Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing’s Syndrome

Nieman, Lynnette K

doi:10.1210/endrev/bnab046

Cited by 34Pituitary Gland Disorders and TreatmentsAdrenal Hormones and DisordersAdrenal and Paraganglionic Tumors

Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing’s Syndrome

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Nieman, Lynnette K·2022·Endocrine Reviews

DOI 10.1210/endrev/bnab046PMC PMC9512149

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Abstract

Endogenous Cushing’s syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed “Cushing’s disease”) and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.

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Plasma ACTH levels will be inappropriately normal or elevated (generally >20 pg/mL) in ACTH-dependent causes of CS.
“Because of decreased glucocorticoid negative feedback effects, plasma ACTH levels will be inappropriately normal or elevated (generally > 20 pg/mL) in ACTH-dependent causes and low (generally < 10 pg/mL) in ACTH-independent causes of CS (70, 71).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [70]
Plasma ACTH levels will be low (generally <10 pg/mL) in ACTH-independent causes of CS.
“Because of decreased glucocorticoid negative feedback effects, plasma ACTH levels will be inappropriately normal or elevated (generally > 20 pg/mL) in ACTH-dependent causes and low (generally < 10 pg/mL) in ACTH-independent causes of CS (70, 71).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [70]
Once CS has been established, plasma ACTH concentrations can help determine whether the cause is ACTH-dependent or ACTH-independent.
“Once CS has been established, plasma ACTH concentrations can help determine whether the cause is ACTH-dependent or ACTH-independent.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [70]

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Dimer-Specific Potentiation of NGFI-B (Nur77) Transcriptional Activity by the Protein Kinase A Pathway and AF-1-Dependent Coactivator Recruitment
Maira, M., Martens, C., Batsché, É., Gauthier, Y., & Drouin, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.3.763-776.2003 · Cited by 153 · see citing works
Discriminatory Value of the Low-Dose Dexamethasone Suppression Test in Establishing the Diagnosis and Differential Diagnosis of Cushing’s Syndrome
Isidori, A. M., Kaltsas, G., Mohammed, S., Morris, D. G., Jenkins, P. J., Chew, S. L., Monson, J. P., BESSER, G. M., & Grossman, A. B. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030510 · Cited by 153 · see citing works
Specific Protein-Protein Interaction between Basic Helix-Loop-Helix Transcription Factors and Homeoproteins of the Pitx Family
Poulin, G. B., Lebel, M., Chamberland, M., Paradis, F., & Drouin, J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.13.4826-4837.2000 · Cited by 152 · cited 2× · see citing works
“Achaete-scute homolog 1 binds to Eboxneuro and, in contrast to NeuroD, is expressed in normal adult corticotrope cells (5).”
Background
Modulation of the Hsp90 Chaperone Cycle by a Stringent Client Protein
Lorenz, O. R., Freiburger, L., Rutz, D. A., Krause, M., Zierer, B. K., Alvira, S., Cuéllar, J., Valpuesta, J. M., Madl, T., Sattler, M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.02.003 · Cited by 151 · cited 1× · see citing works
“Depending on the experimental approach, reports differ as to when the GR binds ligand (20).”
Background
Optimal Response Criteria for the Human CRH Test in the Differential Diagnosis of ACTH-Dependent Cushing's Syndrome
Newell-Price, J. D. C., Morris, D. G., Drake, W. M., Korbonits, M., Monson, J. P., BESSER, G. M., & Grossman, A. B. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.4.8357 · Cited by 149 · see citing works
High variability in baseline urinary free cortisol values in patients with Cushing's disease
Petersenn, S., Newell-Price, J. D. C., Findling, J. W., Gu, F., Maldonado, M., Sen, K., Salgado, L. R., Colao, A. A. L., Biller, B. M. K., & Pasireotide B2305 Study Group (2013) · Clinical Endocrinology · doi:10.1111/cen.12259 · Cited by 147 · see citing works
Opposite regulation of pro-opiomelanocortin gene transcription by glucocorticoids and CRH
Gagner, J.-P., & Drouin, J. (1985) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(85)90154-6 · Cited by 145 · cited 1× · see citing works
“CRH is the main secretagogue for ACTH production and secretion in humans (10).”
Background
Delivery and Transport of Glucocorticoids to Target Cells
Ballard, P. L. (1979) · Monographs on endocrinology · doi:10.1007/978-3-642-81265-1_2 · Cited by 143 · cited 1× · see citing works
“2 ug/dL; ~450 nmol/L) levels, leading to an increase in free cortisol levels (88,89).”
Background
The dexamethasone-suppressed corticotropin-releasing hormone stimulation test and the desmopressin test to distinguish Cushing's syndrome from pseudo-Cushing's states.
Pecori Giraldi, F., Pivonello, R., Ambrogio, A. G., De Martino, M. C., De Martin, M., Scacchi, M., Colao, A., Toja, P. M., Lombardi, G., & Cavagnini, F. (2007) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02717.x · Cited by 141 · see citing works
Diagnosis of endocrine disease: differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)
Findling, J. W., & Raff, H. (2017) · European Journal of Endocrinology · doi:10.1530/eje-16-0946 · Cited by 134 · see citing works
Clinical and Biochemical Characteristics of Adrenocorticotropin-Secreting Macroadenomas
Woo, Y. S., Isidori, A. M., Wat, W. Z. M., Kaltsas, G., Afshar, F., Sabin, H. I., Jenkins, P. J., Monson, J. P., BESSER, G. M., & Grossman, A. B. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0070 · Cited by 134 · see citing works
Simultaneous Measurement of Cortisol in Serum and Saliva After Different Forms of Cortisol Administration
Tunn, S., Möllmann, H., Barth, J. H., Derendorf, H., & Krieg, M. (1992) · Clinical Chemistry · doi:10.1093/clinchem/38.8.1491 · Cited by 130 · cited 1× · see citing works
“This increases free plasma cortisol levels so that the filtered concentration increases, and less of the filtered concentration can be inactivated (89,96,97).”
Background
Protein-Protein Interactions and Transcriptional Antagonism between the Subfamily of NGFI-B/Nur77 Orphan Nuclear Receptors and Glucocorticoid Receptor
Martens, C., Bilodeau, S., Maira, M., Gauthier, Y., & Drouin, J. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0333 · Cited by 128 · cited 1× · see citing works
“However, an elegant series of studies using promoter constructs containing various combinations of REs showed that the nGRE alone did not support either transactivation or repression, TpitRE was involved only in activation, and only NurRE-dependent activity was required for both Pomc activation and GC repression (26,2…”
Background
The corticotrophin‐releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing's syndrome
Reimondo, G., Paccotti, P., Minetto, M. A., Termine, A., Stura, G., Bergui, M., Angeli, A., & Terzolo, M. (2003) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2003.01776.x · Cited by 125 · see citing works
A novel tool in the diagnosis and follow-up of (cyclic) Cushing's syndrome: measurement of long-term cortisol in scalp hair
Manenschijn, L., Koper, J. W., van den Akker, E. L. T., de Heide, L. J. M., Geerdink, E. A. M., de Jong, F. H., Feelders, R. A., & van Rossum, E. F. C. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1852 · Cited by 122 · see citing works
A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease
Riebold, M., Kozany, C., Freiburger, L. A., Sattler, M., Buchfelder, M., Hausch, F., Stalla, G. K., & Páez-Pereda, M. (2015) · Nature Medicine · doi:10.1038/nm.3776 · Cited by 116 · cited 2× · see citing works
“The C-terminal HSP90 inhibitors silibinin and novobiocin cause activated GR to be released from HSP90 and partially restore GC sensitivity in human corticotrope cell lines and a nude mouse tumor model (80).”
Background
Probability theory in the diagnosis of Cushing's syndrome.
NUGENT, C. A., WARNER, H. R., DUNN, J. T., & TYLER, F. H. (1964) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-24-7-621 · Cited by 112 · see citing works
Elevated Salivary Cortisol in the Evening in Healthy Elderly Men and Women: Correlation With Bone Mineral Density
Raff, H., Raff, J. L., Duthie, E. H., Wilson, C. R., Sasse, E. A., Rudman, I. W., & Mattson, D. L. (1999) · The Journals of Gerontology Series A · doi:10.1093/gerona/54.9.m479 · Cited by 108 · see citing works
Physiology of Urinary Cortisol Excretion
Beisel, W. R., COS, J. J., Horton, R., Chao, P. Y., & Forsham, P. H. (1964) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-24-9-887 · Cited by 108 · cited 1× · see citing works
“Early studies (90,91) showed that only a small fraction of the free plasma cortisol was excreted in urine.”
Background
Measurement of urinary free cortisol by tandem mass spectrometry and comparison with results obtained by gas chromatography-mass spectrometry and two commercial immunoassays
Wood, L. H., Ducroq, D., Fraser, H. L., Gillingwater, S., Evans, C., Pickett, A., Rees, D. W., John, R., & Turkes, A. (2008) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1258/acb.2007.007119 · Cited by 105 · cited 1× · see citing works
“Comparisons of LC/MSMS with immunoassay results showed cross-reactivity with cortisone, and the A ring reduced cortisol metabolites 5α- and 5β-dihydrocortisol and their glucuronide conjugates (109,110).”
Background
Specificity of Screening Tests for Cushing’s Syndrome in an Overweight and Obese Population
Baid, S. K., Rubino, D., Sinaii, N., Ramsey, S., Frank, A., & Nieman, L. K. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2766 · Cited by 105 · see citing works
Self-citation
The CpG Island Promoter of the Human Proopiomelanocortin Gene Is Methylated in Nonexpressing Normal Tissue and Tumors and Represses Expression
Newell-Price, J. D. C., King, P., & Clark, A. (2001) · Molecular Endocrinology · doi:10.1210/mend.15.2.0599 · Cited by 104 · cited 2× · see citing works
“In studies of ACTH-producing bronchial, thymic, and pancreatic NETs, that region was hypomethylated in compared to corresponding normal (non-ACTH expressing) tissues, corresponding to increased promoter activation (57,59,60).”
Background
Accuracy of laboratory tests for the diagnosis of Cushing syndrome
Galm, B. P., Qiao, N., Klibanski, A., Biller, B. M. K., & Tritos, N. A. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa105 · Cited by 100 · see citing works
Human 11β-hydroxysteroid dehydrogenase: Studies on the stably transfected isoforms and localization of the type 2 isozyme within renal tissue
Bujalska, I. J., Shimojo, M., Howie, A., & Stewart, P. M. (1997) · Steroids · doi:10.1016/s0039-128x(96)00163-8 · Cited by 100 · see citing works
Diminished urinary free cortisol excretion in patients with moderate and severe renal impairment.
Chan, K. C. A., Lit, L. C. W., Law, E. L. K., Tai, M. H. L., Yung, C. U., Chan, M. H. M., & Lam, C. W. K. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2003.029934 · Cited by 99 · see citing works
Plasma Steroid Metabolome Profiling for Diagnosis and Subtyping Patients with Cushing Syndrome
Eisenhofer, G., Masjkur, J. R., Peitzsch, M., Dalmazi, G. D., Bidlingmaier, M., Grüber, M., Fazel, J., Oßwald, A., Beuschlein, F., & Reincke, M. (2017) · Clinical Chemistry · doi:10.1373/clinchem.2017.282582 · Cited by 99 · see citing works
Differentiating between Cushing's disease and pseudo-Cushing's syndrome: comparison of four tests
Alwani, R. A., Schmit Jongbloed, L. W., de Jong, F. H., van der Lely, A. J., de Herder, W. W., & Feelders, R. A. (2014) · European Journal of Endocrinology · doi:10.1530/eje-13-0702 · Cited by 98 · see citing works
Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing’s disease
Hernández-Ramírez, L. C., Gam, R., Valdés, N., Lodish, M. B., Pankratz, N., Balsalobre, A., Gauthier, Y., Faucz, F. R., Trivellin, G., Chittiboina, P., et al. (2017) · Endocrine Related Cancer · doi:10.1530/erc-17-0131 · Cited by 96 · cited 1× · see citing works
“A germline mutation in CABLES1 (CDK5 and ABL1 enzyme substrate 1) has been reported in four female patients among a cohort of 146 children and 35 adults with Cushing’s disease (83).”
Alcohol-induced Cushingoid syndrome.
Smalls, A., KLOPPENBORG, P. W. C., Njo, K. T., Knoben, J. M., & Ruland, C. M. (1976) · BMJ · doi:10.1136/bmj.2.6047.1298 · Cited by 95 · see citing works
Diagnosis of Cushing’s Syndrome in the Modern Era
Nieman, L. K. (2018) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2018.02.001 · Cited by 93 · cited 1× · see citing works
“The pretest probability increases if the patient’s signs and symptoms are not common in most people of the patient’s age and sex and accumulate over time (107).”
BackgroundSelf-citation
The molecular chaperone Hsp90 can negatively regulate the activity of a glucocorticosteroid-dependent promoter
Kang, K. I., Meng, X., Leclerc, J., Bouhouche, I., Chadli, A., Cadepond, F., Baulieu, É.-É., & CATELLI, M. G. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1439 · Cited by 90 · cited 1× · see citing works
“Decreases and increases in the ratio of nuclear HSP90:GR each lead to decreased GR activity (22,79).”
Background
Neuropsychiatric Findings in Cushing Syndrome and Exogenous Glucocorticoid Administration
Starkman, M. N. (2013) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2013.05.010 · Cited by 87 · cited 2× · see citing works
“Development of mood lability is extremely common in CS and its absence is slightly against the diagnosis (103).”
Background
Expression of 11 -Hydroxysteroid Dehydrogenase Isoenzymes in the Human Pituitary: Induction of the Type 2 Enzyme in Corticotropinomas and Other Pituitary Tumors
Korbonits, M., Bujalska, I. J., Shimojo, M., Nobes, J. P., Jordan, S., Grossman, A. B., & Stewart, P. M. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.6.7563 · Cited by 80 · see citing works
Differences in cortisol profiles and circadian adjustment time between nurses working night shifts and regular day shifts: A prospective longitudinal study
Niu, S.-F., Chung, M.-H., Chu, H., Tsai, J.-C., Lin, C.-C., Liao, Y.-M., Ou, K.-L., O’Brien, A. P., & Chou, K.-R. (2015) · International Journal of Nursing Studies · doi:10.1016/j.ijnurstu.2015.04.001 · Cited by 80 · see citing works
On the Mechanism of Alcohol-Induced Pseudo-Cushing's Syndrome
Veldman, R. G., & Meinders, A. E. (1996) · Endocrine Reviews · doi:10.1210/edrv-17-3-262 · Cited by 79 · see citing works
Concomitant medication use can confound interpretation of the combined dexamethasone-corticotropin releasing hormone test in Cushing's syndrome.
Valassi, E., Swearingen, B., Lee, H., Nachtigall, L. B., Donoho, D. A., Klibanski, A., & Biller, B. M. K. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1500 · Cited by 78 · see citing works
Rapid glucocorticoid feedback inhibition of ACTH secretion involves ligand-dependent membrane association of glucocorticoid receptors
Deng, Q., Riquelme, D., Trinh, L., Low, M. J., Tomić, M., Stojilkovic, S., & Aguilera, G. (2015) · Endocrinology · doi:10.1210/en.2015-1265 · Cited by 77 · cited 2× · see citing works
“As a result, the administration of two 30 min CRH + corticosterone infusions interspersed by 30 min of CRH-only perifusate resulted in 2 ACTH pulses (34).”
Background
Circadian rhythm of salivary cortisol, plasma cortisol, and plasma ACTH in end-stage renal disease
Raff, H., & Trivedi, H. (2012) · Endocrine Connections · doi:10.1530/ec-12-0058 · Cited by 76 · see citing works
DIAGNOSIS OF ENDOCRINE DISEASE: The role of the desmopressin test in the diagnosis and follow-up of Cushing’s syndrome
Vassiliadi, D. A., & Tsagarakis, S. (2018) · European Journal of Endocrinology · doi:10.1530/eje-18-0007 · Cited by 74 · see citing works
Cyclin E-Mediated Human Proopiomelanocortin Regulation as a Therapeutic Target for Cushing Disease
Liu, N., Araki, T., Ramos, D. C., Jiang, H., Ben-Shlomo, A., Tone, Y., Tone, M., & Melmed, S. K. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1606 · Cited by 72 · cited 1× · see citing works
“Finally, treatment of the human tumors in primary culture with R-roscovitine, which suppresses the mouse proopiomelanocortin gene in AtT-20 cells (64), reduced ACTH production and displaced E2F1 from binding sites, and a direct inhibitor of E2F1 reduced ACTH levels in tumor xenografted mice (63).”
Background
Intensive venous sampling paradigms disclose high frequency adrenocorticotropin release episodes in normal men
IRANMANESH, A., LIZARRALDE, G., SHORT, D., & VELDHUIS, J. D. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-71-5-1276 · Cited by 71 · cited 1× · see citing works
“As with cortisol, the diurnal ACTH excursion was modulated by the pulse amplitude, not frequency (42).”
Background
Corticosterone differentially modulates expression of corticotropin releasing factor and arginine vasopressin mRNA in the hypothalamic paraventricular nucleus following either acute or repeated restraint stress
Pinnock, S. B., & Herbert, J. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2000.01406.x · Cited by 70 · cited 1× · see citing works
“However, in adrenalectomized animals given corticosterone replacement at peak physiologic levels, baseline CRH was normal at baseline and after chronic stress (ie, negative feedback was intact), but CRH was increased after acute stress (55).”
Background
TheCables1Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease
Roussel-Gervais, A., Couture, C., Langlais, D., Takayasu, S., Balsalobre, A., Rueda, B. R., Zukerberg, L. R., Figarella-Branger, D. F., Brue, T. C., & Drouin, J. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3324 · Cited by 70 · cited 1× · see citing works
“CABLES1 protein is absent in about 50% of corticotroph adenomas, suggesting that it contributes to tumor formation and GC resistance, without a germline mutation (84).”
Background
Glucocorticoids Regulate Ovine Hypophysial Portal Levels of Corticotropin-Releasing Factor and Arginine Vasopressin in a Stress-Specific Manner
Canny, B. J., Funder, J. W., & Clarke, I. J. (1989) · Endocrinology · doi:10.1210/endo-125-5-2532 · Cited by 69 · see citing works
The T-box Factor Tpit Recruits SRC/p160 Co-activators and Mediates Hormone Action
Maira, M., Couture, C., Martelot, G. L., Pulichino, A.-M., Bilodeau, S., & Drouin, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305626200 · Cited by 69 · cited 1× · see citing works
“A reduction in calcium influx has the opposite effect to suppress CRH-stimulated Pomc transcription (13).”
Background
Urine Free cortisol in the diagnosis of cushing’s syndrome: Is It worth doing and, If so, how?
Raff, H., Auchus, R. J., Findling, J. W., & Nieman, L. K. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3766 · Cited by 68 · see citing works
Self-citation
Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease
Du, L., Bergsneider, M., Mirsadraei, L., Young, S. H., Jonker, J. W., Downes, M., Yong, W. H., Evans, R. M., & Heaney, A. P. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306182110 · Cited by 67 · see citing works
The hsp56 immunophilin component of steroid receptor heterocomplexes: Could this be the elusive nuclear localization signal-binding protein?
Pratt, W. B., Czar, M. J., Stancato, L. F., & Owens, J. K. (1993) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(93)90216-j · Cited by 65 · cited 1× · see citing works
“As proposed by Pratt et al, this converts the heterocomplex to a transportosome, allowing for transport into the nucleus along microtubular tracks (24).”
Background
Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function.
Ray, D. W., Littlewood, A. C., Clark, A. J., Davis, J. R., & White, A. E. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117143 · Cited by 65 · cited 1× · see citing works
“GR mutations in the N-terminal and DNA-binding domain accounted for complete resistance to GC action in 1 small cell lung cancer cell line (66), but normal GR mRNA was found in another study of 3 bronchial carcinoids that showed in vivo suppression to dexamethasone, 8 mg (67).”
Background
Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease
Lu, J., Chatain, G. P., Bugarini, A., Wang, X., Maric, D., Walbridge, S., Zhuang, Z., & Chittiboina, P. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-00464 · Cited by 63 · cited 1× · see citing works
“The oral pan-HDAC inhibitor suberoylanilide hydroxamic acid (Vorinostat) decreased protein levels of LXRa and suppressed POMC transcription in dispersed human corticotrope tumor cells, suggesting that LXRa may play a role in tumorigenesis (70).”
Background
Role of mineralocorticoid receptors on the hypothalamus–pituitary–adrenal axis in humans
Berardelli, R., Karamouzis, I., D’Angelo, V., Zichi, C., Fussotto, B., Giordano, R., Ghigo, E., & Arvat, E. (2012) · Endocrine · doi:10.1007/s12020-012-9750-8 · Cited by 62 · see citing works
Studies of the Regulation of the Hypothalamic-Pituitary-Adrenal Axis in Sheep with Hypothalamic-Pituitary Disconnection. II. Evidence for<i>in Vivo</i>Ultradian Hypersecretion of Proopiomelanocortin Peptides by the Isolated Anterior and Intermediate Pituitary*
ENGLER, D., PHAM, T., LIU, J.-P., FULLERTON, M. J., CLARKE, I. J., & FUNDER, J. W. (1990) · Endocrinology · doi:10.1210/endo-127-4-1956 · Cited by 61 · cited 1× · see citing works
“observation that ACTH pulses remained intact in ewes with transection of the pituitary stalk, which could not receive hypothalamic hormonal signals, also was against the concept that ACTH pulses result from suprapituitary hormonal input (48).”
Background
Glucocorticoid Regulation of Calcium-activated Potassium Channels Mediated by Serine/Threonine Protein Phosphatase
Tian, L., Knaus, H., & Shipston, M. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13531 · Cited by 59 · cited 1× · see citing works
“Glucocorticoids alter large-conductance calcium- and voltage-activated potassium channels by affecting messenger RNA (mRNA) splicing and increasing phosphorylation (32,33).”
Background
Hypomethylation in the promoter region of POMC gene correlates with ectopic overexpression in thymic carcinoids
Ye, L., Li, X., Kong, X., Wang, W., Bi, Y., Hu, L., Cui, B., Li, X., & Ning, G. (2005) · Journal of Endocrinology · doi:10.1677/joe.1.05963 · Cited by 58 · cited 1× · see citing works
“In studies of ACTH-producing bronchial, thymic, and pancreatic NETs, that region was hypomethylated in compared to corresponding normal (non-ACTH expressing) tissues, corresponding to increased promoter activation (57,59,60).”
Background
The limited value of the desmopressin test in the diagnostic approach to Cushing's syndrome
Terzolo, M., Reimondo, G., Alı̀, A., Borretta, G., Cesario, F., Pia, A. R., Paccotti, P., & Angeli, A. (2001) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2001.01260.x · Cited by 57 · see citing works
Measurement of late-night salivary cortisol and cortisone by LC-MS/MS to assess preanalytical sample contamination with topical hydrocortisone
Raff, H., & Singh, R. J. (2012) · Clinical Chemistry · doi:10.1373/clinchem.2012.182717 · Cited by 57 · see citing works
Automated 24-hours sampling of subcutaneous tissue free cortisol in humans
Bhake, R. C., Leendertz, J. A., Linthorst, A. C. E., & Lightman, S. L. (2013) · Journal of Medical Engineering & Technology · doi:10.3109/03091902.2013.773096 · Cited by 56 · see citing works
Elevated levels of cortisol in hair precede acute myocardial infarction
Faresjö, T., Strömberg, S., Jones, M., Stomby, A., Karlsson, J., Östgren, C. J., Faresjö, Å., & Theodorsson, E. (2020) · Scientific Reports · doi:10.1038/s41598-020-80559-9 · Cited by 55 · cited 2× · see citing works
“Hair cortisol has been used in research to evaluate the timing of the onset of hypercortisolism and the relationship of hypercortisolism to various comorbidities (94,142,143).”
BackgroundMethod
Alternative splicing determines sensitivity of murine calcium‐activated potassium channels to glucocorticoids
Tian, L., Hammond, M. S. L., Florance, H., Antoni, F. A., & Shipston, M. J. (2001) · The Journal of Physiology · doi:10.1111/j.1469-7793.2001.0057k.x · Cited by 55 · cited 1× · see citing works
“Glucocorticoids alter large-conductance calcium- and voltage-activated potassium channels by affecting messenger RNA (mRNA) splicing and increasing phosphorylation (32,33).”
Background
Pitfalls in Performing and Interpreting Inferior Petrosal Sinus Sampling: Personal Experience and Literature Review
Perlman, J. E., Johnston, P. C., Hui, F., Mulligan, G., Weil, R. J., Recinos, P. F., Yogi-Morren, D., Salvatori, R., Mukherjee, D., Gallia, G., et al. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab012 · Cited by 50 · see citing works
Assay-Specific Spurious ACTH Results Lead to Misdiagnosis, Unnecessary Testing, and Surgical Misadventure—A Case Series
Greene, L. W., Geer, E. B., Page‐Wilson, G., Findling, J. W., & Raff, H. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00027 · Cited by 49 · see citing works
Neural Control of the Pituitary Gland.—II
Harris, G. W. (1951) · BMJ · doi:10.1136/bmj.2.4732.627 · Cited by 48 · cited 1× · see citing works
“The identification and sequencing of CRH (45) presented an opportunity to test Harris’s theory of hypothalamic hormonal and neuronal control of the anterior pituitary gland (46).”
Method
EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis
Araki, T., Liu, X., Kameda, H., Tone, Y., Fukuoka, H., Tone, M., & Melmed, S. K. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2016-1053 · Cited by 47 · cited 6× · see citing works
“Neuroendocrine tumors (NETs), most commonly of the lung, thymus, pancreas, and appendix, as well as pheochromocytoma and medullary thyroid cancer, produce ACTH ectopically (ie, not in the eutopic place, the D ow nloaded from https://academ ic.oup.com /edrv/advance-article/doi/10.1210/endrev/bnab046/6446164 by guest on…”
BackgroundInfluential
Alcohol-Induced Cushingoid Syndrome
SMALS, A. G. H., Njo, K. T., Knoben, J. M., Ruland, C. M., & KLOPPENBORG, P. W. C. (1977) · Journal of the Royal College of Physicians of London · doi:10.1016/s0035-8819(25)02976-9 · Cited by 44 · see citing works
Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro.
Suda, T., Tozawa, F., Dobashi, I., HORIBA, N., Ohmori, N., Yamakado, M., Yamada, M., & Demura, H. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116898 · Cited by 43 · cited 2× · see citing works
“GR mutations in the N-terminal and DNA-binding domain accounted for complete resistance to GC action in 1 small cell lung cancer cell line (66), but normal GR mRNA was found in another study of 3 bronchial carcinoids that showed in vivo suppression to dexamethasone, 8 mg (67).”
Background
THE RENAL CLEARANCE OF PLASMA CORTISOL
Schedl, H. P., Chen, P. S., GREENE, G., & REDD, D. (1959) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-19-10-1223 · Cited by 42 · cited 1× · see citing works
“Early studies (90,91) showed that only a small fraction of the free plasma cortisol was excreted in urine.”
Background
Common and diverse elements of ion channels and receptors underlying electrical activity in endocrine pituitary cells
Fletcher, P. A., Sherman, A., & Stojilković, S. S. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.06.022 · Cited by 42 · cited 3× · see citing works
“The increased intracellular calcium that results from CRH binding leads to exocytosis of ACTH-containing vesicles, in addition to Pomc transcription (9).”
Background
Performance of LC–MS/MS and immunoassay based 24-h urine free cortisol in the diagnosis of Cushing's syndrome
Oßwald, A., Wang, R., Beuschlein, F., Hartmann, M. F., Wudy, S. A., Bidlingmaier, M., Zopp, S., Reincke, M., & Ritzel, K. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.04.004 · Cited by 42 · see citing works
Primary cortisol resistance: A familial syndrome and an animal model
Chrousos, G. P., Loriaux, D. L., Brandon, D. D., Tomita, M., Vingerhoeds, A. C. M., Merriam, G. R., Johnson, E. O., & LIPSETT, M. B. (1983) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(83)90219-4 · Cited by 41 · see citing works
Urinary free cortisol and cortisone excretion in healthy individuals: Influence of water loading
Fenske, M. J. (2006) · Steroids · doi:10.1016/j.steroids.2006.08.004 · Cited by 40 · see citing works
Evidence From Studies on Co‐Cultures of TtT/GF and AtT20 Cells That Annexin 1 Acts as a Paracrine or Juxtacrine Mediator of the Early Inhibitory Effects of Glucocorticoids on ACTH Release
Tierney, T., Christian, H., Morris, J. F., Solito, E., & Buckingham, J. C. (2003) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2003.01111.x · Cited by 40 · cited 1× · see citing works
“ACTH secretion after dexamethasone exposure and CRH stimulation only when the cells were co-cultured with a folliculostellate cell line (36).”
Background
Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing
Sesta, A., Cassarino, M. F., Terreni, M., Ambrogio, A. G., Libera, L., Bardelli, D., Lasio, G. B., Losa, M., & Giraldi, F. P. (2019) · Neuroendocrinology · doi:10.1159/000500688 · Cited by 38 · see citing works
Subclinical hypercortisolism in adrenal incidentaloma
Debono, M., & Newell-Price, J. D. C. (2015) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000151 · Cited by 37 · cited 20× · see citing works
“First, patients with recurrent CS have increased late night salivary (free) cortisol values before UFC values are increased, suggesting that mild changes in the nadir of cortisol are not sufficient to increase 24-h UFC (98).”
BackgroundInfluential
Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome
Kannankeril, J., Carroll, T., Findling, J. W., Javorsky, B., Gunsolus, I. L., Phillips, J., & Raff, H. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa107 · Cited by 36 · see citing works
Corticotropin-releasing hormone is produced by rat corticotropes and modulates ACTH secretion in a paracrine/autocrine fashion.
Giraldi, F. P., & Cavagnini, F. (1998) · Journal of Clinical Investigation · doi:10.1172/jci443 · Cited by 35 · cited 1× · see citing works
“While it is possible that POMC production is stimulated by other signal transducers (like EGFR), there is some evidence that CRH and vasopressin are produced by mouse corticotrope cells and human tumors (67,77).”
Background
Retinoblastoma and the Related Pocket Protein p107 Act as Coactivators of NeuroD1 to Enhance Gene Transcription
Batsché, É., Moschopoulos, P., Desroches, J., Bilodeau, S., & Drouin, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413427200 · Cited by 35 · cited 1× · see citing works
“However, others have found that NeuroD protein is overexpressed in corticotrope adenomas (6).”
Background
Analysis of the human proopiomelanocortin gene promoter in a small cell lung carcinoma cell line reveals an unusual role for E2F transcription factors
Picon, A., BERTAGNA, X. Y., & de Keyzer, Y. (1999) · Oncogene · doi:10.1038/sj.onc.1202635 · Cited by 35 · cited 2× · see citing works
“Interestingly, this region is mutated in the rodent Pomc promoter (compared to the human), where it is not transcriptionally active (61).”
Background
Morning cortisol levels and glucose metabolism parameters in moderate and severe obstructive sleep apnea patients
Božić, J., Galić, T., Šupe‐Domić, D., Ivković, N., Kurir, T. T., Valić, Z., Lesko, J., & Đogaš, Z. (2016) · Endocrine · doi:10.1007/s12020-016-0925-6 · Cited by 34 · see citing works
Testicular Receptor-4: Novel Regulator of Glucocorticoid Resistance
Zhang, D., Du, L., & Heaney, A. P. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-1379 · Cited by 34 · see citing works
Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease
Araki, T., Tone, Y., Yamamoto, M., Kameda, H., Ben-Shlomo, A., Yamada, S., Takeshita, A., Yamamoto, M., Kawakami, Y., Tone, M., et al. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab387 · Cited by 34 · cited 2× · see citing works
“In all patients, transcription from this region corresponded to the amount of its demethylation (58).”
Background
Tobacco usage interacts with postdisaster psychopathology on circadian salivary cortisol
Olff, M., Meewisse, M., Kleber, R. J., van der Velden, P. G., Drogendijk, A. N., van Amsterdam, J., Opperhuizen, A., & Gersons, B. P. R. (2006) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2005.10.014 · Cited by 33 · see citing works
Circadian Variations in the Amplitude of Corticotropin-Releasing Hormone 41 (CRH41) Episodic Release Measured In Vivo in Male Rats: Correlations with Diurnal Fluctuations in Hypothalamic and Median Eminence CRH41 Contents
IXART, G., Siaud, P., Barbanel, G., Mekaouche, M., Givalois, L., & ASSENMACHER, I. (1993) · Journal of Biological Rhythms · doi:10.1177/074873049300800403 · Cited by 33 · cited 1× · see citing works
“However, CRH pulses in the median eminence of freerunning rats were found to occur about 3 times each hour (47), without variation in diurnal amplitude.”
Background
Human Corticotropin-Releasing Hormone Tests: 10 Years of Real-Life Experience in Pituitary and Adrenal Disease
Ceccato, F., Tizianel, I., Vedolin, C. K., Boscaro, M., Barbot, M., & Scaroni, C. M. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa564 · Cited by 33 · see citing works
The Clinical Features and Molecular Mechanisms of ACTH-secreting Pancreatic Neuroendocrine Tumors
Zhang, C., Jin, J., Xie, J., Ye, L., Su, T., Jiang, L., Zhou, W., Jiang, Y., Wu, L., Wang, T., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa507 · Cited by 33 · cited 1× · see citing works
“In studies of ACTH-producing bronchial, thymic, and pancreatic NETs, that region was hypomethylated in compared to corresponding normal (non-ACTH expressing) tissues, corresponding to increased promoter activation (57,59,60).”
Background
Dynamics of salivary cortisol in chronic kidney disease patients at stages 1 through 4
Cardoso, E. M. D. L., Arregger, A. L., Budd, D., Zucchini, A., & Contreras, L. N. (2016) · Clinical Endocrinology · doi:10.1111/cen.13023 · Cited by 32 · see citing works
Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature
Seltzer, J. A., Ashton, C. E., Scotton, T. C., Pangal, D. J., Carmichael, J. D., & Zada, G. (2015) · Neurosurgical FOCUS · doi:10.3171/2014.10.focus14683 · Cited by 32 · cited 6× · see citing works
“Poulin et al proposed that the observed protein:protein interactions between Tpit and the Eboxneuro complex is bridged by TF PERIANTHIA 1 via a U-shaped bend of the promoter; the complex is further stabilized by direct interaction of one of the Eboxneuro dimers with Tpit (7,8) (Fig.”
BackgroundInfluential
Expression of EGFR in Pituitary Corticotroph Adenomas and Its Relationship With Tumor Behavior
Liu, X.-H., Feng, M., Dai, C., Bao, X., Deng, K., Yao, Y., & Wang, R. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00785 · Cited by 32 · cited 1× · see citing works
“Others have found increased EGFR protein expression in corticotrope tumors that are initially resected (47%) and more frequent expression in tumors that recurred (70%) (76).”
Background
Glucocorticoids Inhibit CRH/AVP-Evoked Bursting Activity of Male Murine Anterior Pituitary Corticotrophs
Duncan, P. J., Tabak, J., Ruth, P., Bertram, R., & Shipston, M. J. (2016) · Endocrinology · doi:10.1210/en.2016-1115 · Cited by 31 · see citing works
E2F1-mediated human POMC expression in ectopic Cushing’s syndrome
Araki, T., Liu, N., Tone, Y., Ramos, D. C., Heltsley, R., Tone, M., & Melmed, S. K. (2016) · Endocrine Related Cancer · doi:10.1530/erc-16-0206 · Cited by 30 · cited 1× · see citing works
“The transcription observed from this region corresponded to the amount of demethylation (71).”
Background
Steroid profiling in the diagnosis of mild and overt Cushing’s syndrome
Athimulam, S., Grebe, S. K. G., & Bancos, I. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101488 · Cited by 30 · cited 4× · see citing works
“Cortisone is metabolized by the same sets of enzymes to dihydrocortisones, tetrahydrocortisones, and cortolones (93).”
BackgroundMethodInfluential
Hair cortisol and cortisone measurements for the diagnosis of overt and mild Cushing's syndrome
Brossaud, J., Charret, L., De Angeli, D., Haissaguerre, M., Ferriere, A., Puerto, M., Gatta-Cherifi, B., Corcuff, J.-B., & Tabarin, A. (2021) · European Journal of Endocrinology · doi:10.1530/eje-20-1127 · Cited by 29 · see citing works
Serum Levels of Dehydroepiandrosterone Sulfate in Patients with Asymptomatic Cortisol Producing Adrenal Adenoma: Comparison with Adrenal Cushing's Syndrome and Non-Functional Adrenal Tumor.
Morio, H., Terano, T., Yamamoto, K., Tomizuka, T., Toru, O. E. D. A., Saitō, Y., Tamura, Y., & Sasano, H. (1996) · Endocrine Journal · doi:10.1507/endocrj.43.387 · Cited by 29 · see citing works
The proneural bHLH genes Mash1, Math3 and NeuroD are required for pituitary development
Ando, M., Goto, M., Hojo, M., Kita, A., Kitagawa, M., Ohtsuka, T., Kageyama, R., & Miyamoto, S. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-18-0090 · Cited by 28 · cited 6× · see citing works
“Poulin et al proposed that the observed protein:protein interactions between Tpit and the Eboxneuro complex is bridged by TF PERIANTHIA 1 via a U-shaped bend of the promoter; the complex is further stabilized by direct interaction of one of the Eboxneuro dimers with Tpit (7,8) (Fig.”
BackgroundInfluential
Accuracy of immunoassay and mass spectrometry urinary free cortisol in the diagnosis of Cushing’s syndrome
Aranda, G. B., Careaga, M., Hanzu, F. A., Patrascioiu, I., Ríos, P., Mora, M., Morales‐Romero, B., Jiménez, W., Halperín, I., & Casals, G. (2016) · Pituitary · doi:10.1007/s11102-016-0730-5 · Cited by 27 · see citing works
Liver X Receptor-α Regulates Proopiomelanocortin (POMC) Gene Transcription in the Pituitary
Matsumoto, S., Hashimoto, K., Yamada, M., Satoh, T., Hirato, J., & Mori, M. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0533 · Cited by 25 · cited 14× · see citing works
“Data support the concept that recruitment of O-GlcNAc transferase prevents Pomc transcription by blocking phosphorylation (86).”
BackgroundInfluential
Functional analysis of the human pro-opiomelanocortin promoter in the small cell lung carcinoma cell line DMS-79
Picon, A., Leblond‐Francillard, M., Raffin‐Sanson, M. L., Lenne, F., BERTAGNA, X. Y., & de Keyzer, Y. (1995) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0150187 · Cited by 25 · cited 1× · see citing works
“Activation of the upstream E2F site by E2F1 (and DP1, 1 of its usual partners), but not the usual E-box-NurRE region, stimulated POMC transcription in DMS79 cells (61,62).”
Background
Reference ranges of late-night salivary cortisol and cortisone measured by LC-MS/MS and accuracy for the diagnosis of cushing's syndrome
Ponzetto, F., Settanni, F., Parasiliti-Caprino, M., Rumbolo, F., Nonnato, A., Ricciardo, M., Amante, E., Priolo, G., Vitali, S., Anfossi, L., et al. (2020) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01388-1 · Cited by 25 · see citing works
Clock Gene Expression in the Human Pituitary Gland
Wunderer, F., Kühne, S., Jilg, A., Ackermann, K., Sebesteny, T., Maronde, E., & Stehle, J. H. (2013) · Endocrinology · doi:10.1210/en.2012-2274 · Cited by 23 · cited 1× · see citing works
“However, examination of human autopsy specimens did not support this possibility: compared to other times of day, ACTH transcripts decreased at night, while period circadian regulator 1 transcripts decreased only at dawn (49).”
Result
Dietary sodium intake and cortisol measurements
Chen, A., Haas, A. V., Williams, G. H., & Vaidya, A. (2020) · Clinical Endocrinology · doi:10.1111/cen.14262 · Cited by 23 · see citing works
Expression and mutational status of USP8 in tumors causing ectopic ACTH secretion syndrome
Perez‐Rivas, L. G., Oßwald, A., Knösel, T., Lucia, K. E., Schaaf, C. P., Hristov, M., Fazel, J., Kirchner, T., Beuschlein, F., Reincke, M., et al. (2017) · Endocrine Related Cancer · doi:10.1530/erc-17-0054 · Cited by 23 · cited 1× · see citing works
“Interestingly, EAS tumors may express epidermal growth factor receptor (EGFR), which can act through E2F to promote this pathway (65).”
Background
Spontaneous and Radiation-Induced Pituitary Adenomas of Mice 2
Upton, A. C., & Fürth, J. (1955) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/15.4.1005 · Cited by 21 · cited 4× · see citing works
“Many theories about the etiology of CD derive from studies of the mouse AtT-20 cell (4), as there are no human CD cell lines.”
BackgroundInfluential
20α- and 20β-dihydrocortisone may interfere in LC-MS/MS determination of cortisol in saliva and urine
Israelsson, M., Brattsand, R., & Brattsand, G. (2018) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/0004563217724178 · Cited by 21 · cited 1× · see citing works
“These do not use antibodies for analyte detection and were thought to measure only cortisol, although a recent report documented interference with 20-alpha and beta-dihydrocortisone (108).”
Background
Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid
Parvin, R., Saito‐Hakoda, A., Shimada, H., Shimizu, K., Noro, E., Iwasaki, Y., Fujiwara, K., Yokoyama, A., & Sugawara, A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175435 · Cited by 20 · cited 1× · see citing works
“Through targeted mutation in the E-box, Parvin et al demonstrated that it, and specifically NeuroD, also was essential for dexamethasone suppression: dexamethasone suppressed NeuroD expression while NeuroD overexpression reconstituted GC suppression (28).”
Background
How serpins transport hormones and regulate their release.
Carrell, R., & Read, R. J. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.12.007 · Cited by 18 · cited 1× · see citing works
“To date, most data suggest that this relationship achieves 4 purposes: (1) providing transport of cortisol in the circulation; (2) providing a reservoir of inactive (bound) cortisol that can be accessed during febrile illness (due to reduced CBG affinity), (3) which can absorb/render inactive excess cortisol, allowing…”
Background
Cortisol circadian rhythm and jet-lag syndrome: evaluation of salivary cortisol rhythm in a group of eastward travelers
Paragliola, R. M., Corsello, A., Troiani, E., Locantore, P., Papi, G., Donnini, G., Pontecorvi, A., Corsello, S. M., & Carrozza, C. (2021) · Endocrine · doi:10.1007/s12020-021-02621-4 · Cited by 17 · see citing works
Corticosterone storage within the adrenal cortex: evidence for a sulphate conjugate
Henry, F. J., & Bassett, J. R. (1985) · Journal of Endocrinology · doi:10.1677/joe.0.1040381 · Cited by 15 · cited 1× · see citing works
“The model assumes that cortisol in humans and corticosterone in rodents terminates pulses and considers various amounts of delay between an ACTH pulse and a subsequent cortisol/corticosterone pulse; this delay is biologically inherent because the adrenal gland does not store GCs but rather synthesizes and secretes the…”
Background
Bedtime Salivary Cortisol as a Screening Test for Cushing Syndrome in Children
Ueland, G. Å., Kellmann, R., Jørstad Davidsen, M., Viste, K., Husebye, E. S., Almås, B., Storr, H. L., Sagen, J. V., Mellgren, G., Júlíusson, P. B., et al. (2021) · Journal of the Endocrine Society · doi:10.1210/jendso/bvab033 · Cited by 12 · see citing works
The diagnostic utility of late night salivary cortisol (LNSF) and cortisone (LNSE) in Cushing’s syndrome
Garrahy, A., Forde, H. E., O’Kelly, P., McGurren, K., Zia-Ul-Hussnain, H. M., Noctor, E., Tormey, W. P., Smith, D., Dennedy, M. C., Bell, M., et al. (2020) · Irish Journal of Medical Science (1971 -) · doi:10.1007/s11845-020-02334-z · Cited by 7 · see citing works
Aberrant Expression and Modification of Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptors Involved in the Pathogenesis of Tumoral Cortisol Resistance
Jiang, J., Li, N., Wang, X., Lu, Y., Bi, Y., Wang, W., Li, X., & Ning, G. (2010) · Endocrinology · doi:10.1210/en.2010-0335 · Cited by 5 · cited 2× · see citing works
“SMRT SUMOylation was confirmed in the DMS-79 and prevented formation of the SMRT-HDAC-GR complex required for GC suppression of POMC (68).”
Background
On the nature of the hypothalamic substance which controls the secretion of ACTH
Guillemin, R., & Schally, A. V. (1961) · Journal of Neural Transmission · doi:10.1007/bf01243953 · Cited by 5 · cited 1× · see citing works
“The foregoing links cortisol and ACTH, but how does the hypothalamic-pituitary unit link to the adrenal gland? The conceptualization of CRH as a hypothalamic hormone (43) and a subsequent report that destruction of the suprachiasmatic nucleus (SCN) ablated circadian rhythms (44) led to an explosion of investigation in…”
Background
O-linked β-N-acetylglucosamine transferase is involved in pro-opiomelanocortin gene expression in mouse pituitary corticotroph AtT-20 cells
Makita, K., Takayasu, S., Usutani, M., Nakada-Nakayama, Y., Kageyama, K., Sugawara, A., & Daimon, M. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134407 · Cited by 4 · cited 1× · see citing works
“Data support the concept that recruitment of O-GlcNAc transferase prevents Pomc transcription by blocking phosphorylation (86).”
Background

Flagged first, then by citations

4 of the 170 references couldn’t be matched to a known paper.

Sorted by citations

Cushing Syndrome
Reincke, M., & Fleseriu, M. (2023) · JAMA · doi:10.1001/jama.2023.11305 · Cited by 273 · see citing works
Cushing's syndrome
Gadelha, M. R., Gatto, F., Wildemberg, L. E., & Fleseriu, M. (2023) · The Lancet · doi:10.1016/s0140-6736(23)01961-x · Cited by 183 · see citing works
Approach to the Patient: Diagnosis of Cushing Syndrome
Savas, M., Mehta, S., Agrawal, N., van Rossum, E. F. C., & Feelders, R. A. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac492 · Cited by 91 · see citing works
“Because of decreased glucocorticoid negative feedback effects, plasma ACTH levels will be inappropriately normal or elevated (generally > 20 pg/mL) in ACTH-dependent causes and low (generally < 10 pg/mL) in ACTH-independent causes of CS (70, 71).”
Background
An individualized approach to the management of Cushing disease
Fleseriu, M., Varlamov, E., Hinojosa-Amaya, J. M., Langlois, F., & Melmed, S. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00868-7 · Cited by 59 · see citing works
Cushing syndrome
Nieman, L. K., Castinetti, F., Newell-Price, J. D. C., Valassi, E., Drouin, J., Takahashi, Y., & Lacroix, A. (2025) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00588-w · Cited by 73 · see citing works
Self-citation
New advances in endocrine hypertension: from genes to biomarkers
Fernandes-Rosa, F. L., Boulkroun, S., Fedlaoui, B., Hureaux, M., Travers, S. A. A., Drossart, T., Favier, J., & Zennaro, M. (2023) · Kidney International · doi:10.1016/j.kint.2022.12.021 · Cited by 28 · see citing works
Paraneoplastic autoimmune hypophysitis: a novel form of paraneoplastic endocrine syndrome
Takahashi, Y. (2023) · Endocrine Journal · doi:10.1507/endocrj.ej23-0050 · Cited by 23 · see citing works
Impact of corticoid receptors on Alzheimer’s disease: a neuroendocrine perspective
Goel, F., Kumar, D., & Sharma, A. (2025) · Inflammopharmacology · doi:10.1007/s10787-025-01734-w · Cited by 19 · see citing works
“11βHSD1, predominantly expressed in the hippocampus, cortex, and other cognitive areas of the brain, acts as a reductase, catalyzing inactive cortisone to active cortisol by amplifying glucocorticoid signalling (Nieman 2022).”
Machine learning models for differential diagnosis of Cushing’s disease and ectopic ACTH secretion syndrome
Lyu, X., Zhang, D., Pan, H., Zhu, H., Chen, S., & Lü, L. (2023) · Endocrine · doi:10.1007/s12020-023-03341-7 · Cited by 15 · see citing works
“In areas with limited medical sources, physicians should consider so many factors that diagnostic and management efforts would be improved by arti ﬁ cial intelligence or machine learning platforms [2, 5].”
BackgroundMethodInfluential
Advances in Molecular Pathophysiology and Targeted Therapy for Cushing’s Disease
Takayasu, S., Kageyama, K., & Daimon, M. (2023) · Cancers · doi:10.3390/cancers15020496 · Cited by 11 · see citing works
“ing tumors are not inhibited even by high doses of glucocorticoids [29,30].”
Background
Comparison of Localization Methods in Cushing Disease—Could [11C]C-Methionine PET/CT Replace MRI or BIPSS?
Durma, A. D., Saracyn, M., Kołodziej, M., Zieliński, G., Zięcina, P., Narloch, J., & Kamiński, G. (2025) · Cancers · doi:10.3390/cancers17193147 · Cited by 3 · see citing works
“To confirm hypercortisolemia, a low-dose dexamethasone suppression test (LDDST) is recommended, along with ACTH concentration measurements to determine the source of cortisol excess [5,6].”
Case Report: Ectopic Cushing’s syndrome caused by a pancreatic neuroendocrine tumor managed through dual steroidogenesis inhibition and endoscopic ultrasound-guided ethanol ablation
Krzystek, Ł., Sagan, K. P., Andrysiak‍-Mamos, E., Retfiński, S., Buć, K., Marczak, W., Brzeska, A., Patalong-Wójcik, M., Żochowska, E., Dąbkowski, K., et al. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1700273 · Cited by 3 · see citing works
“Hormonal tests revealed high cortisol and ACTH levels, consistent with ACTH-dependent CS (21).”
Epigenetic implications in the pathogenesis of corticotroph tumors
Paes, T., Hofland, L. J., Iyer, A. M., & Feelders, R. A. (2025) · Pituitary · doi:10.1007/s11102-025-01522-3 · Cited by 3 · see citing works
“In contrast, it is weakly methylated in pituitary cells, even unmethylated in the AtT20 corticotroph cell line, leading to increased lev - els of POMC expression [ 26–28 ].”
Altered Gut Microbiome Composition in Dogs with Hyperadrenocorticism: Key Bacterial Genera Analysis
Kang, H. W., Kim, S.-W., Kim, S.-M., La, T.-M., Hyun, J., Lee, S., & Kim, J.-H. (2024) · Animals · doi:10.3390/ani14192883 · Cited by 2 · see citing works
Abordagem geral das características da Síndrome de Cushing
Weksler, F. L., Weksler, G. L., Portela, M. V. M., Nobre, C. F. A., & de Siqueira, E. C. (2023) · Revista Eletrônica Acervo Saúde · doi:10.25248/reas.e12852.2023 · Cited by 2 · see citing works
The impact of reproductive hormone changes on the immune response of patients with leukemia
Thabit, J. A., Almzaiel, A. J., Kadhim, M. I., & Alrufaie, M. M. (2023) · Anaesthesia Pain & Intensive Care · doi:10.35975/apic.v27i5.2317 · Cited by 2 · see citing works
“20,21 Another research by Mohammad et al. showed that cancer could impair fertility directly by affecting reproductive organs and indirectly by inhibiting reproductive function or delaying reproduction due to cancer treatment.”
Background
Adrenocorticotropin-Dependent Ectopic Cushing's Syndrome: A Case Report
Matos, A. R., Martins, A., Barbosa, M. J., Quinteiro, I., Faustino, D., Gameiro, R. D. S., & Azevedo, L. (2023) · Cureus · doi:10.7759/cureus.49124 · Cited by 1 · see citing works
“Additionally, medications to control cortisol levels may be necessary to manage the various comorbid conditions associated with CS, such as cardiovascular disease, diabetes, electrolyte imbalances, infections and thrombotic risk [4,5].”
Background
Utility of Simple and Non-Invasive Strategies Alternative to Inferior Petrosal Sinus Sampling and Peripheral CRH Stimulation in Differential Diagnosis of ACTH-Dependent Cushing Syndrome
Attri, B., Goyal, A., Kalaivani, M., Kandasamy, D., Gupta, Y., Agarwal, S., Shamim, S. A., Damle, N., Sharma, M. C., Jyotsna, V. P., et al. (2023) · Hormone and Metabolic Research · doi:10.1055/a-2236-0864 · Cited by 1 · see citing works
“Adrenocorticotrophic hormone (ACTH)-dependent CS accounts for 80–85 % of endogenous CS. Differentiation between the two subtypes of ACTH-dependent CS, that is, Cushing disease (CD) and ectopic ACTH syndrome (EAS), is a clinical challenge [1].”
Multicenter 30-Year Data on the 4-Mg Intravenous Dexamethasone Suppression Test in the Diagnosis of Cushing Syndrome
Jung, C., Derbyshire, M. M., Jauhar, N., Bennett, D., Topliss, D. J., Gogna, R., Markovic, N., Burgess, J. R., & Inder, W. J. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf188 · Cited by 1 · see citing works
“Patients with cyclic CS have phases of biochemical hypercortisolism (at least 2 peaks) interspersed with periods of eucortisolism or even hypocortiso-lism (at least 1 trough) [7, 8].”
Hypercortisolism: Causes, Consequences and Clinical Significance – A Review of Pathophysiology
Eldib, M., Fierro, F., Abad, M. O., & Correa, R. (2026) · Diabetes, obesity and metabolism · doi:10.1111/dom.71022 · Cited by 1 · see citing works
Exploration biochimique de la corticosurrénale
Pilon, A., & Laudat, A. (2022) · Revue Francophone des Laboratoires · doi:10.1016/s1773-035x(22)00246-5
Non-Invasive Biochemical Testing of ACTH-dependent Cushing's Disease: Do We Still Need Petrosal Sinus Sampling?
Espinosa-Cárdenas, E., García-Sáenz, M. R., Espinosa-de-los-Monteros, A. L., & Sosa, E. (2023) · Archives of Medical Research · doi:10.1016/j.arcmed.2023.102882
Синдром ектопічної АКТГ (огляд літератури та випадок із прак тики)
Guda, B. B., Tarashchenko, Y. М., Komisarenko, І. І., & Оstafiichuk, M. V. (2023) · Endokrynologia · doi:10.31793/1680-1466.2023.28-4.363
ĐẶC ĐIỂM XÉT NGHIỆM VÀ HÌNH ẢNH CỘNG HƯỞNG TỪ TUYẾN YÊN TRÊN BỆNH NHÂN MẮC HỘI CHỨNG CUSHING PHỤ THUỘC ACTH
Đỗ, L. A. T., Vũ, Đ. L., Trần, A. T., Nguyễn, Q. A., Lê, H. K., Nguyễn, T. T., & Nguyễn, C. T. (2023) · Vietnamese Journal of Radiology and Nuclear Medicine · doi:10.55046/vjrnm.53.1059.2023
Hipertensión arterial secundaria a Enfermedad de Cushing. Reporte de caso
Garay García, K. J., Flores Enderica, C. G., Andrade Sandoval, E. A., & Moreno Sierra, W. M. (2024) · doi:10.36015/cambios.v23.n1.2024.967
Cushing Syndrome and Subclinical Cushing Syndrome
Shibata, H. (2023) · Nihon Naika Gakkai Zasshi · doi:10.2169/naika.112.2129
Reconstructive Liposuction for Residual Lipodystrophy After Remission of Cushing’s Disease: A Case Report
Rosas, E. M., Flores, J. E. G., Zepeda, R. J. M., Muñóz, A. L. G., Carías, A. D. Z., López, P. E. N., Villaverde, A. A. A., Diaz, C., Méndez, M. C., & Ayala, L. R. (2025) · Cureus · doi:10.7759/cureus.86794
“Within this framework, plastic surgery - such as reconstructive liposuction - has proven to be a valuable therapeutic tool, offering physical restoration that can enhance self-confidence and promote social reintegration [4].”
Endocrine Disorders Associated with Obesity: Cushing's syndrome and Hypothyroidism
Thakur, R., Raj, M. P. N., Raju, D., Mishra, R., Mishra, A., & Mangaraj, S. (2025) · Health Leadership and Quality of Life · doi:10.56294/hl2025594
Consensus on the Diagnosis of Cushing’s Disease: A Collaborative Statement from the Korean Endocrine Society and Japan Endocrine Society
Lee, J., Fukuoka, H., Park, S. S., Hong, A. R., Kim, J. H., Chin, S. O., Baek, H.-S., Lim, D., Kageyama, K., Nishiyama, M., et al. (2026) · Endocrinology and Metabolism · doi:10.3803/enm.2025.2707
“The LDDST typically involves oral administration of 0.5-mg of dexamethasone every 6 hours for 2 days, followed by the measurement of serum cortisol [1].”
Influential
Effet de la modulation de l'équilibre calcique dans le cortex surrénalien
Fedlaoui, B. (2023) · doi:10.70675/45da36b4z01fdz47d6za4b6z8663da88f35d
Paraneoplastic hypercortisolism; mechanisms and management of lung cancer–induced ectopic Cushing syndrome
Bitaraf, M., & Memarian, M. (2026) · Journal of Preventive Epidemiology · doi:10.34172/jpe.39326
“In some cases, ACTH levels may be only moderately elevated, necessitating further investigation (25,42,43).”
Structure and Function of Ubiquitin-Specific Protease 8 and Its Role in the Development of ACTH-Secreting Pituitary Neuroendocrine Tumors
Nerubenko, E., Grineva, E. N., Kostareva, A. A., Tsoy, U. A., & Dmitrieva, R. I. (2026) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093026600338
“To this end, the genetic and molecular characteristics of ACTH-NETs have been actively investigated over the past decade [10–13].”
Carbamazepine masking Cushing disease: A case-based update on diagnostic pitfalls in hypercortisolism
Peixe, C. R., Lopes, M. V., Severino, M. D. G., Gomes, A. C., & Nobre, E. L. (2026) · Endocrinología Diabetes y Nutrición · doi:10.1016/j.endinu.2026.501906
An Overview of Cushing’s Syndrome Caused by Ectopic Adrenocorticotropin Secretion
Ilias, Ι., Maggio, V., Ispas, S., Hoffmann, K., Paczkowska, A., Арманович, А. А., Rangraze, I. R., Wali, A. F., Talath, S., Rabbani, S. A., et al. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15208192
“Molecular studies provide evidence that ectopic aberrant activation of the POMC gene promoter, possibly through hypomethylation or the action of ectopic transcription factors that are not typically expressed in these tissues, is responsible for this pathological expression [12,16].”
Influential

Authors: Nieman, L. K.
Affiliations: National Institutes of Health (US)
Corresponding author: Nieman, Lynnette K
ORCID: Nieman, Lynnette K
Venue: Endocrine Reviews
Publisher: The Endocrine Society
Published: 2021-11-29
Volume: 43
Issue: 5
Pages: 852-877
ISSN: 0163-769X (ISSN-L)
1945-7189
DOI: 10.1210/endrev/bnab046
PMC: PMC9512149
OpenAlex: W3215011458
Cited by: 33
References: 170
Citations by year: 2026: 6 · 2025: 8 · 2024: 1 · 2023: 16 · 2022: 2
FWCI: 0.77
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: public-domain
Locations: Endocrine Reviews (publishedVersion, public-domain)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: NIH (1 ZIA DK075121-06)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
Keywords: Cushing's syndrome, ACTH-dependent Cushing's syndrome, Cushing's disease, ectopic ACTH syndrome, ACTH regulation, corticotrophs, hypercortisolism, differential diagnosis
MeSH terms: Adrenal Glands, Adrenocorticotropic Hormone, Cushing Syndrome, Diagnosis, Differential, Glucocorticoids, Humans, Hydrocortisone

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Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing’s Syndrome

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