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Cited by 141Adrenal Hormones and DisordersPituitary Gland Disorders and TreatmentsStress Responses and Cortisol

Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia

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Raff, Hershel, Sharma, Susmeeta T., Nieman, Lynnette K.·2014·Comprehensive Physiology
DOI 10.1002/cphy.c130035PMC PMC4215264
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Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control.

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Crossref · 10.1002/cphy.c130035

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298 of 298 references verified0 citation errors · 0 not checkable

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  • Late-night salivary cortisol is a reliable, simple, and cost-effective first-line test for the diagnosis of Cushing syndrome.

    “Late-night salivary cortisol (LNSC) is a reliable, simple, and cost-effective first-line test for the diagnosis of endogenous neoplastic hypercortisolism (CS) [15, 16, 34, 35, 42-52].”

    From Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome (2020) · cites this paper as [16]

    The “Screening tests for endogenous hypercortisolism” section describes late-night salivary cortisol as a widely accepted screening test with high sensitivity, specificity, and simplicity. It supports the test’s reliability and first-line screening role, but does not assess whether it is cost-effective. No page number is available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Complete recovery of cortisol production can remain impaired in a minority of patients.

    “Complete recovery of cortisol production can remain impaired in a minority of patients (58, 84-86) (Fig. 1).”

    From European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency (2024) · cites this paper as [86]

  • The negative feedback loop on the HPA axis mainly involves CRH, which is the most important driver of ACTH release.

    “This effect is mediated by the negative feedback loop on the hypothalamus-pituitary-adrenal (HPA) axis, which mainly involves corticotropin-release hormone (CRH), which represents the most important driver of adrenocorticotropic hormone (ACTH) release.”

    From Treatment with synthetic glucocorticoids and the hypothalamus-pituitary-adrenal axis (2017) · cites this paper as [29]

  • In some tissues, such as distal tubules of the kidney, the action of 11-β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts active cortisol into inactive cortisone, protects MRs from cortisol.

    “In some tissues, such as distal tubules of the kidney, the action of 11-β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts the active cortisol into inactive cortisone, “protects”s MRs from the cortisol.”

    From Treatment with synthetic glucocorticoids and the hypothalamus-pituitary-adrenal axis (2017) · cites this paper as [29]

  • The protective mechanism of 11β-HSD2 can be unbalanced in conditions of overexposure to glucocorticoids that override 11β-HSD2 activity, as observed in hypertension related to Cushing's syndrome.

    “However, this mechanism can be unbalanced in conditions of overexposure to GCs that override 11β-HSD2 activity, as observed in hypertension related to Cushing’s syndrome [29].”

    From Treatment with synthetic glucocorticoids and the hypothalamus-pituitary-adrenal axis (2017) · cites this paper as [29]

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2 of the 300 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. [11]Arlt W Longo Dan L Fauci Anthony S Kasper Dennis L Hauser Stephen L Larry Jameson J Loscalzo Joseph Chapter 342 Disorders of the Adrenal Cortex Harrison’s Online, Internal Medicine 18 2012 McGraw-Hill New York
  2. [15]Aron DC Findling JW Tyrrell JB Gardner DG Shoback D Glucocorticoids and adrenal androgens Greenspan’s Basic and Clinical Endocrinology McGraw-Hill New York 2007
  3. [71]Felig P Frohman L Endocrinology and Metabolism 4/e McGraw-Hill New York 2001 Figure 14–11 627
  4. [77]Findling JW Raff H Ectopic ACTH Endocrine Tumors Cambridge Blackwell Scientific Publications 554 566 1993

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Authors
Raff, H., Sharma, S. T., & Nieman, L. K.
Affiliations
  • Medical College of Wisconsin (US)
  • National Institutes of Health (US)
Corresponding author
Raff, Hershel
ORCID
Venue
Comprehensive Physiology
Publisher
Wiley
Published
2014-03-19
Volume
4
Issue
2
Pages
739-769
ISSN
2040-4603 (ISSN-L)
DOI
10.1002/cphy.c130035
PMC
PMC4215264
OpenAlex
W1519533122
Cited by
141
References
300
Citations by year
2026: 2 · 2025: 6 · 2024: 11 · 2023: 22 · 2022: 10 · 2021: 10 · 2020: 23 · 2019: 11 · 2018: 11 · 2017: 13 · 2016: 10 · 2015: 8 · 2014: 4
Type
other
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
Locations
  • Comprehensive physiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01HD000638, Z01HD008831)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
hypothalamic-pituitary-adrenal axis, Cushing's syndrome, adrenal insufficiency, congenital adrenal hyperplasia, iatrogenic Cushing's syndrome, ACTH-dependent Cushing's syndrome, ACTH-independent Cushing's syndrome, ectopic ACTH syndrome, proopiomelanocortin, secondary adrenal insufficiency, glucocorticoid withdrawal, hyperandrogenism
MeSH terms
Adrenal Insufficiency, Adrenal Hyperplasia, Congenital, Cushing Syndrome, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System

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