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tion of the data without adjustments for multiple comparisons. Simply defined, these adjust- ments test for no effects in all the primary end points undertaken vs. an effect in one or more of those end points. This is a difficult methodological issue because there are divergent views on the need for statistical adjustment for multiplicity. This is also reflected in the Lancet papers by Schulz and Grimes (36;37), who advocate a restrictive approach toward adjust- ments for multiple comparisons. If we consider our own data and if we would assume that the differences would mostly reflect false-positive results, it is to be expected that the positive significant results would have been randomly distributed among the different variables. However, this is not the case, as shown in Table 3. We designed this study in our patients with PAI with the primary aim to evaluate cognitive function in detail, in view of the documented abnormalities in previous studies and those observed in experimental animal studies. In- deed, the main results of our study point toward similar adverse effects of PAI documented in previous studies, although these had a different study design. According to Schulz and Grimes, statistical adjustments somewhat rescue the positive results of scattershot analyses. However, we performed a targeted evaluation and analysis focused on cognitive function related to PAI rather than a scattershot analysis of cognitive functions in general. Therefore, in our opinion, our data should not be neglected merely because of the absence of adjustments for multiple comparisons. Moreover, this would carry the serious risk of missing an important association between PAI and cognitive impairments.

Cognitive functioning can be affected by many factors. In order to minimize the effect of external variables, participants and healthy controls were matched for age, gender, and education. However, the present study still has some limitations. Certain prescribed drugs, such as DHEA or levothyroxin, might have an effect on cognitive functioning. Due to power limitations, subgroup analyses to explore possible confounding effects could not be car- ried out. Future studies might take this into account and explore the effect of DHEA and levothyroxin intake on cognitive functioning in patients with PAI. Another limitation of the present study concerns the different types of PAI. We have no information about the different types of autoimmune causes of PAI, which could be accompanied by comorbidities. These comorbidities in turn could have an effect on cognitive functioning. In addition, regularity of HC intake was not asked nor controlled for. Furthermore, the study was not blinded, and therefore patients were aware of postponed HC intake. This awareness might have resulted in a higher motivation and, therefore, better performance in a subset of the cognitive tests in patients who postponed HC intake compared with patients who took the morning dose of HC at the habitual time. Likewise, patients might have been more motivated than healthy controls, which could explain why patients with HC intake performed better on the concen- tration subscale of the WMS and made fewer errors during the first trail of the trail making test. Lastly, due to the cross-sectional design of the present study, no causal conclusions could be drawn. Future studies might want to implement a randomized controlled trial with

cross-over design with different substitution dosing regimens. Such a design would provide more relevant data to control our hypothesis that patients’ substitution therapy is not equal to physiologic cortisol secretion which in turn might affect cognitive functioning. To provide more insight into the underlying neuronal mechanisms of the observed cognitive deficits in patients with PAI, future (functional) magnetic resonance imaging studies using a longitudi- nal design are needed.

In conclusion, the present study shows that patients with PAI show mild cognitive deficits compared to controls. Furthermore, the present study is the first to examine the effect of postponing HC intake in patients with PAI and demonstrates that there was no immediate effect of postponement of hydrocortisone intake on cognition. Future studies in animal models and (functional) MRI research in patients with PAI could provide more insight into underlying mechanisms of cognitive impairment due to cortisol imbalances.

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