Adrenocorticotropic Hormone (ACTH)-
Dependent Cushing’s Syndrome

ACTH-dependent Cushing’s syndrome (ADCS) results from a pituitary tumor (or tumor in another part of the body as in ectopic ADCS) that secretes excess ACTH that, in turn, causes the downstream synthesis and over-secretion of cortisol by the adrenal glands. Cortisol is the body’s main stress hormone, and excess amounts can cause significant increases in morbidity and mortality.

Clinical manifestations

Excess ACTH stimulates the adrenal glands to over-secrete cortisol and androgens, leading to a myriad of symptoms that can include:

A round and red face
A hump on the back of the neck
Purple stretch marks on the chest, armpits, and belly
Skin changes, such as acne, excessive facial hair, and easy bruising
Rapid weight gain, especially around the stomach

Longer term complications of ACTH-dependent Cushing’s syndrome include:

Muscle weakness
Vision problems
Headaches
Infections
Osteoporosis
High blood pressure
High blood sugar or diabetes
Extreme fatigue or trouble sleeping
Depression
Memory loss
Loss of periods (amenorrhea), excessive facial and body hair (hirsutism) in women
Erectile dysfunction in men

The burden on patient lives

First-line treatment is surgical resection of the ACTH-secreting tumor, with pharmaceutical intervention required in cases where surgery is not an option, when surgery is not successful, or if the tumor recurs.

While several pharmaceutical options exist to help control symptoms in these patients, significant unmet needs exist due to serious side effects and tolerability issues, including cardiac issues (QTc prolongation), liver toxicity, low blood potassium, and GI symptoms.