In Reply

Letters to the Editor The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint Inhibitors by Prof. Dr. med. Knut Mai, Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Dagmar Führer-Sakel, Prof. Dr. med. Jürgen B. Honegger, Prof. Dr. med. Matthias M. Weber, Prof. and Dr. med. Dr. rer. nat. Matthias Kroiss in issue 23/2021

We thank Prof. Koch for his additional comments regarding the development of autoimmune diabetes mellitus in existing type 2 diabetes and of polyglandular autoimmune syndrome, especially during anti-PD-1 based therapy (1), which underlines the need for comprehensive endocrine evaluation in patients treated with checkpoint inhibitors (CPI).

Even though the diagnostic emphasis in CPI induced hypophysitis from a therapeutic perspective is sure to lie on the analysis of the corticotroph and thyrotroph function, the evaluation of gonadotropic dysfunction makes sense. While contraindications should be considered, sexual hormone supplementation can be relevant in terms of wellbeing, anabolic effects, and therapy of concomitant anemia in tumor patients, especially in the setting of increasing CPI use in the context of neoadjuvant therapeutic concepts in earlier tumor stages in individual tumor entities.

We thank Prof. Scherbaum for his comment regarding rare CPI induced diabetes insipidus (CDI), which we—in view of space restrictions to our manuscript—have only been able to hint at. Especially in the differentiation from polydipsia/polyuria symptoms in CPI induced diabetes mellitus, awareness of this entity is important.

In the authors’ experience, the development of diabetes mellitus during CPI therapy is variable and does not always take a fulminant course with diabetic ketoacidosis (2). For this reason we think—in contrast to the explanations of Dr Alexopoulos—that simple blood glucose measurement, which is ubiquitously available as a point of care test, is very helpful, among others in the context of hypoglycemic tendencies due to corticotropic insufficiency. The differential diagnostic evaluation of occurring hyponatremia also requires measurement of blood glucose level.

As we mentioned in our article, the symptoms of CPI induced endocrinopathies are often masked in the context of the underlying severe disease and are therefore not always groundbreaking (3). Laboratory screening is therefore urgently required. Magnetic resonance imaging (MRI) plays an important part, as described, although it was not possible to assess the exclusive additive value of MRI within the study design of the cited study, as this was assessed as diagnostic only in combination with hormonal deficiency (1/3 asymptomatic).

The diagnosis of corticotropic insufficiency can actually be more complex. If it could not be excluded by basal hormone measurement, the insulin tolerance test as the gold standard is certainly not recommended outside endocrine centers. The metyrapone stimulation test requires an inpatient stay. The ACTH stimulation test has a high predictive value for excluding corticotropic insufficiency (4) and—if its methodological weaknesses are taken into consideration—has been found to be practical and safe. In view of the great variability of the cortisol response in the corticotropin releasing hormone (CRH) test, this test may yield a pathological result in spite of normal pituitary function (5). Further to the greater effort and higher costs, this limits the utility of the CRH test in our experience to such a clear extent that we do not perform this test in this question in our departments and would therefore rather not recommend it for non-endocrine centers either.

DOI: 10.3238/arztebl.m2021.0314

On behalf of the authors
Prof. Dr. med. Knut Mai
Medizinische Klinik m.S. Endokrinologie, Diabetes und Stoffwechsel
Charite – Universitätsmedizin, Berlin

Conflict of interest statement

Prof. Mai has received lecture honoraria from BMS and Eisai.

References

1. Shi Y, Shen M, Zheng X, et al.: ICPis-induced autoimmune polyendocrine syndrome type 2: a review of the literature and a protocol for optimal management. J Clin Endocrinol Metab 2020; 105: dgaa553

2. Tittel SR, Laubner K, Schmid SM, et al.: Immune-checkpoint inhibitor-associated diabetes compared to other diabetes types—a prospective, matched control study. J Diabetes 2021. doi: 10.1111/1753–0407.13215. Online ahead of print

3. Mai K, Fassnacht M, Führer-Sakel D, Honegger JB, Weber MM, Kroiss M: The diagnosis and management of endocrine side effects of immune checkpoint inhibitors. Dtsch Arztebl Int 2021; 118: 389–96

4. Petersenn S, Quabbe HJ, Schofl C, Stalla GK, von Werder K, Buchfelder M: The rational use of pituitary stimulation tests. Dtsch Arztebl Int 2010; 107: 437–43

5. Maghnie M, Uga E, Temporini F, et al.: Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. Eur J Endocrinol 2005; 152: 735–41