Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. The Pituitary gland (P) is located in the Sella turcica (S) at the base of the skull. It measures less than 10 millimeters in diameter. Its importance can be judged by the fact that it is known as the ‘master’ gland of the endocrine ‘orchestra’ in view of the control it exerts on majority of endocrine glands in the body.

Pituitary-adenoma-Anat-01 Pituitary-adenoma-Anat-02


The Pituitary gland is an amalgam of two tissues consisting of the Anterior and Posterior components which are distinctly different in structure, reflecting their differing embryological origins.

The hormone predominantly affected in Cushing disease is the Adrenocorticotropic hormone (ACTH) with the following features:

  • Produced by the Adenohypophysis (Anterior Pituitary)
  • Target tissue (Primary site of action): Adrenal cortex
  • Action: Stimulates Steroid hormone biosynthesis and secretion

Cushing’s disease is a severe endocrine disease caused by a ‘corticotroph’ pituitary tumor and associated with increased morbidity and mortality.

Like most tumors the exact cause of pituitary adenomas is not known. In the majority of cases these may occur as isolated tumors or as components of a syndrome like Multiple Endocrine Neoplasia type 1 and Carney complex. Few genetic predictors of Pituitary adenoma development exist.

A clinical condition of Familial Isolated Pituitary Adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like Multiple Endocrine Neoplasia Type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas. The aryl hydrocarbon receptor interacting protein (AIP) gene has been implicated in 20% of FIPA families.

Most GH secreting Pituitary adenomas usually form from a genetic mutation in one a single, pituitary cell called a ‘Corticotropic’ cell. This mutation causes uncontrolled growth and reproduction of these cells.

Cushing’s disease due to ACTH-secreting pituitary adenomas is a rare, slowly progressive, acquired disorder that affects adults but may rarely affect children. Majority of all ACTH-positive adenomas are located in the anterior lobe of the pituitary gland and are discrete adenomas.

ACTH-secreting pituitary adenomas are considered the most common cause of endogenous hypercortisolemia, accounting for about two-thirds of cases of endogenous Cushing’s syndrome. The majority of ACTH-secreting pituitary adenomas are microadenomas, and these do not cause mass effect symptoms. They are usually identified on the basis of clinical features of hypercortisolism. Clinical symptoms of hypercortisolism include weight gain, central obesity, plethora, hirsutism, and proximal muscle weakness,

Pituitary-adenoma-Clinical-Cushing Pituitary-adenoma-Clinical-02-Cushing
  1. Cushing’s disease is a rare disorder that affects females three times more than males. This disorder occurs in 40 cases per million and mainly occurs during the fourth to sixth decades of life.
  2. The clinical presentation of Cushing’s disease can be highly variable and the diagnosis can often be challenging in cases with mild or cyclic hypercortisolism. This may delay the diagnosis for 2–4 years.  Diagnosis of Cushing’s disease is made based on:
    1. Clinical features of Cushing’s disease mainly include weight gain with central obesity, fatigue with proximal myopathy, skin thinning with purplish striae, and diffuse bruising. The face of the patient progressively becomes resembling a ‘moon’ and this is called ‘Moon facies’ in the picture above.
    2. Hormone profile:
    3. ACTH more than 10 pg/ml
    4. High dose dexamethasone suppression test (8 mg/day during 2 days): a decrease of more than 50% urinary cortisol level is observed in 90% of patients with Cushing’s disease. Of note, more than 90% suppression of urinary cortisol has 100% specificity in the diagnosis of Cushing’s disease
    5. CRH test (100 μg intra-venously): more than 50% ACTH and 20% cortisol increase is in favor of Cushing’s disease. Sensitivity and specificity are close to 90%.
    6. Desmopressin test (10 μg intravenously), ACTH and cortisol increases similar to those observed with the CRH test are in favor of CD with 70% sensitivity and 85% specificity.]
    7. Concordant responses to at least 2/3 of these tests should lead to the diagnosis of Cushing’s disease, and pituitary MRI.
    8. Bilateral intra-petrosal sinus sampling (stimulated by CRH or desmopressin) should be performed: it will give a definite answer to confirm the etiology of ACTH dependent CS. The principle is to measure a ratio defined by central ACTH/peripheral ACTH. A central to peripheral plasma ACTH ratio exceeding 2 (or 3 after stimulation by CRH) is in favor of Cushing’s disease
  3. Magnetic Resonance Imaging of Brain including Sella turcica: The pituitary adenoma responsible for Cushing’s disease is a microadenoma in more than 90% of cases, and a macroadenoma in less than 10% of cases. The causative microadenomas are not visible during radiological examination in up to 40% of cases.
  4. Comorbidities that may coexist and need evaluaton: Hyperglycemia, Hypertension, Diabetes mellitus, Dyslipidemia, Osteoporosis and Depression

MR Imaging confirms a mass in the sella turcica.

The desire for surgical cure of Cushing’s disease, is greater because sustained secretion of ACTH is physically deforming and eventually life threatening.

The goals of treatment in Cushing’s disease are:

  1. To return ACTH and Cortisol levels to normal,
  2. To decrease the size of a pituitary adenoma (if present) thereby relieving pressure on the surrounding tissue,
  3. To maintain normal pituitary function, and reverse or improve associated symptom.

First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The picture above shows the transnasal approach to the sella turcica. The picture below shows removal of adenoma in progress.


Medical therapy is recommended in individuals in whom:

  1. Surgery in contraindicated,
  2. Surgery did not work or failed to return hormone levels to normal or
  3. Large tumors may require shrinkage before tumor decompression

Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency.

Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. These include:

  1. Ketoconazole an adrenal directed drug is the most commonly used drug mainly because of its rapid action
  2. Mifepristone an glucocorticoid receptor antagonist, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus
  3. Somatostatin analogues including Pasireotide when surgery has failed or when surgery is not an option
  4. Dopamine antagonists like Cabergoline result in disease remission