Endocrine Reviews 2003 24 4: 523-538 Ze ev Hochberg Presentation by Chou Chien-Wen MD 9 Jan 2004

1. Endocrine Reviews 2003 24 (4): 523-538Ze�ev Hochberg Presentation by Chou Chien-Wen MD 9 Jan 2004

2. Table of Content (1) I. Introduction  II. Glucocorticoids A. Withdrawal syndrome after discontinuation of glucocorticoid therapy  B. Withdrawal syndrome after correction of hypercortisolism in Cushing�s syndrome  C. Possible mechanisms of the glucocorticoid withdrawal syndrome  D. Therapeutic approaches to glucocorticoid withdrawal  III. Estrogens and Progestins A. Postpartum as a withdrawal syndrome  B. Menopause as a withdrawal syndrome  C. Withdrawal syndrome after interruption of hormone replacement therapy  D. Premenstrual syndrome as a withdrawal phenomenon  E. Possible mechanisms of the estrogen withdrawal syndromes  F. Therapeutic approaches to estrogen withdrawal 

3. Table of Content (2) IV. Androgens A. Withdrawal syndrome after discontinuation of replacement therapy  B. Withdrawal syndrome in athletes abusing androgens  C. Withdrawal from physiological androgen levels  D. Possible mechanisms of the androgen withdrawal syndrome  E. Therapeutic approaches to androgen withdrawal  V. GH A. Withdrawal syndrome after discontinuation of GH therapy  B. Withdrawal syndrome after correction of hypersomatotropism in acromegaly  C. Possible mechanisms of the GH withdrawal syndrome  D. Therapeutic approaches to GH withdrawal  VI. Conclusions A. Possible pathways for a unified endocrine withdrawal syndrome  B. Therapeutic approaches to endocrine withdrawal 

4. Introduction Tolerance Progressively decreased response to the effect of a drug, necessitating ever-larger doses to achieve the same effect Dependence During the period of additive substance use, the body adjusts to a new level of pathological homeostasis. When the drug is abruptly discontinued, this equilibrium is disturbed and the organism reacts both behaviorally and physiologically with a consellation of manifestations called withdrawal syndrome Addiction Both psychological and physiological dependence, with clear adverse behavioral and social consequences

5. FIG. 1. Phases in the development of hormonal withdrawal syndromes. Similar to the phases after the consumption of drugs of abuse, chronic hormonal excess production or administration may lead to tolerance for the respective hormone. This may be followed by dependence and, rarely, addiction. Correction of the chronic hormone excess syndrome at each of these phases may lead to withdrawal syndromes. The severity of the withdrawal syndrome depends on the phase and degree of dependence. Similar to the phases after the consumption of drugs of abuse, chronic hormonal excess production or administration may lead to tolerance for the respective hormone. This may be followed by dependence and, rarely, addiction. Correction of the chronic hormone excess syndrome at each of these phases may lead to withdrawal syndromes. The severity of the withdrawal syndrome depends on the phase and degree of dependence.

6. Endocrine Withdrawal Syndromes Mixed picture of two different syndromes: a typical hormone deficiency syndrome and a generic withdrawal syndrome Hormones with completely different physiological effects can produce similar withdrawal syndromes Changes of the hypothalamic-pituitary-adrenal (HPA) axis and the central opioid peptide, noradrenergic and dopaminergic systems act as shared features in the pathogenesis of several endocrine withdrawal syndromes Potentiation of G protein receptor coupling, up-regulation of cAMP, increased activities of protein kinases, and changes in the expression and activities of several transcription factors

7. Withdrawal syndrome after discontinuation of glucocorticoid therapy To control the activity of the diseases, suppress the HPA axis and exert numerous central nervous system (CNS) effects, including anxiety, insomnia, impairment of cognition, and mo od changes ranging from euphoria to hypomanaia, mania, depression and psychosis Some of these symptoms have been attributed to the suppression of hypothalamic CRH and proopiomelanocortin (POMC)-derived peptides such as B-endorphin, stimulation of amygdala, and initial stimulation followed by tolerance and inhibiton of dopaminergic mesocorticolimbic system After abrupt discontinuation of the glucocorticoid therapy, patient may develop anorexia, nausea, emesis and weight loss, fatigue, myalgias, arthralgias and headache, abdominal pain, lethargy and postural hypotension, fever and skin desquamation

8. Withdrawal symdrome after correction of hypercortisolemia in Cushing�s syndrome Flu-like syndrome characterized by anorexia, nausea, fatigue, somnolence, arthralgia myalgias and fever Atypical depressive disorder develops in over half of postoperative Cushing�s disease patients, which persisted in a quarter of the patients for up to a year Biochemical evidence includes hypercalcemia and hyperphosphatemia, mirroring the loss of the suppressive effects of glucocorticoids on calcium absorption Recovery may take as long as a year or more

10. Therapeutic approaches to glucocorticoid withdrawal Gradual tappering of high-dose glucocorticoid therapy In attempting to minimize postoperative withdrawal symptoms and signs, the clinician is faced with two options: the first is to normalized cortisol secretion before surgery, empolying medical suppression of steroidogenesis. The second option is to reinstitute high-dose glucocorticoid replacement therapy after surgery and taper it off gradually

11. Estrogens and Progestins Estrogens are potent stimuli to the HPA axis and the LC/NE system Postpartum, menopause, and the premenstrual syndrome are all associated with decreasing estrogen and withdrawal syndrome-like manifestations These may include hot flushes and autonomic hyperactivity but also fatigue, irritability, anxiety and depression and even psychosis

12. Postpartum as a withdrawal syndrome Pregnancy is a complex endocrine condition, associated with high levels of cortisol, estrogen, progesterone, CRH, GH variant, human placental lactogen, and other placental products The withdrawal syndrome that follows labor and delivery Possible role of changes in gonadal steroid levels in postpartum blues or depression When women with histories of puerperal psychosis or major depression were treated with high dose oral estrogen immediately after delivery, they remained healthy and required no treatment with psychotropic medications during 1 yr follow up period compared with an expected 35-60% recurrence rate

13. Menopause as a withdrawal syndrome Women who suffer hot flushes soon after menopause have lower estrogen levels than those who not have hot flushes It can ameliorated by estrogen replacement therapy Self-limited More severe withdrawal symptoms of autonomic hyperactivity, hot flushes, and hyperemic coronary flow occur when menopause is instituted abruptly by surgery or antiestrogens, such as clomiphene citrate or tamoxifen, but not in slowly progressing forms of hypogonadism and less so in slowly progressing premature ovarian failure Climacteric depression

14. Withdrawal syndrome after interruption of hormone replacement therapy Estrogens are psychoactive: they cause mood changes and their use has powerful psychological effects Menopausal like symptoms sometimes evolve despite high serum levels of estradiol, perhaps as tolerance to estrogen Hormone replacement therapy is often withdrawn abruptly for a variety of clinical indication but little attention is given to symptoms and signs of withdrawal

15. PMDD Late or premenstrual dysphoric disorder is associated with the cyclically recurring increase and decrease in the levels of estrogens and progesterone clear onset and offset of symptoms closely linked to the menstrual cycle and the prominence of symptoms of anger, irritability and internal tension Women who suffer a premenstrual withdrawal syndrome are more likely to develop late pregnancy depression and anxiety, as well as postpartum blues and depression

17. Therapeutic approaches to estrogen withdrawal The currently recommended treatment for postpartum and climacteric depression is antidepressants In PMDD, at least 60% of patients respond to selective serotonin reuptake inhibitors Lower-dose hormone replacement therapy could diminish dependence Postpartum administration of high-dose estrogen and tapering off minimize the psychiatric estrogen withdrawal syndrome

18. Withdrawal syndrome after discontinuation of androgens replacement therapy Traditionally, replacement therapy in patients with testicular failure of any etiology utilizes long-acting preparations, the most common of which is testosterone enanthate The pharmacokinetics of a dose given every 3-4 weeks is such that it provides supraphysiological serum levels over the initial week and subphysiological levels on wk 3-4 A few days before each injection, emotional lability and mood swings may occur This cyclic withdrawal syndrome is easily prevented by administration if lower doses of testosterone enanthate every 1 or 2 wk or continuous administration with skin patches or gels

19. Withdrawal syndrome in athletes abusing androgens The abuse of anabolic steroids by athletes and body builders Doses of abused steroid may be up to 100 times greater than therapeutic replacement doses Have severe psychological and behavioral side effects, including aggressive and violent behavior Withdrawal may result in decreased sexual drive but also in a flu-like syndrome

20. Withdrawal from physiological androgen levels Orchiectomy or GnRH analog therapy, such as that given to patients with prostatic cancer, often result in hot flushes The symptoms are alleviated by either androgen or estrogen therapy, suggested a role for androgen-derived estrogen

22. Therapeutic approaches to androgen withdrawal Preventing by refraining from any abuse of androgens The acute flu-like syndrome has been ameliorated by administration of clonidine, tranquilizers and analgesics The antidepressant fluoxetine has also been effective in treating the androgen withdrawal syndrome The more rational approach would be substitution therapy, and tapering of the dose, or use of chorionic gonadotropin treatment

23. Withdrawal syndrome after discontinuation of GH therapy GHD: growth deceleration Non-GH-deficient children: catch-down growth, deceleration of growth despite normal GH and IGF-I levels, indicating tolerance to GH The withdrawal deceleration of growth is time dependent, the dose appears to be of no major consequence Decline in resting cardiac output, an increase in fat mass, a decrease in metabolic rate and negative balances of nitrogen, phosphorus, sodium and potassium Mild shortening of night sleep

24. Withdrawal syndrome after correction of hypersomatotropism in acromegaly Body composition and metabolism are affected after removal of a GH-producing adenoma Within 2 wk of surgery, patients lose weight markedly, due to a decrease in body water and cell mass and recover gradually over next month

26. Therapeutic approaches to GH withdrawal Taper off GH therapy gradually To prevent GH dependence Prevent daily exposure to GH, by administering it on alternate days Whereas the growth-promoting effect of such a therapy is expected to be smaller, the prevention of a catch-down growth may turn out to pay off in the long run Gradually normalize GH secretion before surgery by octreotide in acromegaly

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

28. FIG. 3. Interrelations between the stress system [CRH/arginine vasopressin (AVP) neurons and LC-NE neurons] with the POMC-related opioid peptide system, mesocorticolimbic dopaminergic system (MCLS), and the amygdala. Acutely, glucocorticoids, estrogens, androgens, thyroid hormones, and GH may activate the MCLS and POMC-related opioid peptide system. Tolerance and dependence to these actions may develop though. Upon withdrawal of the hormone, the POMC-related peptide system and MCLS are suppressed, producing dysphoria and anxiety; the latter via amygdala activation ( , stimulation; ----, inhibition). Acutely, glucocorticoids, estrogens, androgens, thyroid hormones, and GH may activate the MCLS and POMC-related opioid peptide system. Tolerance and dependence to these actions may develop though. Upon withdrawal of the hormone, the POMC-related peptide system and MCLS are suppressed, producing dysphoria and anxiety; the latter via amygdala activation ( , stimulation; ----, inhibition).