Endocrine Physiology During Critical Illness

Critical illness changes the signals coordinating circulation, fuel availability, water balance, growth, and reproduction. Hormone secretion, transport, metabolism, and tissue responsiveness can move in different directions. A high concentration does not necessarily mean excessive secretion, and a low concentration does not establish that replacement improves recovery. Understanding the response requires connecting the initiating stress, circulating signal, receiving tissue, and consequences over time.

65.1 A Hormone Concentration Is the Result of Several Processes

Endocrine glands release signals into a circulation that distributes and removes them. Their concentrations depend on secretion, distribution volume, binding, conversion to other molecules, and clearance. Some hormones are secreted in pulses; others have prominent circadian patterns. A single blood sample therefore captures a state of this system rather than directly measuring its output.

Consider a deliberately simplified hormone whose circulating concentration has reached a steady state. Let C be concentration in nmol/L, Q its entry into the sampled circulation in nmol/h, and CL its clearance in L/h. Clearance is the hypothetical volume completely cleared per unit time, not a volume of hormone-containing fluid physically removed.

For an illustrative entry rate of 20 nmol/h and clearance of 4 L/h, concentration is 20 ÷ 4 = 5 nmol/L. If clearance falls to 2 L/h while entry remains unchanged, concentration becomes 20 ÷ 2 = 10 nmol/L. The concentration doubles without increased secretion. These invented values teach the relationship and are not reference values for a particular hormone.

During changing illness, entry and removal need not balance. Concentration can rise while secretion is falling if clearance has fallen further. Distribution into an expanded extracellular space, altered protein binding, and intermittent administration add further possibilities. Nonlinear or concentration-dependent metabolism also limits the simple equation.

The liver and kidneys influence hormone metabolism and excretion; tissues can activate or inactivate hormones locally. Organ failure consequently changes measurements through mechanisms beyond injury to the secreting gland. Extracorporeal support and administered hormones can add routes of entry or removal, depending on the molecule and treatment.

Feedback responds to the biologically relevant signal reaching regulatory tissues, which may differ from the total concentration reported by the laboratory. Interpreting an endocrine result therefore requires asking what was sampled, when it was sampled, and which processes could have changed. The same numerical concentration can arise from quite different combinations of production and disposal.

65.2 Binding Proteins Separate Total Concentration from Tissue Exposure

Many circulating hormones partition between free and protein-bound forms. Cortisol binds principally to corticosteroid-binding globulin and albumin; thyroid hormones and sex steroids have their own major transport proteins. Binding provides a circulating reservoir and influences distribution and clearance. The free concentration is more closely related to immediately available hormone than the total concentration, although neither alone fully describes tissue exposure or response.

Let Ctotal and Cfree be concentrations in nmol/L and f the dimensionless free fraction. For a specified sample, the accounting relationship is straightforward.

In a constructed comparison, a total concentration of 400 nmol/L with a free fraction of 0.05 gives 20 nmol/L free hormone. A later total concentration of 250 nmol/L with a free fraction of 0.10 gives 25 nmol/L. Thus, total concentration falls while free concentration rises. The fractions are illustrative; they are not a formula for correcting a patient's result.

This distinction has been demonstrated in critical illness. Hamrahian and colleagues studied 66 critically ill patients and 33 healthy volunteers. Patients with low serum protein had lower total cortisol concentrations than those with better-preserved protein concentrations, while free cortisol did not show the corresponding reduction. The study illustrates a binding-related discrepancy; it does not establish a universal diagnostic rule or an outcome benefit from measuring free cortisol.1

Binding effects also depend on the clinical setting. In a prospective study of septic and nonseptic patients with hypotension, Molenaar and colleagues found that relationships among albumin, total cortisol, and directly measured free cortisol differed between groups. An albumin concentration cannot therefore supply a universal conversion from total to free cortisol.2

Finally, arrival at the cell is only another step. Transporters, intracellular conversion, receptor abundance, receptor affinity, and downstream signaling modify action. A high circulating free concentration can coexist with reduced responsiveness in one tissue and preserved or excessive signaling in another. Plasma measurements should not be treated as direct assays of whole-body hormone action.

65.3 The Adrenal Response Coordinates Fuel, Circulation, and Inflammation

The hypothalamic–pituitary–adrenal axis links neural and inflammatory information to cortisol production. Hypothalamic corticotropin-releasing hormone and vasopressin influence pituitary adrenocorticotropic hormone (ACTH) release; ACTH stimulates the adrenal cortex. Cortisol feeds back while acting on metabolic, vascular, and immune pathways. Critical illness can disturb normal pulsatility and circadian concentration patterns.

Catecholamines operate alongside this axis. Neural sympathetic release and adrenal medullary secretion can rapidly alter cardiac performance, vascular tone, glycogen breakdown, and lipolysis. Cortisol has slower transcriptional effects as well as more rapid actions, and helps maintain responsiveness to other stress mediators. The pathways are coordinated without being interchangeable: an ACTH measurement does not report sympathetic traffic, and plasma catecholamines do not describe glucocorticoid action.

Cortisol supports substrate availability through effects on hepatic metabolism and peripheral protein and glucose handling. Its vascular actions include modulation of adrenergic responsiveness and endothelial and smooth-muscle signaling. Its immune effects depend on cell type, exposure, timing, and the inflammatory environment. Describing cortisol simply as a hormone that raises pressure misses much of its role.

Hepatic A-ring reduction and conversion to cortisone by 11β-hydroxysteroid dehydrogenase type 2 contribute to cortisol inactivation. Conversely, type 1 can regenerate cortisol from cortisone within tissues. Altered metabolism can therefore change exposure independently of adrenal output.

Boonen and colleagues combined several human investigations, including tracer kinetics and studies of cortisol metabolism. Elevated cortisol coexisted with lower ACTH, increased production, and substantially reduced clearance. Their tissue and metabolic findings supported reduced cortisol inactivation as a contributor to the circulating pattern.3

A low ACTH concentration in the presence of high cortisol can reflect feedback within an altered kinetic system. Conversely, an apparently adequate circulating concentration does not prove adequate signaling in every tissue. Local metabolism, receptor function, binding, and disease severity remain relevant.

The adrenal response also changes with exogenous glucocorticoids and other medications. Administered hormone contributes to exposure and can suppress endogenous drive. Consequently, measurements obtained during treatment describe a different system from untreated endocrine physiology.

65.4 Acute and Prolonged Illness Have Different Endocrine Trajectories

An immediate threat favors rapid availability of energy and maintenance of perfusion. Growth, reproduction, and some energy-intensive functions can become less prominent. With prolonged illness, persistent inflammation, nutritional changes, loss of normal sleep and activity, organ dysfunction, and treatment reshape the original response. There is no single day on which every patient changes from an acute to a prolonged endocrine state.

Early changes may arise largely from altered peripheral metabolism, binding, and responsiveness. Later patterns can include diminished pulsatile hypothalamic–pituitary drive in selected axes. Different axes and tissues need not change together; an individual's state can fluctuate with new infection, surgery, recovery, or medication exposure.

Prospective observations of prolonged critical illness illustrate this complexity. Peeters and colleagues followed patients from the first week of intensive care and through recovery in a subgroup, examining ACTH, cortisol, binding proteins, and metabolism. Their free cortisol estimates were calculated from total cortisol and binding variables rather than directly measured. The evolving patterns supported contributions from binding, reduced metabolism, and changing central drive; they did not establish a universal timetable for endocrine failure.4

Medication effects are part of the physiology being observed. Glucocorticoids alter feedback, dopamine can suppress selected pituitary signals, and opioids can influence hypothalamic–pituitary regulation. Sedation, disrupted light exposure, nutritional delivery, and loss of normal activity further change inputs to the system. A laboratory pattern during these exposures cannot automatically be attributed to the underlying disease alone.

Calling a change adaptive describes a plausible function, not a demonstrated benefit at every duration or severity. Reducing energy expenditure may help during an acute shortage while sustained loss of anabolic signaling may contribute to weakness or impaired recovery. Observational associations cannot resolve that tradeoff by themselves.

Established endocrine disease, structural pituitary injury, and primary gland failure can also coexist with critical illness. Recognizing illness-related changes should sharpen the search for these alternatives when the history and phenotype support them, rather than turning every abnormal result into either definite failure or harmless adaptation.

65.5 Glucose Availability Reflects Production, Utilization, and Counter-Regulation

Stress hyperglycemia reflects a changing balance between glucose entry and disposal. Hepatic glycogenolysis provides a rapidly available source, while gluconeogenesis uses substrates including lactate, glycerol, and amino acids. The kidney also contributes to glucose production. Nutrition and administered glucose add exogenous entry, while tissue uptake, oxidation, storage, and urinary loss influence removal.

Glucagon, catecholamines, cortisol, and growth hormone influence this balance through different mechanisms and time courses. Insulin normally restrains endogenous production and promotes uptake and storage in responsive tissues. During critical illness, insulin concentrations can be elevated while its metabolic effects are attenuated. Hyperglycemia therefore does not necessarily imply absent insulin secretion.

Insulin resistance is not uniform. Hepatic glucose production can remain insufficiently suppressed while skeletal-muscle glucose uptake is impaired. Other tissues retain substantial insulin-independent uptake. Inflammation, adrenergic signaling, circulating fatty acids, inactivity, and intracellular signaling changes contribute, while perfusion and oxygen availability influence what cells can do with the delivered substrate.

Human tracer experiments provide direct evidence that entry and production must be separated. Shaw and colleagues found increased glucose and urea production in patients with sepsis and incomplete suppression of selected gluconeogenic and protein-catabolic processes during glucose administration. This small mechanistic study supports persistence of endogenous production despite an external substrate supply; it does not define a nutrition prescription.5

Muscle proteolysis and adipose lipolysis supply substrates but impose costs. Loss of muscle mass can continue despite a high circulating glucose concentration. Glucose abundance in plasma is consequently not equivalent to adequate cellular nutrition or successful anabolic recovery.

Renal and hepatic dysfunction further complicate the pattern by changing insulin clearance, glucose production, and substrate disposal. Interrupted nutrition, altered counter-regulation, and administered insulin can produce rapid transitions. Severe illness can also accompany hypoglycemia, particularly when production and reserves fail or disposal exceeds entry. Neither high nor low glucose alone identifies which endocrine mechanism dominates.

The physiological question is therefore a flux question: where glucose enters, where it goes, and which tissues respond. The laboratory concentration is an important observation within that balance, not its complete explanation.

65.6 Thyroid Hormone Changes Involve Central Signals and Local Metabolism

The circulating pattern commonly called nonthyroidal illness includes reduced triiodothyronine (T₃), with variable thyroxine (T₄), reverse T₃, and thyroid-stimulating hormone (TSH). These variables do not move as a fixed package. Severity, duration, nutrition, medications, binding, and organ function affect the result. A TSH concentration that is not elevated despite low thyroid hormones differs from the usual feedback pattern of uncomplicated primary hypothyroidism, but does not independently establish its cause.

Peripheral conversion is important. Deiodinases D1 and D2 can generate active T₃ from T₄; D3 inactivates T₄ and T₃. Transport across cell membranes, intracellular metabolism, and receptor signaling determine local action. Changes in transport proteins alter total concentrations, while tissue-specific enzyme regulation allows local exposure to diverge from plasma measurements.

Central changes also occur. In a small human postmortem study, Fliers and colleagues related premortem thyroid measurements to hypothalamic thyrotropin-releasing hormone gene expression. Their findings supported a central component to the illness-associated pattern. The selected patients, terminal setting, and observational tissue analysis limit claims about causation or the trajectory of all critically ill patients.6

Experimental work shows why a serum result cannot define every tissue's state. Simonides and colleagues demonstrated hypoxia-inducible regulation of the thyroid-hormone-inactivating enzyme D3 in cell systems, and local changes in a rat model of hypoxic right-ventricular disease. This provides a mechanism for reducing thyroid hormone action within a stressed tissue. It is not proof that low circulating T₃ is beneficial in every human illness.7

Reducing thyroid-dependent energy expenditure could conserve resources, yet insufficient signaling in some tissues could impede function or recovery. Both possibilities are physiologically plausible. Neither establishes that replacing a circulating deficit will restore the appropriate local pattern, because administered hormone encounters altered transport, conversion, feedback, and tissue responsiveness.

Pre-existing thyroid disease remains relevant, as do the timing and reliability of previous measurements. Interpreting the illness-associated pattern requires these observations and the clinical course. It should not depend on labeling all low values as gland failure or assuming that normalization of serum T₃ would necessarily improve patient-centered outcomes.

65.7 Growth Hormone and IGF Signaling Can Become Uncoupled

Growth hormone secretion is pulsatile and influenced by hypothalamic growth-hormone-releasing hormone, somatostatin, sleep, nutrition, and metabolic feedback. Some actions occur directly through growth hormone receptors; others involve insulin-like growth factor I (IGF-I) produced by the liver and other tissues. Circulating IGF-binding proteins and the acid-labile subunit influence IGF distribution and persistence.

During acute illness, growth hormone can be elevated despite low circulating IGF-I. This discordance is compatible with reduced hepatic responsiveness and altered nutritional and inflammatory signaling. It does not mean that all growth hormone effects are absent: its effects on lipid mobilization and insulin sensitivity need not track IGF-mediated growth-related effects.

Prolonged illness can produce a different secretory pattern. In a physiological study of 26 long-stay critically ill adults, van den Berghe and colleagues used frequent sampling and secretagogue interventions to examine the somatotropic axis. Reduced pulsatile activity and changes in the IGF system demonstrated abnormalities beyond a single morning growth hormone concentration. Responses to experimental stimulation showed remaining secretory capacity, not a proven treatment benefit.8

Low IGF-I can reflect several mechanisms simultaneously: reduced synthesis, altered growth hormone signaling, insufficient substrate, changes in binding proteins, and altered disposal. Conversely, a circulating IGF-I increase after an intervention confirms a biochemical effect without proving restoration of effective muscle protein accretion. Muscle contraction, innervation, perfusion, inflammation, mitochondrial capacity, and nutrient availability remain necessary parts of recovery.

This distinction is especially important in a catabolic patient. Mobilizing fat and amino acids may support immediate substrate needs while accelerating depletion of functional tissue. Increased hormone exposure does not guarantee that the receiving tissue can redirect metabolism toward useful synthesis. The acute metabolic effects of growth hormone can also interact with insulin resistance.

The axis therefore supplies an example of endocrine uncoupling: gland output, circulating mediator concentration, and desired organ effect can separate. Interpreting one component without the others obscures why a physiological response to stimulation may coexist with persistent weakness, and why intervention trials must assess outcomes beyond laboratory correction.

65.8 Gonadal and Prolactin Changes Reflect More Than Reproductive Suppression

The gonadal axis depends on pulsatile hypothalamic gonadotropin-releasing hormone (GnRH), pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), gonadal responsiveness, and feedback from sex steroids and inhibins. Illness can alter several levels together. Sex-hormone-binding globulin and albumin also separate total sex-steroid concentrations from free exposure. Sex, age, menstrual state, pregnancy, and pre-existing gonadal disease are essential context.

In men with prolonged critical illness, low testosterone can coexist with a gonadotropin concentration that fails to rise as expected for isolated testicular failure. That pattern suggests a central contribution without excluding peripheral dysfunction. In a small study of 15 long-stay critically ill men, pulsatile GnRH increased LH and transiently increased testosterone, but did not fully overcome the abnormality. The findings supported combined hypothalamic–pituitary–gonadal involvement in that selected population.9

This selected population cannot represent all sexes, ages, or illnesses. Its hormonal response does not establish that restoring sex-steroid concentrations improves strength, survival, or reproductive recovery. Aromatization, metabolism, binding, and inflammation further separate glandular secretion from plasma concentrations.

Prolactin illustrates another form of central regulation. Hypothalamic dopamine normally provides tonic inhibition of prolactin release, unlike the predominantly stimulatory control of several other anterior pituitary hormones. Stress, medications, altered clearance, and changes in central regulation can therefore affect prolactin through different routes. A high or low value cannot be interpreted as a general measure of pituitary activation.

Frequent-sampling studies of prolonged critical illness have demonstrated altered thyrotropin and prolactin release, including reduced pulsatile contributions and loss of usual nocturnal patterns. These observations emphasize secretion dynamics rather than a universal direction of change in every sample.10

These axes matter beyond reproduction or lactation because their signals interact with bone, muscle, metabolism, and immune function. Nevertheless, documenting an endocrine correlate of catabolism does not identify the sole cause of tissue loss. Nutrition, immobilization, denervation, inflammation, and organ injury remain simultaneous contributors.

65.9 Water and Circulatory Hormones Integrate Osmotic and Nonosmotic Signals

Vasopressin links water regulation to circulatory stress. Osmotic sensing influences hypothalamic release, while reduced effective circulatory filling, pain, nausea, and other nonosmotic inputs can sustain secretion despite an osmotic signal that would otherwise suppress it. The resulting concentration reflects competing inputs, release capacity, distribution, and clearance.

Receptor and organ context determine the effect. Renal V₂ signaling promotes collecting-duct water permeability through aquaporin regulation; vascular V₁ signaling can influence smooth-muscle tone. A circulating concentration cannot be translated directly into urine concentration or arterial pressure because renal function, medullary gradients, solute excretion, receptors, and the cardiovascular state intervene.

Landry and colleagues compared vasodilatory septic shock with cardiogenic shock and described relatively low vasopressin concentrations in the septic group despite severe circulatory stress. Small infusion and withdrawal observations supported a contribution to vascular tone in that setting. The study does not establish universal vasopressin depletion across sepsis or demonstrate a survival benefit from replacement.11

The renin–angiotensin–aldosterone system responds to renal perfusion-related signals, distal sodium-chloride delivery, sympathetic influences, and potassium. Angiotensin II affects vessels, adrenal secretion, thirst, and renal handling; aldosterone changes epithelial sodium and potassium transport. Their plasma concentrations are nevertheless shaped by organ function, medications, feedback, and clearance. Neither renin nor aldosterone is a direct measurement of circulating blood volume.

Natriuretic peptides provide another interacting signal, often associated with cardiac wall stress. Their concentrations and biological effects depend on secretion, processing, clearance, receptor pathways, and renal responsiveness. A high concentration can accompany congestion while effective arterial filling and organ perfusion remain inadequate. It does not guarantee an appropriate natriuretic response.

These systems may therefore send apparently conflicting messages because they respond to different sensed variables. Retaining water or sodium can coexist with edema and impaired perfusion. The cell and extracellular fluid consequences are developed in the electrolyte chapters; here the central lesson is that endocrine signals must be connected to renal and vascular capacity before their effects can be inferred.

65.10 Endocrine Tests and Glucocorticoid Trials Answer Different Questions

An endocrine test is interpreted within a measurement and physiological context. Relevant details include sampling time, pulsatility, total versus free measurement, assay method, binding proteins, recent drug exposure, and renal and hepatic function. A concentration obtained after an exogenous hormone or secretagogue belongs to a perturbed system rather than an untreated baseline.

A stimulation test observes the concentration response to an imposed signal. That response depends on glandular reserve, starting concentration, distribution, binding, and clearance. A small increment need not have the same meaning when baseline exposure is high or the distribution and binding conditions have changed. The cortisol studies discussed above illustrate why a single increment or binding adjustment cannot resolve every critically ill patient's physiology.

Equally, an intervention trial asks whether a defined strategy improves specified outcomes in a selected population. It need not require that the intervention correct a demonstrable primary gland deficiency. Glucocorticoids can act pharmacologically on vascular and inflammatory pathways even when the mechanism of an individual patient's hormone pattern is uncertain.

In ADRENAL, hydrocortisone in mechanically ventilated patients with septic shock accelerated shock resolution but did not significantly reduce the primary 90-day mortality outcome. In APROCCHSS, a hydrocortisone-plus-fludrocortisone strategy reduced 90-day mortality in its enrolled septic-shock population.12

The trials tested different strategies and populations. They were not a direct comparison of hydrocortisone alone against the combination, and their comparison cannot isolate the contribution of fludrocortisone. Their findings should not be collapsed into a universal claim that glucocorticoids either always improve survival or only change pressure.

Nor do these outcomes validate a universal cortisol threshold, establish that every participant had deficient endogenous secretion, or show that a laboratory value selected the responding patients. Diagnostic classification, pharmacological mechanism, and clinical efficacy are related questions with different evidence requirements. Keeping them separate allows endocrine physiology to inform interpretation without converting an uncertain assay into an unsupported treatment rule.

65.11 Correcting a Biochemical Pattern Can Have Unexpected Clinical Effects

Endocrine interventions alter networks rather than isolated numbers. Increasing a hormone can change feedback, receptor exposure, substrate turnover, fluid handling, and other axes. The intended biochemical effect may occur alongside consequences that offset or exceed it. This makes clinical outcome trials particularly important when an illness-associated pattern is interpreted as a replaceable deficiency.

Growth hormone provides a clear example. Two parallel randomized trials in adults with prolonged critical illness found increased mortality with pharmacological growth hormone treatment. Biochemical and metabolic effects did not establish improved recovery. These findings apply to the tested intervention and population; they are not evidence about every circumstance of established pituitary hormone replacement.14

Glucose control supplies a related lesson. In NICE-SUGAR, intensive glucose control increased 90-day mortality and severe hypoglycemia compared with the conventional strategy. Achieving a concentration closer to the usual fasting range was therefore not equivalent to improving the overall physiological state of critically ill patients.15

Context still matters. A later large trial, TGC-Fast, tested algorithm-guided tight glucose control while withholding early parenteral nutrition in both groups. It found no improvement in its primary outcome of time to alive ICU discharge, and no significant difference in 90-day mortality. It did not reproduce the entire nutritional or glucose-management setting of NICE-SUGAR and should not be treated as the same experiment repeated.16

These results do not imply that glucose or hormone abnormalities are physiologically irrelevant. They show that the pathway from abnormal concentration to effective intervention is not automatic. Lowering glucose can reduce one exposure while introducing hypoglycemia or changing substrate availability; increasing anabolic signaling can intensify other metabolic demands or counter-regulatory effects.

A surrogate response establishes engagement of part of the system. Patient-centered outcomes determine whether a strategy produced a net benefit in its studied setting. Normalization of a blood result cannot substitute for that distinction.

65.12 Interpreting Endocrine Physiology Across the Course of Illness

Consider a constructed patient whose total cortisol falls as albumin decreases, whose glucose rises during increasing nutritional delivery, and whose T₃ remains low. None of these observations identifies a single common gland failure. The cortisol change could involve binding and clearance; the glucose change could combine external entry with persistent endogenous production and reduced disposal; the thyroid pattern could reflect altered central drive and tissue conversion.

Reconstructing the trajectory requires earlier health, established endocrine diagnoses, previous treatment, illness onset, and sample timing. A result during circulatory deterioration is not necessarily comparable to one during recovery after medications or nutrition have changed.

Next, distinguish concentration from action. For cortisol, total and free exposure can diverge. For thyroid hormones, local conversion can separate plasma and tissue states. For insulin, concentration may remain high despite resistance in selected pathways. Clinical observations supply essential information about the organ response, although weakness, hypotension, altered consciousness, and abnormal glucose each have many possible causes.

Organ function belongs in the explanation rather than as an afterthought. Kidney and liver dysfunction affect hormone clearance and substrate metabolism, while receiving tissues may have limited perfusion, receptor responsiveness, or synthetic capacity. An endocrine signal cannot overcome every downstream constraint. Conversely, an apparent recovery in a hormone concentration may reflect altered disposal before the underlying tissue function has recovered.

Serial observations can clarify whether changes accompany resolution of illness, withdrawal of suppressive drugs, restoration of nutrition and activity, or persistent evidence of a separate endocrine disorder. The useful question is not whether every value has returned to a healthy reference range, but what mechanism best explains the pattern and what evidence supports any proposed intervention.

Stress responses can support survival while contributing to sustained catabolism and impaired recovery. Uncertainty remains where plasma measurements cannot reveal local action or physiological experiments have not established an outcome benefit.

References

1. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350:1629–1638. Original human study.

2. Molenaar N, Groeneveld ABJ, Dijstelbloem HM, et al. Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness. Intensive Care Med. 2011;37:1986–1993. Original prospective study.

3. Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477–1488. Original human kinetic and tissue investigations.

4. Peeters B, Meersseman P, Vander Perre S, et al. Adrenocortical function during prolonged critical illness and beyond: a prospective observational study. Intensive Care Med. 2018;44:1720–1729. Original longitudinal study.

5. Shaw JH, Klein S, Wolfe RR. Assessment of alanine, urea, and glucose interrelationships in normal subjects and in patients with sepsis with stable isotopic tracers. Surgery. 1985;97:557–568. Original human tracer study.

6. Fliers E, Guldenaar SEF, Wiersinga WM, Swaab DF. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab. 1997;82:4032–4036. Original human postmortem study.

7. Simonides WS, Mulcahey MA, Redout EM, et al. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic–ischemic disease in rats. J Clin Invest. 2008;118:975–983. Original cell and animal experiments.

8. Van den Berghe G, de Zegher F, Veldhuis JD, et al. The somatotropic axis in critical illness: effect of continuous growth hormone (GH)-releasing hormone and GH-releasing peptide-2 infusion. J Clin Endocrinol Metab. 1997;82:590–599. Original human physiological intervention study.

9. Van den Berghe G, Weekers F, Baxter RC, et al. Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic–pituitary–gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab. 2001;86:3217–3226. Original small human intervention study.

10. Van den Berghe G, de Zegher F, Veldhuis JD, et al. Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone-secretagogues. Clin Endocrinol (Oxf). 1997;47:599–612. Original human secretion study.

11. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122–1125. Original human mechanistic study.

12. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378:797–808. ADRENAL randomized trial.

13. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378:809–818. APROCCHSS randomized trial.

14. Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785–792. Two parallel randomized trials.

15. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283–1297. Original randomized trial.

16. Gunst J, Debaveye Y, Güiza F, et al. Tight blood-glucose control without early parenteral nutrition in the ICU. N Engl J Med. 2023;389:1180–1190. TGC-Fast randomized trial.