Adrenal Disorders (Addison’s Disease & Cushing’s Syndrome)
The standard therapy for treating Addison’s disease consists of replacing the deficient hormones (Ten 2001). Hydrocortisone, which is a synthetic glucocorticoid, is one of the most common cortisol replacement therapies (Lennernas 2008). In acute illnesses, such as adrenal crisis, immediate administration of intravenous hydrocortisone and saline is needed to prevent potentially life-threatening complications (Kearney 2007).
Though effective, there are many challenges associated with using hydrocortisone. Since cortisol levels follow a diurnal variation, it is difficult to choose an optimal drug dosing regimen to simulate this natural circadian rhythm (Ten 2001; Grossman 2010). Furthermore, it is difficult to regulate levels of ACTH after administering hydrocortisone; ACTH levels can become very high because the hydrocortisone is released into the blood several hours after the morning dose (Ten 2001). Persistently high ACTH levels can lead to an increase in the size of the pituitary gland or even, in rare cases, to the development of a pituitary tumor (Himsworth 1978; Sugiyama 1996). Since the optimum glucocorticoid dose is difficult to determine, there is significant risk of overtreatment. Signs of overtreatment include dark pigmentation of the skin, weight gain, high blood pressure, high blood glucose, easy bruising, osteoporosis, and osteonecrosis (death of bone tissue) (Weinstein 2012; Ten 2001).
With regard to the replacement of aldosterone, fludrocortisone (also known as 9α-fluorohydrocortisone; a synthetic compound chemically similar to aldosterone with glucocorticoid and mineralocorticoid activity) can be orally administered. However, care needs to be taken to deliver an optimal dose because overtreatment can lead to hypertension (Ten 2001).
Cushing’s disease resulting from a pituitary tumor is treated by surgically removing the tumor (Biller 2008; Pozza 2012). However, only about 50% of people with large tumors benefit from surgery because the complete removal of the tumor is challenging. The tumors are also known to recur in up to 45% of people (Tritos 2012; Biller 2008; Pozza 2012). Moreover, repeat surgeries to the pituitary or adrenal gland are required in almost 25% of the people with a recurrence of Cushing’s syndrome (Schteingart 2009; Tritos 2011).
In Cushing’s syndrome where the cause is an ectopic tumor, removal of the tumor is required (Tritos 2012; Biller 2008). However, this is not always possible since: 1) identifying and locating the primary ACTH-secreting ectopic tumor may be difficult; 2) the tumor may have spread to different organs via the blood stream (metastasis); or 3) the tumor may be located at a site where surgery is difficult, eg, in the pancreas (Pozza 2012; Biller 2008; Tritos 2012).
Pharmacologic treatment of Cushing’s syndrome includes the administration of drugs that prevent steroid production or that suppress the release of ACTH from pituitary or ectopic tumors (Tritos 2012). With the exception of mifepristone, which was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of high blood sugar in people with Cushing’s syndrome who are either not surgical candidates or who had failed surgery, none of the other medications are FDA approved for use in Cushing’s syndrome as of the time of this writing (Tritos 2012). There are also limitations of these pharmacologic treatments. For instance, blocking steroid production has its own challenges—people on these medicines require frequent hospital visits and laboratory tests to ensure that the treatment does not result in adrenal insufficiency or adrenal crisis (Hahner 2010; Tritos 2012). If adrenal insufficiency is detected, glucocorticoids can be started; however, great care must be taken to ensure that this preventive measure does not worsen Cushing’s syndrome (Tritos 2012).
The antifungal drug ketoconazole inhibits several steps in steroid synthesis within the adrenal cortex. It is also likely that ketoconazole directly inhibits ACTH secretion from the pituitary gland. It is one of the most widely used and effective medications for Cushing’s syndrome (Tritos 2012). However, prolonged treatment with ketoconazole has been shown to cause adrenal crisis (Sarver 1997; Hahner 2010). Other side effects associated with ketoconazole are erectile dysfunction in men, low libido, and an increase in certain liver enzymes (Tritos 2012). This increase in liver enzymes occurs through injury to liver cells (García Rodriguez 1999). Moreover, ketoconazole is known to interact with and possibly interfere with actions of several other medications through the inhibition of the cytochrome P450 enzymes, which are critical for the metabolism of several drugs (Tritos 2012; Loose 1983).
Mitotane (Lysodren™) is used to treat people with tumors of the adrenal cortex. It prevents the production of steroids by interfering with enzymes involved in the conversion of cholesterol to various other steroid hormones. Though effective, mitotane has a late onset of action – it can take up to 2 weeks before showing beneficial effects. Mitotane has teratogenic effects (potential to cause birth defects) and can cause nervous system and gastrointestinal side effects (Tritos 2012).