Rare pituitary problem with ICPIs

What previously rare pituitary problem is seen with ICPIs? Which medication is it most commonly associated with? How does it present clinically?

Hypophysitis or inflammation of the pituitary gland and stalk leading to pituitary dysfunction is seen relatively frequently with certain ICPIs. Common symptoms of hypophysitis include headache, weakness, and fatigue. Imaging often shows pituitary enlargement, which may be subtle and only evident if pretreatment imaging is available for comparison. The most commonly seen hormonal disorder is central hypothyroidism, followed by central adrenal insufficiency and hypogonadotropic hypogonadism. Prolactin levels are also often low but growth hormone (GH) secretion is relatively spared. Hypophysitis develops most commonly with ipilimumab by itself or in combination with nivolumab, occurring on average in 3.2% and 6.4% of treated patients, respectively; it usually appears 8 to 12 weeks after initiation of the medication. This is thought to be caused, in part, by pituitary cells having a higher level of CTLA-4, which leads to complement activation. The incidence appears to be less with PD-1 and PD-L1 inhibitors as noted in the below table.

Rates of More Common Endocrinopathies Caused by Immune Checkpoint Inhibitors When Used Alone or in Combination

Ipilimumab0.5%–18%0.7%–15% Subclinical hypothyroidism 6% in one study1%–2.3%, 16% experienced subclinical hyperthyroidism in one study2% in one study
Ipilimumab and Nivolumab7.7%–12%13%–22%, 5% Subclinical Hypothyroidism 5%4.3%–9.9%, 22% subclinical hyperthyroidism in one study9% in one study
Nivolumab and PembrolizumabNA13%13% developed subclinical hyperthyroidismNA

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