Hypercortisolism

Monitor patients receiving surgical, medical, or radiation therapy for resolution of the clinical manifestations of hypercortisolism. Symptoms often improve immediately after surgery and soon after initiation of drug therapy. However, it may take months for symptoms to resolve following radiation therapy. 

TABLE 42-11. Principles of Glucocorticoid Administration to Avoid Hypercortisolism or Hypocortisolism... 

Measure plasma cortisol after surgery to determine if the patient displays persistent hypercortisol ism (surgical treatment failure) or hypocortisolism (adrenal insufficiency requiring steroid replacement therapy). 

Monitor cortisol, ACTH, low-dose dexamethasone suppression, or other tests to assess for risk of relapse of hypercortisolism. 

Hyperfunction of the adrenal glands occurs in Cushing s syndrome, a disorder caused by excessive secretion of cortisol by the adrenal gland (hypercortisolism). Other causes of adrenal gland hyperfunction include primary and secondary aldosteronism (not discussed in this chapter refer to textbook Chap. 79 for more information on these disorders). 

The presence of hypercortisolism can be established with a midnight plasma cortisol, late-night (11 PM) salivary cortisol, 24-hour urine free cortisol, and/or low-dose dexamethasone suppression test. 

The goals of treatment for Cushing s syndrome are to limit morbidity and mortality and return the patient to a normal functional state by removing the source of hypercortisolism without causing any pituitary or adrenal deficiencies. 

The antithromboxane effect of ginger is of potential significance in stress and depression. Hypercortisolism is found in approximately 50% of patients with major depression. Plasma thromboxane B levels correlated in a group of depressed patients with high levels of cortisol, but not with depressed individuals with low cortisol or with normal controls... 

There is evidence that inadequately treated, or xmtreated, major depression is associated with a decrease in the hippocampal volume. This could be a consequence of the increase in proinflammatory cytokines and hypercortisol-... 

Infusion of exogenous CRF increases ACTH levels and provides a test of pituitary sensitivity. In several studies of major depression, the ACTH response to CRF was shown to be blunted, reflecting a reduced sensitivity of the pituitary to CRF (e.g., Krishnan 1993). This finding has been widely interpreted as reflecting a downregulation of pituitary CRF receptors secondary to CRF hypersecretion, but may also reflect increased cortisol inhibition of ACTH secondary to hypercortisolism (Krishnan 1993 Yehuda and Nemeroff 1994). 

Holsboer F (2001) Stress, hypercortisolism and corticosteroid receptors in depression implications for therapy. J Affect Disord 62 77-91 Ito K, Yoshida K, Sato K, et al (2002) A variable number of tandem repeats in the serotonin transporter gene does not affect the antidepressant response to fluvoxamine. Psychiatry... 

The first point is that treatment with steroids is generally palliative rather than curative, and only in a very few diseases, such as leukemia and nephrotic syndrome, do corticosteroids alter prognosis. One must also consider which is worse, the disease to be treated or possible induced hypercortisolism. The patient s age can be an important factor, since such adverse effects as hypertension are more apt to occur in old and infirm individuals, especially in those with underlying cardiovascular disease. Glucocorticoids should be used with caution during pregnancy. If steroids are to be employed, prednisone or prednisolone should be used, since they cross the placenta poorly. 

Treatment with steroids may initially evoke euphoria. This reaction can be a consequence of the salutary effects of the steroids on the inflammatory process or a direct effect on the psyche. The expression of the unpredictable and often profound effects exerted by steroids on mental processes generally reflects the personality of the individual. Psychiatric side effects induced by glucocorticoids may include mania, depression, or mood disturbances. Restlessness and early-morning insomnia may be forerunners of severe psychotic reactions. In such situations, cessation of treatment might be considered, especially in patients with a history of personality disorders. In addition, patients may become psychically dependent on steroids as a result of their euphoric effect, and withdrawal of the treatment may precipitate an emotional crisis, with suicide or psychosis as a consequence. Patients with Cushing s syndrome may also exhibit mood changes, which are reversed by effective treatment of the hypercortisolism. 

Metyrapone is used in the differential diagnosis of both adrenocortical insufficiency and Cushing s syndrome (hypercortisolism). The drug tests the functional competence of the hypothalamic-pituitary axis when the adrenals are able to respond to corticotrophin that is, when primary adrenal insufficiency has been ruled out. 

Ketoconazole can be used as palliative treatment for Cushing s syndrome in patients undergoing surgery or receiving pituitary radiation and in those for whom more definitive treatment is still contemplated. Because surgical treatment is not always well tolerated by elderly patients, ketoconazole 200 to 1,000 mg/day can be a valuable alternative for the control of hypercortisolism. Common side effects include pruritus, fiver dysfunction, and gastrointestinal symptoms. 

A number of studies have repeatedly measured increased CRF-like immunoreactivity in the CSF of untreated patients with major depression (e.g., Nemeroff et ah, 1984). A recent study using serial CSF sampling over 30 hours has provided evidence for inadequately high CRF activity in major depression in the face of sustained hypercortisolism (Wong et ah, 2000). Postmortem studies have further provided evidence for increased CRF concentrations and CRF mRNA expression in hypothalamic tissue of depressed patients as well as decreased CRF receptor binding, likely due to chronic CRF hypersecretion, in the frontal cortex of suicide victims (Nemeroff et ah, 1988 Raadsheer et ah, 1994, 1995). These findings are consistent with indices of increased CRF activity in the hypothalamus and other structures in animals models of early-life stress. Direct measures of central CRF release in humans with early-life stress are still unavailable. 

As a possible consequence of direct neurotoxic effects of sustained hypercortisolism, hippocampal atrophy has now repeatedly been reported for depressed patients (Sheline et ah, 1996 Bremner et al., 2000a). Hippocampal atrophy may be associated with disinhi-bition of CRF secretion and further increases in cortisol secretion, which in turn may further damage the hippocampus. Impaired inhibition of the HPA axis is also evidenced by nonsuppression of cortisol by dexame-thasone and decreased GR numbers in depressed patients both findings parallel those in maternally separated rats. 

Wong, M.L., Kling, M.A., Munson, P.J., Listwak, S., Licinio, J., Prolo, R, et al. (2000) Pronounced and sustained central hyper-noradrenergic function in major depression with melancholic features relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA 97 325-330. 

A 27-year-old female is diagnosed with hypercortisolism. To determine whether cortisol production Is Independent of the pituitary gland, you decide to suppress ACTH production by giving a high-potency glucocorticoid. Which glucocorticoid is the best for this indication ... 

An intriguing hypothesis first proposed by Schatzberg and colleagues (1985) is that the development of delusions in patients with depression is secondary to the effects of hypercortisolism on dopaminergic systems. 

Given that the seat of hormonal modulation is in the limbic-hypothalamic-pituitary axis, endocrine changes serve as important correlates to major psychiatric disorders. These changes include basal hormone concentrations, as well as responses to pharmacological challenges. Equally important, endocrine disorders may present with psychiatric symptoms (e.g., manic symptoms in hyperthyroidism, severe depression in hypercortisol ism, psychotic symptoms associated with Cushing s syndrome). Commonly used neuroendocrine tests include the following. 

Vegetative (e.g., appetite, sleep, sexual drive) and neuroendocrine (e.g., hypercortisolism) dysreguiation, characteristic of severe depression and mediated by centrencephalic structures, are improved by ECT. 

Biason-Lauber A, Suter SL, Shackleton CH, Zachmann M (2000) Apparent cortisone reductase deficiency a rare cause of hyperandrogenemia and hypercortisolism. Horm Res 53 260-266... 

Phillipov G, Palermo M, Shackleton CH (1996) Apparent cortisone reductase deficiency a unique form of hypercortisolism. J Clin Endocrinol Metab 81 3855-3860... 

Because of its effects on the pituitary/adrenal system, ketoconazole has been used in the long-term control of hypercortisolism of either pituitary or adrenal origin (SED-12, 677). In seven patients with Cushing s disease and one with an adrenal adenoma, ketoconazole 600-800 mg/day for 3-13 months produced rapid persistent clinical improvement (585). Plasma dehydroepiandrosterone sulfate concentrations and urinary 17-ketosteroid and cortisol excretion fell soon after the start of treatment, and remained normal or nearly so throughout treatment. Urinary tetrahydro-ll-deoxycortisol excretion rose... 

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