Table 2.

Cases of hypophysitis following ipilimumab therapy in patients with metastatic melanoma

Case	Age, gender	mg/kg (no. of doses)	Symptoms	Hormone axes affected	Onset of hypophysitis	Biochemistries	Imaging, MRI brain/sella	Recovery of pituitary function	Received high-dose steroids	Status	Non- dermato- logical irAEs	Protocol no.
1	54, m	10 (3)	Mild fatigue and abnormal screening of TSH	Panhypopituitarism	4 weeks after the third dose	Cortisola, am 0.25, ACTHb 0.22, TSHc 0.03, FT4d12.87, T3e 2.42, LHf 0.4, FSHg 2.7, testosteroneh <3.47, and prolactini 0.53	Enlarged sella	Yes, with normal ACTH stimulation test	Yes	Dead	None	NCT00495066
2	71, m	3 (4)	Fatigue, increased sleep, weight loss, and night sweats/chills	ACTH and TSH	2 months after the fourth dose	Cortisol 0.275, ACTH <1.1, TSH 0.35, FT4 5.79, LH 9.1, FSH 12.6, and testosterone 74.29	Not done	No	Yes	NEDj	None	NCT00495066
3	69, m	10 (16)	Nausea, emesis, and dehydration	ACTH	3 months after the fourth dose	Cortisol 0.58, ACTH <1.1, TSH 1.68, FT4 11.84, T3 3.77, LH 9.8, FSH 22.5, testosterone 133, and prolactin 0.83	Partial empty sella no abnormal enhancement	No	Yes	NED	None	NCT00495066
4	69, m	3 (4)	Severe headache, poor oral intake, and hypotension	ACTH, LH/FSH, and most probably TSH	2 weeks after the the fourth dose	Cortisol, am 0.6, ACTH <1.1, TSH 0.5, FT4 11.58, T3 0.88, LH undetectable, and testosterone <3.47	Ill-defined nodular enhancement of sella, resolved after 2 months	No	Yes	Dead	None	NCT00495066
5	61, m	3 (3)	Headaches	ACTH and LH/FSH. (thyroiditis)	3 weeks after the third dose	TSH 0.04, FT4 14.93, T3 2.05 (screening TFTs) TSH <0.02, T3 1.62, cortisol 0.35, ACTH <1.1, FSH 1.8, testosterone <3.47, TSH <0.02, FT4 25.35, T3 0.88, and thyroid peroxidase antibody (TPO Ab)k <10	Enlarged sella	Partial recovery of gonadotrophs but not ACTH-persistent thyroiditis	Yes	Dead	None	NCT00495066
6	75, f	3 (2)	Fevers, sweats, and weakness	Possibly TSH and could not assess ACTH	4 weeks after the second dose	Prolactin 3.17, TSH 0.15, FT4 20.59, estradiol <10l, LH 11, and FSH 60	Interval increase the in size of sella	Yes; patient weaned off steroids for autoimmune hepatitis, not put on replacement hormones	Yes for hepatitis	Dead	Hepatitis	NCT00495066
7	38, f	3 (8)	Asymptomatic	Possibly TSH, and could not assess ACTH or LH/FSH	15 months after induction	TSH 0.26, FT4 0.77, and FT3 0.12. No other laboratory test results available	Not done	Not assessed	No	NED	None	NCT00495066
8	78, m	3 (8)	Flu-like syndrome, nausea, poor appetite, and weakness	Panhypopituitarism	4 weeks after the third dose	Cortisol, am 0.925, ACTH 2.2, TSH 5.88, FT4 10.16, and testosterone <3.47	Not done	Partial – hypogonadism resolved	Yes	Dead	None	NCT00495066
9	71, m	10 (3)	Fatigue, poor appetite, and weakness	Not adequately assessed	2 weeks after the second dose	ACTH 2.64, no cortisol, TSH 0.7, no FT4	Thickening and prominence of sella and infundibulum	Not assessed	Yes	Dead	None	NCT00495066
Xm	48, m	3 (4)	Fatigue and headache	Possibly TSH and ACTH	Before ipilimumab therapy (received anti-PD1 therapy before ipilimumab therapy)	ACTH, am <1.1, no cortisol TSH 4.93, and FT4 11.06	Normal sella	Not assessed	No	Dead	None	NCT00495066
10	58, f	10 (4)	Headache, blurred vision, nausea, and emesis	Probable ACTH and TSH	1 day after the third dose	Cortisol, am 1.58 (48 h after prednisone therapy), no ACTH, TSH 0.12, FT4 14.80, T3 1.77 TSH 0.05, FT4 13.12, TPO Ab <10, thyroglobulin antibody (Tg Ab)n <20 LH 25.8, FSH 53.9, and prolactin 0.31	Homogenous enlargement	No symptoms recurred after prednisone dose tapered	Yes	Dead	None	NCT00920907
11	74, m	10 (8)	Fatigue and weakness	ACTH	2–3 weeks after the fifth dose	Cortisol 0.25, ACTH <1.1, TSH 1.51, FT4 16.34, LH 2.16, FSH 7.17, and testosterone 159	Normal	No	Yes	Unknown	None	NCT00920907
12	69, f	10 (7)	Severe fatigue and poor appetite	ACTH	3 months after the first dose	Cortisol, am <0.05, ACTH 2.2, TSH 3.60, FT4 11.58, T3 2.76, and prolactin 1.34	Not done	No	Yes	NED	Colitis	NCT01323517
				LH and FSH not assessed		Repeat TFTs: TSH 2.73, and FT4 15.7
13	71, f	10 (6)	Arthralgias, fatigue, weight loss, and dehydration	ACTH LH and FSH not assessed	8 months after the first dose	Cortisol 0.275, ACTH 1.54, and TSH 2.93	Normal sella	No	Yes	Alive	Hypercalcemia	NCT01323517
14	77, f	10 (3)	Unknown	TSH and possibly ACTH	2 months after the first dose	Cortisol, am 0.875 (had been on prior steroid therapy), ACTH evaluation not done, TSH 0.01, and FT4 7.72 Repeat TFTs off thyroid hormone: TSH 3.72, FT4 7.72, and T3 1.03	Not done	No	Yes	Alive	Colitis	NCT01323517
15	78, m	10 (4)	Headaches and fatigue	Panhypopituitarism	3 months after the first dose	Cortisol, am 0.25, ACTH 2.86, TSH 0.09, FT4 9.01, and testosterone <6.94	Patchy enhancement of sella with thickening of stalk	No	Yes	NED	None	NCT01323517
16	47, f	3 (4)	Fevers, chills, and fatigue, arthralgias	ACTH and LH/FSH not assessed	3.5 months after the first dose	Cortisol, am <0.125, ACTH <1.1, and TSH 4.80	Not done	No	Yes	NED	Thyroiditis Pneumonitis	NCT01024231
17	73, f	3 (4)	Headache, visual changes, fatigue, nausea and emesis, diarrhea, altered mental status	ACTH	3.5 months after the first dose	Cortisol, pm 0.6, ACTH <1.1, TSH 1.53, FT4 14.03, FSH 18.9, and LH 5.2	Enlargement of sella with heterogeneous enhancement and focal nodular area of hypointensity	Not assessed	Yes	NED	Pancreatitis	NCT01024231
18	52, f	3 (5)	Fatigue	ACTH and TSH, LH/FSH not assessed	5 months after 1st dose	Cortisol, am 0.675, ACTH, am 1.1, TSH 2.59, and FT4 15.06	Not done	Not assessed	Yes	SDo	1)Hypothyroidism	NCT01024231
						Repeat TFTs: TSH 1.88 and FT4 9.78					2)Hepatitis 3)Colitis
19	74, m	3 (7)	Severe fatigue, arthralgias, and mental status changes	ACTH and TSH and preserved LH/FSH	19 months after the first ipilimumab infusion	Cortisol, am <0.05, ACTH <1.1, TSH 3.02, and FT4 11.12	Normal	Not assessed	Yes	SD	1)Thyroiditis	NCT01024231
					6 months after re-induction with ipilimumab 3 months after the first nivolumab infusion	Repeat TFTs: TSH 0.97 and FT4 11.19					2)Myocarditis

^aCortisol: reference ranges am=1.25–6.25 nmol/l; pm=0.75–3 nmol/l.

^bAdrenocorticotropin (ACTH): reference range 1.32–10.56 pmol/l.

^cThyroid-stimulating hormone (TSH): reference range 0.55–4.78 mIU/l.

^dFree T₄: reference range 11.58–23.17 pmol/l.

^eTotal T₃: reference range 0.924–2.772 nmol/l.

^fLuteinizing hormone (LH): reference range 2–9 IU/l.

^gFollicle-stimulating hormone (FSH): reference range 1–18 IU/l.

^hTotal testosterone: reference range 62.80–263.03 pmol/l.

ⁱProlactin: reference range 0.087–0.78 nmol/l.

^jNo evidence of disease.

^kThyroid peroxidase antibody (TPO Ab): reference range 0–35 IU/l.

^lEstradiol: reference range for postmenopausal females, not detectable to 14 pg/ml.

^mPatient received nivolumab therapy before ipilimumab therapy.

ⁿThyroglobulin antibody (Tg Ab): reference range <20 IU/l.

^oStable disease.