the incentivefor their use seems to overpower reason, and certain athletesand body builders continue steroid abuse despite the adverseconsequences of these agents. The acute flu-like syndromehas been ameliorated by administration of clonidine (123),tranquilizers, and analgesics. The antidepressant fluoxetinehas also been effective in treating the androgen withdrawalsyndrome (125). A more rational approach would be sub-stitution therapy and tapering of the dose, or use of chorionicgonadotropin treatment. This should be limited to individ-uals who can be certain of unequivocal termination of drugabuse. This is done under the understanding that withdrawalfrom androgen overdose is associated with hypogonado-tropic hypogonadism (129), which warrants replace-ment therapy until recovery of the hypothalamic-pituitary-gonadal axis.

V. GH

Some of the generalizations about a common withdrawalsyndrome apply weakly to GH. Yet, several lines of evidencesupport tolerance to GH and a withdrawal syndrome.

A. Withdrawal syndrome after discontinuation ofGH therapy

When treatment of patients with GH deficiency is discon-tinued in growing children, these patients manifest thesymptoms and signs of their original disease, primarilygrowth deceleration, within a short period of time. Childrenwith idiopathic short stature (143), intrauterine growth re-tardation (144146), or Noonans syndrome (147), with nounderlying hormone deficiency, also develop deceleration ofgrowth after discontinuation of GH therapy (Table 4). On theother hand, a single study of patients with Russell-Silversyndrome did not observe such deceleration of growth (148).The most obvious presentation of withdrawal symptomsafter exogenous GH therapy in non-GH-deficient children iscatch-down growth, i.e., deceleration of growth despitenormal GH and IGF-I levels (143), indicating tolerance to GH.Apparently, the withdrawal deceleration of growth is timedependent and more pronounced after prolonged GH treat-ment. The dose appears to be of no major consequence,whereas the daily schedule of injections might be important

for the development of tolerance (149). The withdrawal com-plex also includes a decline in resting cardiac output (143),an increase in fat mass, a decrease in metabolic rate, andnegative balances of nitrogen, phosphorus, sodium, and po-tassium, reported after withdrawal of GH in children withGH deficiency (150). A mild shortening of night sleep hasbeen reported after withdrawal of GH therapy in childrenwith idiopathic short stature (151).

Tolerance to GH is obvious: after a year of GH therapy, itloses some of its growth-promoting effect, some of its po-tential to stimulate IGF-I levels, and some of its anaboliceffect (150). Increasing GH dose, as observed also in drugs ofabuse, can restore these actions. Whereas deceleratinggrowth may be viewed as an asymptotic trend of the childapproaching his or her genetic height potential, the negativebalances of nitrogen, phosphorus, sodium, and potassiumare clear signs of tolerance.

Doping with GH has become an increasing problem insports during the last 10 yr. GH has a reputation of beingfairly effective among abusers, although the few controlledstudies that have been performed with administration ofsupraphysiological GH doses to athletes have shown no sig-nificant positive effects of GH from the point of view of adoping agent (152). No study on GH withdrawal amongabusers has been reported so far.

B. Withdrawal syndrome after correction ofhypersomatotropism in acromegaly

We are uncertain whether patients with acromegaly de-velop tolerance to GH. But, similarly to findings observedwith withdrawing GH therapy, body composition and me-tabolism are affected after removal of a GH-producing ad-enoma. Within 2 wk of surgery, patients lose weight mark-edly, due to a decrease in body water and cell mass, andrecover gradually over the next month (153). We speculate,although it remains unproven, that such patients develop awithdrawal syndrome with negative nitrogen and electrolytebalance, as observed in children during the GH withdrawalsyndrome.

C. Possible mechanisms of the GH withdrawal syndrome

The mechanism through which chronic exposure to eitherexogenous or endogenous GH leads to tolerance, depen-dence, and a withdrawal syndrome is unclear and does notinvolve detectable suppression of hormone secretion, as withother endocrine withdrawal syndromes (Table 4). During thenadir of growth velocity and after prolonged drug therapyof children with no GH deficiency, serum GH levels arenormal, as are serum IGF-I and IGF-binding protein-3 levels(143). GH therapy for as long as 12 months does not interferewith the endogenous pulsatile secretion of GH (154). If itexists, the mechanism of tolerance to GH may lie in theperipheral target tissues. Chondroprogenitor cells in thegrowth plate may wear off in the face of continuous high-level GH, in the absence of the unique pulsatile pattern ofserum GH (Table 4). Subcutaneous administration of dailyGH results in an unphysiological serum GH profile, withpeak levels at 4 h and a slow decline over the course of 1224

TABLE 4. Symptoms, signs, and mechanisms for GH withdrawal


Growth deceleration Suppressed GH pulsatilitya Fat mass Progenitor cell wearinesss Metabolic rate and cardiac

outputs Central noradrenergic system

Insomnia s Central dopaminergic system



h. This pattern can be regarded as continuous administrationof GH, rather then the physiological pulses, which occur witha frequency of about eight per day. As previously observedin short-term studies, alternate day therapy, which in anon-GH deficient child would allow for normal GH pulsa-tility in the interval day, resulted in zero or minimal catch-down of growth (155). Moreover, GH doses commonly usedtherapeutically often stimulate IGF-I to supraphysiologicalserum levels. The mechanism seems, therefore, to rest withdiminished GH and IGF-I action at the target cells of thegrowing bone and other tissues and organs.

D. Therapeutic approaches to GH withdrawal

Although untested, two approaches come to mind to pre-vent GH withdrawal symptoms and signs. The first is totaper off GH therapy gradually, as is the usual approach afterhigh-dose glucocorticoid therapy. The second is to preventGH dependence. A possible mode may be to prevent dailyexposure to GH, by administering it on alternate days (79).Whereas the growth-promoting effect of such a therapy isexpected to be smaller, the prevention of a catch-downgrowth may turn out to pay off in the long run.

To minimize postoperative withdrawal symptoms andsigns in acromegaly, one could attempt to gradually nor-malize GH secretion before surgery by octreotide. This ap-proach has been shown by some, but not all, to also minimizesurgical and postsurgical mortality (156, 157).

VI. Conclusions

A. Possible pathways for a unified endocrine withdrawalsyndrome

The symptoms and signs of endocrine withdrawal syn-dromes are different from those of the respective endocrine

deficiency syndromes, and, thus, the mechanisms appeardistinct. Several of the endocrine withdrawal syndromesshare common symptoms and signs and, therefore, mayshare common pathophysiological mechanisms. In others,common pathways are activated in opposite directions.Based on the mechanisms proposed for each of these hor-mones, we now offer a hypothetical unified concept thatapplies to hormone withdrawal (see Fig. 3). Fear and anxietyoccur due to marked decreases in levels of steroid hormonessuch as glucocorticoids, estrogens, androgens, and possiblythyroid hormones, whereas the withdrawal syndrome thatfollows decreases in levels of GH emerges with a differentpattern. Euphoria has been reported in glucocorticoid, es-trogen, androgen, GH, and thyroid hormone overdosing.Indeed, these hormones interrelate in many ways. To men-tion a few examples, glucocorticoids affect GH secretion andGH receptor expression, and GH affects cortisol productionand metabolism (158). Sex steroids have numerous effects onglucocorticoids and the lactogenic hormones. Also, somecommonalties could be due to the psychological aspects ofaddictive behavior.

Some of the symptoms and signs of endocrine overdoseand withdrawal syndromes are also observed with drugs ofabuse (Fig. 2A). Labile mood and paranoid ideas are commonsymptoms in overdose of both hormones and psychoactiveagents, and depression occurs in withdrawal syndromes ofglucocorticoids, estrogens, androgens, thyroid hormone, anddrugs of abuse. Interestingly, the withdrawal symptomsfrom different classes of drugs of abuse also share commonsigns, such as mood disturbances and flu-like symptoms thatinclude muscle aches and gastrointestinal disturbances (159).Intense cigarette smoking and also administration of nicotineand other drugs of abuse induce changes in hormones as-sociated with dysfunction of the HPA axis and the autonomic

FIG. 2. Withdrawal syndromes of several hormones share common symptoms and signs (A) and mechanisms (B). Many of these symptoms andsigns are also manifestations of withdrawal syndromes after discontinuation of drugs of abuse. Endogenous opioid peptides as well as the centraldopaminergic systems may play a central role in the pathogenesis of several of these syndromes.



nervous system and are similar to those seen in stress con-ditions. In both stress and withdrawal from hormones oropiates (160162), the clinical picture and experimental datasuggest the involvement of the dopaminergic systems withactivation followed by decreased activity upon cessation ofthe hormonal or drug effect (Fig. 2B and Ref. 161). Involve-ment of the noradrenergic system has also been suggested inthe expression of symptoms of opiate withdrawal (161).Clonidine was shown to ameliorate the withdrawal syn-dromes from glucocorticoids and anabolic steroids (123) aswell as those of the menopause (163).

Opioid peptides may play a role in the crossroads of sev-eral hormones and drugs of abuse, although they maychange in different directions during different stages of thewithdrawal syndromes of different hormones. A high doseof glucocorticoids suppresses POMC expression, with con-ceivable adjustment of that system to a new steady state thatis abruptly changed after withdrawal. Likewise, sex steroidsmodulate POMC-related peptide secretion and opioid pep-tide activity, as shown by the effect of naloxone on the neg-ative feedback of gonadotropins (164). Even the milder moodfluctuations during the menstrual cycle may be related to themidcycle increase and premenstrual withdrawal of -endor-phin (165). One of the earliest known actions of opiates wasthe inhibition of gastrointestinal secretion and motility. An-orexia, nausea, and emesis would be obvious symptoms ofabrupt opiate deficiency, because they are present in thewithdrawal syndromes of glucocorticoids, estrogens, andandrogens, as well as those of drugs of abuse. The mesolim-bic dopaminergic system is known to participate in the opiatewithdrawal syndrome (162).

The molecular and cellular bases of endocrine or drug-related addiction and withdrawal syndromes are only partlyunderstood. Table 5 summarizes the mechanisms and the

time courses of acute and chronic hormone action, tolerance,dependence, and short-term and long-lasting withdrawal(162). Relatively short-term dependence and addiction todrugs of abuse result from adaptations in specific target cellscaused by prolonged exposure to a supraphysiological levelof a hormone or a drug of abuse. These adaptive mechanismsmay explain the apparent contradiction between suppressedPOMC in Cushings disease and increased POMC in climac-teric hot flushes. The best established mechanism of adap-tation is up-regulation of cAMP pathway. Acute opiate ex-posure inhibits neuronal cAMP pathway, whereas chronicexposure leads to a compensatory cAMP up-regulation (162).Adaptation in membrane receptors, membrane receptor-Gprotein coupling, protein kinase A activity, and other com-ponents of this signal transduction pathway has also beenshown to be involved in the case of opiates and cocaine(162, 166).

Long-lasting molecular and cellular adaptations may in-volve other mechanisms. By analogy to other models of long-term memory and long-term drug addiction and abstinence,such long-lived adaptations to hormones may involve rela-tively stable changes in molecular switches and transcriptionfactors, such as those implicated in persistent drug-inducedplasticity (162). In the case of opiate withdrawal, changes inthe sensitivity and density of 2- and -adrenoreceptors oc-cur as a consequence of decreased presynaptic noradrenergicactivity, which is induced during opiate dependence.

Figure 2 displays the overlaps in symptoms and signs ofwithdrawal syndromes as well as the postulated commonpathways. It is obvious that withdrawal from glucocorti-coids, estrogen, and androgen share many of the symptomsand signs with clinical manifestations of withdrawal fromdrugs of abuse. We suggest, therefore, that changes of theopioid peptide systems and the mesolimbic dopaminergic

TABLE 5. Mechanisms and time course for drugs of abuse and glucocorticoid withdrawal syndrome as a paradigm for the unified concept

Molecular and cellular mechanisms Responding mechanisms Time course

Acute hormone excess state Hormone actionActivation of receptor s CRHActivation of message cascade s VasopressinAction on target proteins s Central noradrenergic system Minutes to hoursEndocrine negative feedback a Central dopaminergic systemDown regulation of receptor s GABA and serotoninDown regulation of message cascade s POMC, Opioid peptides

Chronic hormone excess state Tolerance, dependenceReceptor adaptationup-regulation a VasopressinMessage adaptationup-regulation a Central noradrenergic system Days to yearsTranscription factors up-regulation s Central dopaminergic systemEndocrine positive feedback a GABA and serotonin

Withdrawalshort term PerpetuationAbrogation a CRH

a Central noradrenergic systems Central dopaminergic system Hours to dayss POMC, opiatesa Prostaglandinsa IL-6

Withdrawallong lasting Sustained adaptationStable changes in gene expression, s CRH

neurotransmission, s Central noradrenergic systemsynaptic connections a Central dopaminergic system Days to years

a POMCa Glutamatergic system



system act as a link in the pathogenesis of all four withdrawalsyndromes. Central aminergic receptors, CRH, and vaso-pressin also stand out as common pathways for the with-drawal syndromes of all three steroid hormones (Fig. 3).

B. Therapeutic approaches to endocrine withdrawal

The goals of therapy are to ease withdrawal symptoms, aswell as to expedite weaning of the patient from the hormonalexcess or abstinence from the hormone or drug of abuse.Should one accept the concept of endocrine withdrawal syn-dromes, there is no reason to repeat the historic trials anderrors from drug-abuse treatment. In endocrine withdrawalsyndromes, one can use a more rational approach thanabrupt cessation of hormonal effect. Until we gain a betterunderstanding of the molecular and cellular mechanisms ofdependence and withdrawal, clinicians must resort to thefundamentals of tapering hormones down over time, as wehave been doing with glucocorticoids for many years. In thecase of abrupt removal of a hormone-producing tumor, asimilar strategy must be developed that will allow for grad-ually diminishing hormonal levels. This can be accomplishedbefore surgery or attempted thereafter. To prove the efficacyof such new strategies, the endocrine community shouldconduct controlled studies. The analogy made to drugs of

abuse and the possibly shared mechanisms suggest that pre-vention of stress may ameliorate withdrawal symptoms andthat antidepressants may be a helpful aid in moderate stress(166). Withdrawal syndromes that develop after natural de-creases of physiological hormonal levels may be easier totreat. Gonadal hormonal replacement therapy can be startedshortly before gonadectomy to prevent endocrine with-drawal syndromes.

Acknowledgments

Address requests for reprints to: George P. Chrousos, M.D., Pediatricand Reproductive Endocrinology Branch, National Institute of ChildHealth and Human Development, National Institutes of Health, Build-ing 10, Room 9D42, 10 Center Drive, MSC 1583, Bethesda, Maryland20892-1583. E-mail: [email protected]

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