Pathophysiology

The HPA axis is a set of interactions between three glands; the hypothalamus, the pituitary gland and the adrenal gland. Together, these form a complex system that regulates endocrine release in the body. The hypophyseal portal system connects the hypothalamus and the pituitary gland and the fenestrated structure of the capillaries facilitates the rapid transport and exchange of hormones (Clarke, 2015). The HPA axis controls reactions to stress as well as processes such as digestion, mood, emotions, and energy storage and expenditure. When the HPA axis is activated by stress, it causes the release of cortisol from the adrenal glands. A negative feedback system ensures that cortisol levels remain within a healthy physiological range (Raff and Carroll, 2015).

The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis).

Figure 1. The HPA axis.
ACTH: adrenocorticotropic hormone; AVP: arginine vasopressin; CRH: corticotropin-releasing hormone.

Cushing’s Syndrome is defined by the presence of excess cortisol in the body, regardless of the physiological cause, and can be classified as either exogenous or endogenous. Exogenous CS (or medication-induced CS) is the most common form and is caused by external administration of high doses of glucocorticoids, such as prednisone used to treat inflammatory conditions (Newell-Price et al., 2006; Newell-Price et al., 2011). Other important sources are inhaled ‘steroids’ (strictly speaking, corticosteroids) for asthma, and occasionally topical and injected steroids.

Endogenous CS, meanwhile, is typically caused by tumours of the pituitary or adrenal gland, although other causes, such as ectopic tumours, can also result in CS. While all cases of CS are characterised by excessive levels of cortisol, some forms of the disease are a consequence of increased production of adrenocorticotropic hormone (ACTH), which promotes the production of cortisol. Endogenous CS can, therefore, be defined as ACTH-dependent (typically pituitary tumours or ectopic tumours) or ACTH-independent (adrenal tumours or other adrenal disorders). Most cases of CS are ACTH-dependent and caused by tumours of the pituitary gland (Figure 2). This form of CS is also called Cushing’s Disease (Valassi, 2011).

ACTH-independent CS is most commonly caused by the development of adrenal cortical tumours. As many as 10% of adults over 40 years of age may have an adrenal cortical tumour with CS manifesting itself in approximately one-third of these tumours. In adults, the majority of these tumours are adenomas, however, malignant neoplasms of the adrenal cortex still account for 0.05–0.20% of all cancers, with a prevalence of 2 per million people per year, and can occur at any age (Stratakis, 2008). Patients with advanced adrenal cortical carcinoma (ACC) have a poor prognosis with 5-year survival rates of less than 15% in patients with metastatic disease (Fassnacht et al., 2012). Meanwhile, adrenal adenomas are increasingly being diagnosed when patients are scanned for other reasons. In approximately 4% of patients undergoing abdominal imaging, adrenal ‘incidentalomas’ are identified offering the opportunity to assess for unrecognised secretory tumours and improve patient care (Ioachimescu et al., 2015).

Figure 2. Classification of Cushing’s Syndrome.

Figure 2. Classification of Cushing’s Syndrome.
ACTH: adrenocorticotropic hormone.