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\begin{document}

\title{What is the Value of the 60 Minute Cortisol Measurement in the Short
Synacthen Test (SST)? Evidence for the Defence}



\author[1]{Maria Michaelidou}%
\author[2]{Ghasem Yadegarfar}%
\author[1]{Lauren Morris}%
\author[1]{Samantha Dolan}%
\author[3]{Adam Robinson}%
\author[1]{Asma Naseem}%
\author[4]{Mark Livingston}%
\author[5]{Christopher Duff}%
\author[6]{Anthony Fryer}%
\author[7]{Peter Trainer}%
\author[3]{Adrian Heald}%
\affil[1]{Salford Royal NHS Foundation Trust}%
\affil[2]{Isfahan University of Medical Sciences}%
\affil[3]{Salford Royal Hospitals NHS Trust}%
\affil[4]{Walsall Healthcare NHS Trust}%
\affil[5]{University Hospitals of North Midlands}%
\affil[6]{Keele University}%
\affil[7]{Christie Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
The Short Synacthen Test is the way that we most often determine whether
people's adrenal glands are working. We here have shown that an extra
blood sample taken at 60 minutes post Synacthen vs a 30 minute sample
alone, may make the test more effective at excluding those people who do
not need to go on hydrocortisone supplementation or need further
evaluation.%
\end{abstract}%



\sloppy


\textbf{What is the Value of the 60 Minute Cortisol Measurement in the
Short Synacthen Test (SST)?}

\textbf{Evidence for the Defence}

Michaelidou M\selectlanguage{ngerman}\textsuperscript{1§}, Yadegarfar G\textsuperscript{2,3 §},
Morris L\textsuperscript{1}, Dolan S\textsuperscript{1}, Robinson
A\textsuperscript{1}; Naseem A\textsuperscript{1}; Livingston
M\textsuperscript{4}, Duff CJ\textsuperscript{5,6},

Fryer AA\textsuperscript{5,6}, Trainer P\textsuperscript{7}, AH
Heald*\textsuperscript{1,2}

\textsuperscript{1}Department of Endocrinology and Diabetes, Salford
Royal Hospital, Salford, \textsuperscript{2}The School of Medicine and
Manchester Academic Health Sciences Centre, University of
Manchester;\textsuperscript{3}Isfahan University of Medical Sciences,
Isfahan, Islamic Republic of Iran; United Kingdom\textsuperscript{4};
Department of Clinical Biochemistry, Black Country Pathology Services,
Walsall Manor Hospital, Walsall; \textsuperscript{5}Department of
Clinical Biochemistry, University Hospitals of North Midlands NHS Trust,
Stoke on Trent; \textsuperscript{6}School of Primary, Community and
Social Care, Keele University; Department of Endocrinology; Christie
Hospital, Manchester\textsuperscript{7}

\textbf{*} Corresponding Author

§ Joint first author

Key words: adrenal insufficiency, cortisol, short synacthen test

\emph{Corresponding author:}

Dr Adrian H Heald

Department of Diabetes and Endocrinology

Salford Royal Hospital

Salford

M6 8HD

Telephone +44 161 206 5157

Email: adrian.heald@manchester.ac.uk

Word Count (main text only): 596

\textbf{Abstract}

The Short Synacthen Test is the way that we most often determine whether
people's adrenal glands are working.

We here have shown that an extra blood sample taken at 60 minutes post
Synacthen vs a 30 minute sample alone, may make the test more effective
at excluding those people who do not need to go on hydrocortisone
supplementation or need further evaluation.

\textbf{Letter to the editor}

Adrenal insufficiency is caused by failure of the adrenal glands to
produce physiological amounts of cortisol and sometimes aldosterone (in
the case of Addison's Disease). Adrenal insufficiency can be a
consequence of pituitary / adrenal insufficiency or suppression of
endogenous cortisol production as a result of taking exogenous steroids
for a prolonged period of time.

The short synacthen test (SST) is the most commonly performed
investigation to assess adrenal function (1,2) as it is more practical
than the `gold standard' insulin tolerance test (ITT) (3).

In some, but far from all centres a 60-minute serum cortisol
post-synacthen is still checked as part of the STT protocol, while in
other centres it is not deemed necessary to do this. In the light of
these differences in practice, we investigated whether the 60-minute
serum cortisol adds value to interpretation of the SST.

All patients attended a single centre, Salford Royal Foundation Trust
(SRFT) for their tests. Data from 207 consecutive SSTs were obtained
from the Hospital Electronic Patient Record (EPR). All tests were
performed before midday. We looked at a period of 12 months from
mid-June 2017 to mid-June 2018. Where a patient had more than one SST,
the first of the SSTs was analysed.

Serum cortisol was measured by immunoassay on the Siemens Centaur XP
analyser (Erlangen, Germany). The analytical range of this assay is
13.8--2069 nmol/L.

Whenever possible, an individual on oral corticosteroids was changed to
oral hydrocortisone for 48 hours prior to the SST being performed (if
they were not already on this) with omission of hydrocortisone on the
evening before and the morning of the test or omission on the morning of
the test if on daily prednisolone/dexamethasone. A 30-60-minute cortisol
concentration of \selectlanguage{english}[?]450nmol/L defined a pass; 350-449nmol/L defined
borderline.

Our findings were that in relation to the laboratory assay
post-synacthen cortisol pass cut-off of \selectlanguage{english}[?]450nmol/L, in 16/207 (7.2\%) of
cases the 60-minute cortisol was \selectlanguage{english}[?]450nmol/L (adequate adrenocortical
function) but the 30-minute cortisol was below this. Importantly in all
cases where the 30-minute cortisol did indicate a pass (i.e. was
\selectlanguage{english}[?]450nmol/L) the 60-minute cortisol was also \selectlanguage{english}[?]450nmol/L. Thus the
60-minute cortisol measurement resulted in 7.2\% of patients being
deemed to have adequate adrenocortical function when the 30-minute
cortisol would not have done so.

The 60-minute cortisol therefore retains utility in ruling out
adrenocortical insufficiency. Determination of the 60-minute cortisol is
done in some endocrine centres and was supported by the work of Chitale
et al (4). The authors of that paper stated that individuals passing the
SST only at 60 min tend to exhibit a `delayed response' to exogenous
adrenocorticotrophic hormone (ACTH) but in essence have normally
functioning adrenal glands. This conclusion was supported in a recent
paper by Butt et al (5) who looked at 849 people undergoing SSTs and
reported that 9.5\% of patients had a suboptimal response at 30 minutes,
but reached the threshold value at 60 minutes. There is also the
possibility that the 60-minute serum cortisol level may actually be more
representative of physiological adrenocortical function than the
30-minute serum cortisol (6).

If patient management is based solely on the 30-min sample, the
individual have to undergo further tests or may be commenced on
unnecessary, long-term steroid replacement therapy.

To conclude, we propose that the 60-minute cortisol should be part of
the SST as relying on 30-minute cortisol level alone may falsely ascribe
individuals to having adrenocortical insufficiency.~It would surely be
sensible to work towards an international consensus in relation to
whether or not the 60-minute cortisol should be part of all SST
protocols.

\emph{Acknowledgements}

The authors thank Dr Lewis Green (Salford Royal Foundation Trust)
assisting with data collation.

\subsubsection*{}

{\label{section}}

\subsubsection*{Transparency statement}

{\label{transparency-statement}}

Dr. Heald as corresponding author affirms that this is an honest,
accurate, and transparent account of the study being reported; that no
important aspects of the study have been omitted; and that any
discrepancies from the study as planned (and, if relevant, registered)
have been explained.

\subsubsection*{Ethics Statement}

{\label{ethics-statement}}

As this project was deemed by our local Research and Development
Committee as a quality improvement (QI) project, no individual patient
was contacted in the course of the evaluation and data was fully
anonymised prior to analysis, it was not felt that formal ethics
permission was required.

\subsubsection*{Funding}

{\label{funding}}

We have no external funding to declare.

\subsubsection*{Role of the Sponsor}

{\label{role-of-the-sponsor}}

There was no research sponsor for this study

\subsubsection*{Dissemination of study results to
participants}

{\label{dissemination-of-study-results-to-participants}}

Dissemination to interested patient groups both locally and nationally
will be done once the analysis has been finalised

\subsubsection*{}

{\label{section-1}}

\subsubsection*{Patient Consent}

{\label{patient-consent}}

This was not deemed necessary as no individual patient was contacted or
asked to do anything beyond their usual clinical care.

\subsubsection*{Data Availability}

{\label{data-availability}}

We used patient level data which was fully anonymised prior to analysis.
Any requests for access to this data should be made to the corresponding
author, Dr Adrian Heald.

\subsubsection*{Duality of interest}

{\label{duality-of-interest}}

No author has anything to disclose in relation to conflict of interest.

\subsubsection*{Contribution Statement}

{\label{contribution-statement}}

AHH and AR conceived the study. MM and LM collected the data. MM, AAF
and GY conducted the data analysis. CJD, ML and AAF provided perspective
from the laboratory. AN assisted with the literature review.

MM, LM, GY, ML, SD, AR, AN, AAF, CJD, PT and AHH all contributed to
writing of the paper. AAF, and PT provided an overview of the
manuscript.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Grossman AB. Clinical review: The diagnosis and management of central
  hypoadrenalism. J Clin Endocrinol Metab 2010; 95: 4855--4863
\item
  Hanna FWF, Issa BG, Keevil B et al. Investigating cortisol excess or
  deficiency: a practical approach. BMJ. 2019; 367: l6039.
\item
  Jones SL, Trainer PJ, Perry L et al. An audit of the insulin tolerance
  test in adult subjects in an acute investigation unit over one year.
  Clin Endocrinol (Oxf) 1994; 41: 123--128
\item
  Chitale A,~Musonda P,~McGregor AM et al. Determining the utility of
  the 60~min cortisol measurement in the short synacthen test. Clin
  Endocrinol (Oxf) ~2013; 79: 14-9
\item
  Butt MI, Alzuhayri N, Amer L, Riazuddin M, Aljamei H, Khan MS,
  Abufarhaneh M, Alrajhi E, Alnassar A, Alahmed R, Aljayar DMA,
  Abothenain FF, De Vol E. Comparing the utility of 30- and 60-minute
  cortisol levels after the standard short synacthen test to determine
  adrenal insufficiency: A retrospective cross-sectional study. Medicine
  (Baltimore) 2020; 99: e22621
\item
  Zueger T, Jordi M, Laimer M, Stettler C. Utility of 30 and 60 minute
  cortisol samples after high-dose synthetic ACTH-1-24 injection in the
  diagnosis of adrenal insufficiency. Swiss Med Wkly 2014; 144: w13987.
  doi: 10.4414/smw.2014.13987
\end{enumerate}

\selectlanguage{english}
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