CHAPTER 32 Hypothalamic, Pituitary, and Adrenal Diseases

Andrew Y. Hwang, Steven M. Smith, and John G. Gums

Drug- induced disorders of the , pitu- The , also known as the hypo- itary, and adrenal glands are difficult to classify physis, is under the control of the hypothalamus because of the complex interrelationship of the var- through direct nerve stimulation (posterior lobe) ious endocrine glands. Nonetheless, the most com- and by the actions of inhibitory and stimulating monly reported are those caused by adrenocortical hormones (anterior lobe) such as thyrotropin- dysfunction and excess prolactin secretion by the releasing hormone and corticotropin- releasing . Adrenal glands are responsible hormone (CRH). The anterior lobe of the pitu- for the secretion of catecholamines and three hor- itary gland is responsible for the synthesis of mones responsible for the regulation of some of growth hormone (GH), prolactin, luteinizing the most vital processes in the body. , hormone, follicle- stimulating hormone, - the main end product of mineralocorticoid pro- stimulating hormone, and adrenocorticotropic duction, is secreted preferentially by the zona glo- hormone (ACTH). In addition, vasopressin, also merulosa and is responsible for electrolyte and known as antidiuretic hormone, and oxytocin volume homeostasis. The zona fasciculata is pri- are synthesized in neurons of the hypothalamus, marily responsible for production, stored in the posterior lobe of the pituitary, and mainly , and controls fat, protein, and glu- released upon direct nerve stimulation. The com- cose metabolism. The is primarily plex interplay between the hypothalamus, pitu- responsible for production of the sex steroids (estro- itary, and adrenal glands is commonly referred to gen and testosterone) that control the development as the hypothalamic–pituitary–adrenal (HPA) axis of primary and secondary sex characteristics. (Figure 32-1).

729 730 DRUG-INDUCED DISEASES: Prevention, Detection, and Management

CAUSATIVE AGENTS

Specific drugs that have been reported to induce 1-40 Hypothalamus Cushing syndrome are listed in Table 32-1. Pro- () longed or excessive administration of is the most common cause of drug-in­­ duced Cushing (–) CRH Release syndrome; these drug-­­induced cases can occur fol- lowing administration of virtually any GH by any route.1-24,41-43 Other drug-­­induced causes FSH PRL include progestins and ACTH administration. TSH LH Anterior Pituitary EPIDEMIOLOGY

(–) ACTH Release The incidence of drug-in­­ duced Cushing syndrome in the general population is unknown, although CORTISOL it likely substantially exceeds the estimated 1 to 3 cases per million person-­­years observed in per- sons with Cushing syndrome secondary to pituitary tumors or adrenal adenomas and carcinomas (col- lectively referred to as endogenous Cushing syn- drome).44,45 Approximately 2–5% of obese patients (–) with uncontrolled type 2 diabetes and hypertension screen positive for Cushing syndrome, although Cortisol Release scarce data exist to help differentiate the drug-­ induced disease from other causes. Nevertheless, the vast majority of Cushing syndrome cases are Periphery thought to be drug-­­induced, and the syndrome has FIGURE 32-1 Hypothalamus been recognized with increased frequency as the use of for a wide range of nonendo- ACTH = adrenocorticotropin, CRH = corticotropin-­­releasing hormone, GH = growth hormone, FSH = follicle-­­stimulating crine diseases has expanded. hormone, LH = luteinizing hormone, PRL = prolactin, TSH = thyroid-­­stimulating hormone. MECHANISMS

Mechanisms for drug-in­­ duced Cushing syndrome GLUCOCORTICOID EXCESS are listed in Table 32-2. In vivo, glucocorticoid (CUSHING SYNDROME) drugs resemble the naturally occurring glucocorti- coid, cortisol, and bind with high affinity to spe- In 1932, Cushing first described a syndrome of cific cytoplasmic glucocorticoid receptors (GRs) pituitary basophilism that attracted national atten- found in virtually all tissues of the body. This bind- tion. Until that time, no definitive diagnosis was ing induces a response by modifying transcription available for patients with unexplained central and ultimately by causing changes in protein syn- obesity, striae, osteoporosis, weakness, hyperten- thesis that can produce adverse physiologic effects sion, and diabetes mellitus. Daughaday discovered similar to those seen in classic Cushing syndrome elevated steroids in the urine of patients with this (hypercortisolism secondary to a pituitary tumor). clinical presentation, and the syndrome was at last Increased sensitivity to glucocorticoids may play a correctly explained as an excess of cortisol in the role in some cases of drug-­­induced Cushing syn- plasma (hypercortisolism). drome, especially when the route of administration