Glucocorticoid Withdrawal Syndrome

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Glucocorticoid Withdrawal Syndrome

• CME Review article 18 2004
• Z.Hochberg
• Presents by
• Chen T.T.

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Introduction

• Hypersecretion of endogen or chronic
  administration the same hormon tolerance or
  dependence.
• Termination Hormon deficiency -withdrawal
  syndrome.
• Endocrine withdrawal synd. changes HPAx and
  centr. Opiate, Noradrenal a. dopaminergic system
  of the brain.

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Introduction

• High dose glucocorticoid suppressed HPA axis.
• Osteoporosis, cataract formation, increase BP.
• Increase glucose level
• Increase cholesterol level
• Myopathy
• Avascular necrosis
• Growth retardation.

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Clinical manifestation

• Anorexia
• Weight loss
• Nausea and vomiting
• Headache
• Lethargy, fever, myalgia, arthralgia,
• Skin desquamation
• Postural hypotension.

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Tolerance, dependence and addiction

• Tolerance Functional adjustments of target
  tissue signal transduction systems and/or form
  metabolic adjustment associated with increased
  catabolism and disposition of the drug taken
  chronically.

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Tolerance, dependence and addiction

• Progressive decreased response to the effect of a
  drug, necessitating ever-larger doses to achieve
  the same effect.
• Addiction Psychological and physiological
  dependence with clear adverse behavioral and
  social consequences, mainly with regard to drugs
  of abuse.

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Withdrawal syndrome after discontinuation of
glucocorticoid therapy

• Glucocorticoid control the activity of
  autoimmune, inflammatory, allergy and neoplasm of
  the hematopoietic system.
• High therapy dose control suppress the HPA axis
  and exert numerous CNS effect- anxiety, insomnia,
  impairment of cognition , euphoria, mania,
  depression and psychosis.

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Withdrawal syndrome after discontinuation of
glucocorticoid therapy

• Relapse of illness.
• HPA axis and POMC-derived peptide secretion
  remain suppressed for long time.
• Nonspesific withdrawal syndrome could develop
  even receiving physiological replacement dose.
• Psychologic dependence.
• Syndrome could occur during weaning pharmacologic
  high dose therapy while replacement is adequat.

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Withdrawal synd. After correction of
hypercotisolism in Cushing synd.

• Successful surgery of Cushing synd. Patient feels
  worse.
• Atypical depressive disorder develops in over
  half of postoperative patient, ¼ of patient for
  up to 1 year while still glucocorticoid
  replacement.

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Possible mechanism of the Glucocorticoid
withdrawal Synd

• Corticotropin-Releasing hormone suppressed.
• Patient with Cushings disease show markedly
  decreased CRH in CSF.
• Hypersecretion of CRH? Hypercortisolism -?
  melancholia
• Glucocorticoid induced hyperactivity of CRH
  neuron in the amygdala -? arousal, fear response
  and anxiety.

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Possible mechanism of the Glucocorticoid
withdrawal synd

• Hyposecretion of CRH plays the important role in
  pathogenesis of atypical depression.
• Abrupt glucorticoid withdrawal -? psychopathology
  ? long standing hypoactivity of central CRH
  neuron.
• Fatigue, hypersomnia, lethargy and hyperphagia.
• Hypercoritsolism ? 2/3 patient depression.

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Vasopressin

• Adrenal insufficiency elevated plasma
  vasopressin, normalized by glucocorticoid
  replacement.
• Cushing synd. suppress vasopressin with increase
  frequency urination.
• Improved short-and long term memory processes,
  mood, concentration of depressed patient.
• Oxytocin impair memory performance.
• Glucocorticoid withdrawal induced disturbance of
  vasopressin and oxytocin neurons.

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Neurotransmitters

• Glucocorticoid treatment increase dopamine
  release in nucleus accumbens associated with the
  Euphoric state.
• Acute stress dopamine release from mesolimbic
  systemin defensive responses.
• But prolonged exposure to stress ---gt inhibition
  of the mesolimbic dopanergic system.

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Neurotransmitters

• Chronic hypercotisolemia( animal )? central
  noradrenegic system is inhibited.
• Adrenalectomy increase norepinephrine release in
  brain and periphere, cortisol. Replacement blunt
  this change.
• Chronic cortisolism inhibit periphere
  sympathoadrenal activity.
• Cushings synd. decrease glucose up take rate in
  all brain, except striatum.

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Neurotransmitters

• Post op patient of Cushing synd.? increase panic
  behavior together with increased sympathoadrenal
  activity? normalized after steroid replacement.
• Corticosteroid withdrawal -gt Panic and increased
  central noradrenergic activity. When the function
  of noradrenagenic neuron recover, symptoms of
  anxiety subsided.

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Neurotransmitters

• Thus,
• Major depression hyperadrenegic and
  hypercortisolemic.
• Depressed Cushing patient Hypoadrenergic and
  hypercoticolemic
• Patient after glucocorticoid withdrawal
  Hypernoradrenergic and hypocortisolemic.

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Pro-opiomelanocortin

• CRH and Vasopressin stimulate serum level of
  lipotropin, MSH and Beta-endorphin.
• Glucoriticoid supppress pituitary and
  hypothalamic POMC expression.
• Hence, some of the symptoms of Cushing synd.
  Related to deficiency of these peptids.
• So some of CNS symptoms of glucocorticoid
  dependence and withdrawal are related to those of
  opiate withdrawal.

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Interleukin and Prostaglandins

• Acute phase of gluc. withdrawal and the flu like
  syndrome?IL-6, TNF-alpha and IL 1beta increased.
• Exogenous administration of IL-6 ? Flu like synd.
• PGE2 and PGI2 may induce many of the feature of
  the flu like synd.

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Nicotine

• Habitual smoker- dose dependent increase plasma
  cortisol after smoking 2 cigarette and fall in
  plasma cortisol level with withdrawal of nicotine
  stimulus.
• Nicotine withdrawal? change of CRH and cortisol
  level.
• Thus cigarette cessation program ?
• 1-2 ACTH injections help smoker stop.

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Therapeutic approaches to glucocorticoid
withdrawal

• 2 Option to minimize postoperative withd.synd.
• 1. Normalize cortisol secretion Pre- Op. with
  medical suppression of steroidegenesis.
• 2. High-dose glucocorticoid replacement therapy
  Post0-Op and tape it off gradually.

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Therapeutic approaches to glucocorticoid
withdrawal

• Sucessful withdrawal of a long term low dose
  glucocort. Therapy depends on the recovery of
  ther pituitary adrenal axis.
• Assess by a low dose ACTH stimulation and CRH
  stimulation tests.
• Fluoxetine- effective for Tx of glucocorticoid
  and androgen withdrawal synd.

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Withdrawal syndrome of other steroid hormones.

• Estrogen and Progestins
• Estrogen potent stimuli to HPA axis.
• Manisfestation of withdrawal synd.
• Hot flushes and autonomic hyperactivity, also
  fatigue, irritability, anxiety and depression
  even psychosis.

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Withdrawal syndrome of other steroid hormones.

• Supra physiological gonadal steroid levels of
  pregnancy and withdrawal from these high levels
  to hypogonadal state-?mood symptoms-gt post partum
  depression.
• 60 mild depression.
• 13 Fullfledged depression.

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Withdrawal syndrome of other steroid hormones.

• Estrogens are psychoactive and change mood.
• Psychological and physiological dependence-
  Replacement therapy promotes feeling of well
  being.
• Premenstrual dysphoric disorder (PMDD)-Premens.
  Irritability, fatique and mood change associated
  with increase and decrease in levels of estrogen
  and progresterone.

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Withdrawal syndrome of other steroid hormones

• Abuser of anabolic steroid of athletes could be
  up 100 times greater than therapeutic replacement
  doses.
• Have severe psychologic and behavioral side
  effect, including aggressive and violent
  behavior.
• Withdrawal and dependence Decreased sexual
  drive, also in a flu like synd that mimics in
  many ways, the glucocorticoid withdrawal synd.

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Withdrawal syndrome of other steroid hormones

• 23 of anabolic user reported major mood
  syndromes mania, hyponamia, and depression.

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Common mechanisms possibly underlying steroid
hormones withdrawal synd.

• Symptoms or signs of endocr. withdr. Syndrome are
  different.
• Fear and anxiety decrease steroid hormonal
  level.
• Euphoric Glucocorticoid, estrogen and androgen
  overdosing.
• Depression in vice versa.

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Common mechanisms possibly underlying steroid
hormones withdrawal synd.

• Labile mood and paranoid idea
• Withdrawal symptoms from different classes of
  drugs of abuse- common sign of mood disturbance
  and flu like symptoms.
• Clonidine ameliorate the withdrawal syndrome from
  glucocorticoid, anabolic steroid as well as those
  of menopause.

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Common mechanisms possibly underlying steroid
hormones withdrawal synd

• High dose glucocorticoid suppress POMC-expression
  with conceivable adjustment of that system to a
  new steady state that is abruptly changed after
  withdrawal.
• Sex steroid modulate POMC-related peptid
  secretion and opioid peptide activity- Effect of
  naloxone on neg. feed back of gonadotropins.

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Common mechanisms possibly underlying steroid
hormones withdrawal synd

• Mesolimbic dopaminergic system is known to
  participate in the opiate withdrawal syndrome.
• Relatively short-term dependence and addiction to
  drugs Resulte from adaptation in specific
  target cells-caused by prolonged exposure to a
  supraphysiological level of drug or hormone
  abuse.
• Acute opiate exporure inhibits neuronal cAMP ,
  whereas chronic exporure leads to a compensatory
  cAMP upregulation.

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