Endocrine Abstracts

Background: Immune checkpoint inhibitors are now commonly used in melanoma, renal cell carcinoma and non-small cell lung cancers. Patients on immune check point inhibitors experience at least one type of immune related adverse event(irAEs) which can occur even after discontinuation of therapy. Endocrine toxicities are commonly reported irAE′s and tend to be irreversible. The most frequently recognized endocrine complications include thyroid dysfunction (30%) hypophysitis (5.6-11%), type-1diabetes (0.2-2%) and adrenal insufficiency (0.7%) Literature is limited on potential impact on gonadal axis.

Case presentation: We report a 50-year-old Caucasian female with metastatic renal cell carcinoma, who was treated with a nephrectomy followed by immune checkpoint blockade with ipilimumab plus nivolumab. After 4 months of treatment she presented with fatigue, generalized pains and being emotional. She was switched to single agent nivolumab, however her symptoms persisted. Investigations revealed hypocortisolism(cortisol 50 nmol/l [range 160-550 nmol/l], hypogonadism(testosterone <0.7 nmol/l [range 0-2.8 nmol/l], estradiol 280 pmol/l [range 45-1461 pmol/l], FSH10.9 IU/l [normal 25.8-134.8 IU/l]) and hypothyroidism (TSH 0.15 mIU/l [0.27-4.20 mIU/l]), IGF-1 levels were noted to be 20.7 nmol/l (range7.5-35 nmol/l). Patient had been started on prednisolone 10 mg/day, prior to referral to endocrine therefore ACTH was uninterpretable. She was switched to physiological dose hydrocortisone(10 mg/5 mg/5 mg) Retrospective evaluation revealed a background of previous hyperandrogenism related to polycystic ovarian syndrome one year prior to starting immunomodulators. However gradual drop in testosterone was noted from 4.8 nmol/l to undetectable levels (rangel 0-2.8 nmol/l) after starting immunotherapy. Prolactin was also noted to fall from normal values (158 mIU/l) pre-immunotherapy to undetectable level(<20 mIU/l)(range 102-496 mIU/l). PET Scan did not reveal any abnormalities in pituitary/adrenal gland.

Conclusion: Our case demonstrates gradual onset hypopituitarismwith recognition of only cortisol deficiency. Hypogonaidsm was not identified.

Discussion: Thyroid function and Cortisol are commonly checked hormones. All components of the endocrine axis should be assessed and considerations for correcting each part of pituitary-target axis is needed. Further research is needed on potential impacts on sexual function, fertility in both males and females and bone health. Sexual dysfunction are not reported early on or be taken as part of ongoing treatment or underlying disease, being aware of endocrine dysfunction can improve patients well being as weel as timely counselling of the patinets. Most European guidelines emphasize that hypophysitis is not a contraindication for immunotherapy, we therefore recommend that all patients undergoing immunotherapy with nivolumab and ipilimumab should have a pre-treatment endocrine profile with periodical monitoring and timely endocrinology input to ensure early recognition and appropriate treatment of endocrine dyscrasias.