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ACTH

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ACTH

ACTH is produced in the pituitary gland, the second stage of the HPA axis.
Pituitary (2nd stage): ACTH

1. Formation and inhibition of ACTH

1.1. Increased ACTH formation due to

1.1.1. CRH

  • Injected CRH causes1
    • ACTH blood plasma response maximum after 15 min
    • Cortisol blood plasma maximum after 30 minutes
    • Cortisol saliva maximum after 45 minutes
  • Injected CRH and vasopressin causes1
    • ACTH blood plasma response maximum after 15 min
    • Cortisol blood plasma maximum after 45 minutes
    • Cortisol saliva maximum after 60 minutes

1.1.2. Interleukin-2 (IL-2)

Interleukin-2 from T lymphocytes increases ACTH secretion.2

1.1.3. Tumor Necrosis Factor (TNF)

Tumor necrosis factor (TNF) of macrophages increases ACTH secretion.2

1.1.4. Vasopressin

Vasopressin increases ACTH secretion.3

1.1.5. Delta(9)-tetrahydrocannabinol

Delta(9)-tetrahydrocannabinol increases ACTH release.3

1.1.6. Adrenalin

  • Adrenalin4
    • Adrenaline from the adrenal medulla stimulates ACTH secretion by binding to α1-adrenergic receptors on corticotroph cells of the anterior pituitary lobe5
    • Adrenaline stimulates CRF-induced cAMP accumulation, which acts as a “second messenger” of ACTH secretion5
    • Adrenaline stimulates ACTH more strongly than noradrenaline5
    • Adrenaline co-modulates basal, peak, and mean ACTH concentrations and determines the level of ACTH pulse amplitude alone6

1.1.7. Norepinephrine

Norepinephrine increases ACTH secretion5 (possibly only indirectly?).4

1.1.8. Chronic inhibition of nitric oxide synthase

Chronic inhibition of nitric oxide synthase increases ACTH secretion.

1.1.9. Glucagon-like peptide 1 (GLP-1)

Glucagon-like peptide 1 (GLP-1) injected into the medial paraventricular nucleus of the hypothalamus increases ACTH, but not when injected into the amygdala.7

1.2. Reduced ACTH formation due to

1.2.1. Cortisol (feedback loop)

  • Cortisol inhibits the pituitary gland and thus the secretion of ACTH
  • Negative feedback needs several hours5
  • Cortisol causes inhibition of pro-opiomelanocortin (POMC) transcription by binding the glucocorticoid receptor-steroid complex to DNA. Proteolytic cleavage of POMC decreases ACTH in the pituitary gland.5
  • Desipramine reverses the negative feedback by cortisol to a positive one, and Resipin reverses the reversal in Cushing’s disease.8
  • If cortisol is given without diurnal rhythm fluctuations, this causes a reduced inhibition of ACTH release.9 This indicates that disturbances of the circadian system can trigger excessive ACTH release.
    In our understanding, ADHD-HI and ADHD-C are often characterized by shutdown problems of the HPA axis.
  • Long-term cortisone treatment causes a strong reduction to cessation of ACTH production by the pituitary gland.10 According to our understanding, this could be a long-term consequence of unrestrained ACTH secretion by eliminating the diurnal cortisol rhythm.

1.2.2. Oxytocin

Oxytocin reduces ACTH release.
Blockade of brain oxytocin receptors by intracerebral administration of oxytocin antagonists to the paraventricular nucleus of the hypothalamus increased HPA axis activity and basal ACTH and cortisol blood levels in rats, whereas stress-induced blood levels of ACTH and cortisol were decreased. Stress-induced anxiety behavior did not change. Administration of oxytocin antagonists into the medio-lateral septum did not produce a basal ACTH change but reduced stress-induced ACTH elevation to emotional stress but not to combined emotional and physical stress. Administration of oxytocin antagonists to the amygdala did not produce basal or stress-induced changes in the HPA axis.1112
In summary, this means that oxytocin downregulates the HPA axis by inhibiting the hypothalamus and pituitary gland and thereby

  • Decreased basal blood levels of ACTH and cortisol (which is typical in many mental disorders)
  • As well as reduces stress-induced blood levels of ACTH and cortisol (which is typical in externalizing mental disorders).

1.2.3. Alcoholism

Excessive alcohol consumption alters the HPA axis,13 with changes already occurring at the CRH and ACTH levels of the HPA axis in the form of decreased hormone response levels.14

2. Effect of ACTH

2.1. Neuroendocrine effect of ACTH

  • ACTH acts on the adrenal cortex
    • Promotion of
      • Cortisol production
      • DHEA production
  • ACTH acts on the PFC
    • Increases the dimensional complexity of the EEG,15 which reduces inhibition between competing active cell assemblies, producing less focused perception
    • Decreases the negative difference wave (processing negativity) for different signals on the left and right ear,16 which leads to an increased attention to irrelevant stimuli

2.2. Behavioral effect of ACTH

ACTH16

  • Worsens
    • The selection of attention (paying attention to individual stimuli, blocking out others)
    • The focus of attention
    • Increases distractibility
  • Leaves unchanged
    • Divided attention (observe all stimuli)

The reduction in attentional focus is induced by ACTH given intravenously as well as intranasally.
ACTH triggers a special processing mode of the cortex characterized by a further allocation of resources in the processing of stimuli.15

ACTH impaired behavioral performance on convergent thinking tasks when presented orally. ACTH appears to reduce inhibitory control of the PFC, which is necessary for orderly analytic thinking.15

3. ACTH details

  • In children with ADHD, altered basal ACTH levels were not found in any subtype.1718
  • Augmentative (supportive) treatment with an ACTH 4-9 analog (Semax) for ADHD is discussed.19 Studies show that MPH (alone) shows significantly higher improvements than an ACTH 4-9 analog (alone).20
  • Chronic inhibition of nitric oxide synthase increases the ACTH response to exercise and decreases the ACTH response to the stressor constraint/movement restriction. This suggests stressor-specific modulation of ACTH by nitric oxide synthase.21
  • Unlike cortisol (see Cortisol: Details on Cortisol), plasma ACTH levels secreted in response to a stressor do not differ by personality trait.22
    • In healthy adults, Novelty Seeking does not correlate with ACTH levels.23
  • Epilepsy is treated with ACTH administration.24
    • In a study in rats, ACTH administration at higher interictal spikes improved attention problems.25
  • Early experiences of stress can cause disturbances in the ACTH receptor systems that prevent extinction of the fear experience, causing long-term stress. This can be ameliorated by ACTH administration.26 In our opinion, the alteration of ACTH receptor systems could possibly be a consequence of a downregulation/upregulation response. ⇒ Downregulation / Upregulation
  • SHR rats, considered an animal model of ADHD-HI, show increased ACTH and decreased basal cortisol levels.27
  • ACTH treatment promoted hyperactivity in some rats.28

4. Changes in ACTH due to chronic stress

Chronic stress causes in terms of ACTH:

  • ACTH elevated in the pituitary gland293031
  • ACTH response to CRH increased3233
  • Basal blood ACTH levels unchanged343536

It should always be kept in mind that momentary reports as consequences of chronic stress may only represent a transitional stage of receptor down- or upregulation, depending on the duration of stress exposure (compare the phase model of stress development).


  1. Schlotz, Kumsta, Layes, Entringer, Jones, Wüst (2008): Covariance Between Psychological and Endocrine Responses to Pharmacological Challenge and Psychosocial Stress: A Question of Timing; Psychosomatic Medicine: September 2008 – Volume 70 – Issue 7 – p 787-796, doi: 10.1097/PSY.0b013e3181810658

  2. Gutscher (2002): Der Glucocorticoidrezeptor des Schweins: Herstellung und Charakterisierung eines polyklonalen Antiserums. sowie Studien zur Verteilung des GCR im Testinaltrakt von Ebern und Kastraten, Dissertation, Seite 16 mwNw

  3. Steiner, Wotjak (2008): Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res. 2008;170:397-432. doi: 10.1016/S0079-6123(08)00433-0.

  4. Plotsky, Cunningham, Widmaier (1989): Catecholaminergic modulation of corticotropin-releasing factor and adrenocorticotropin secretion. Endocr Rev. 1989 Nov;10(4):437-58.

  5. Brechtel (1998): Das parasympathikotone Übertrainingssyndrom – Ein Modell zur Maladaption an Streß – Diagnostik und Pathophysiologie. Dissertation. Seite 203, mit weiteren Nachweisen

  6. Brechtel (1998): Das parasympathikotone Übertrainingssyndrom – Ein Modell zur Maladaption an Streß – Diagnostik und Pathophysiologie. Dissertation. Seite 204, mit weiteren Nachweisen

  7. Kinzig, D’Alessio, Herman, Sakai, Vahl, Figueiredo, Murphy, Seeley (2003): CNS Glucagon-Like Peptide-1 Receptors Mediate Endocrine and Anxiety Responses to Interoceptive and Psychogenic Stressors. Journal of Neuroscience 16 July 2003, 23 (15) 6163-6170; DOI: https://doi.org/10.1523/JNEUROSCI.23-15-06163.2003

  8. Fehm, Voigt, Pfeiffer: Die Bedeutung des Zentralnervensystems in der Ätiologie des Morbus Cushing, in: Deutsche Gesellschaft der inneren Medizin, 86. Kongress: Gehalten zu Wiesbaden vom 13. bis 17. April 1980; Seite 62

  9. Jacobson, Akana, Cascio, Shinsako, Dallman (1988): Circadian variations in plasma corticosterone permit normal termination of adrenocorticotropin responses to stress. Endocrinology. 1988 Apr;122(4):1343-8. doi: 10.1210/endo-122-4-1343. PMID: 2831028.

  10. https://www.endokrinologie.net/krankheiten-nebenniereninsuffizienz.php

  11. Neumann, Wigger, Torner, Holsboer, Landgraf (2000): Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus. J Neuroendocrinol. 2000 Mar;12(3):235-43.

  12. Neumann, Krömer, Toschi, Ebner (2000): Brain oxytocin inhibits the (re)activity of the hypothalamo-pituitary-adrenal axis in male rats: involvement of hypothalamic and limbic brain regions. Regul Pept. 2000 Dec 22;96(1-2):31-8.

  13. Wand, Dobs (1991): Alterations in the hypothalamic-pituitary-adrenal axis in actively drinking alcoholics. J. Clin. Endocrinol. Metab. 1991, 72: 1290-1295.

  14. Inder, Joyce, Ellis, Evans, Livesey, Donald (1995): The effects of alcoholism on the hypothalamic-pituitary-adrenal axis: interaction with endogenous opioid peptides. Clin. Endocrinol. (Oxf.) 1995, 43: 283-290. n = 18

  15. Mölle, Pietrowsky, Fehm, Born (1997): Regulation of human thought by neuropeptide ACTH 4-10: An analysis of the EEG’s dimensional complexity. NeuroReport: August 18th, 1997 – Volume 8 – Issue 12 – p 2715–2720

  16. Lautenbacher, Gauggel (2013): Neuropsychologie psychischer Störungen, Springer, Seite 135

  17. Ma, Chen, Chen, Liu, Wang (2011): The function of hypothalamus-pituitary-adrenal axis in children with ADHD. Brain Res. 2011 Jan 12;1368:159-62. doi: 10.1016/j.brainres.2010.10.045. n = 158

  18. Chen, Chen, Liu, Lin, Wei, Chen (2009): [Function of the hypothalamus-pituitary-adrenal axis in children with attention deficit hyperactivity disorder]. Zhongguo Dang Dai Er Ke Za Zhi. 2009 Dec;11(12):992-5. Chinese. PMID: 20113607. n = 158

  19. Tsai (2007): Semax, an analogue of adrenocorticotropin (4-10), is a potential agent for the treatment of attention-deficit hyperactivity disorder and Rett syndrome. Med Hypotheses. 2007;68(5):1144-6.

  20. Butter, Lapierre, Firestone, Blank (1984): Efficacy of ACTH 4-9 analog, methylphenidate, and placebo on attention deficit disorder with hyperkinesis. Prog Neuropsychopharmacol Biol Psychiatry. 1984;8(4-6):661-4.

  21. Jankord, McAllister, Ganjam, Laughlin (2009): Chronic inhibition of nitric oxide synthase augments the ACTH response to exercise; Am J Physiol Regul Integr Comp Physiol. 2009 Mar; 296(3): R728–R734; doi: 10.1152/ajpregu.90709.2008; PMCID: PMC2665849

  22. Tyrka, Wier, Price, Rikhye, Ross, Anderson, Wilkinson, Carpenter (2008): Cortisol and ACTH Responses to the Dex/CRH Test: Influence of Temperament; Horm Behav. 2008 Apr; 53(4): 518–525; doi: 10.1016/j.yhbeh.2007.12.004; PMCID: PMC2637444; NIHMSID: NIHMS45728

  23. Tyrka, Wier, Anderson, Wilkinson, Price, Carpenter (2007): Temperament and response to the Trier Social Stress Test; Acta Psychiatr Scand. 2007 May; 115(5): 395–402; doi: 10.1111/j.1600-0447.2006.00941.x; PMCID: PMC4469468; NIHMSID: NIHMS698884

  24. Massey, Lerner, Holmes, Scott, Hernan, (2016):ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures; Front Neurol. 2016; 7: 65. doi: 10.3389/fneur.2016.00065; PMCID: PMC4852169

  25. Hernan, Alexander, Lenck-Santini, Scott, Holmes (2014): Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH. PLoS One. 2014 Feb 24;9(2):e89812. doi: 10.1371/journal.pone.0089812. eCollection 2014.

  26. Massey, Lerner, Holmes, Scott, Hernan, (2016): ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures; Front Neurol. 2016; 7: 65. doi: 10.3389/fneur.2016.00065; PMCID: PMC4852169

  27. King, Barkley, Delville, Ferris (2000): Early androgen treatment decreases cognitive function and catecholamine innervation in an animal model of ADHD. Behav Brain Res. 2000 Jan;107(1-2):35-43.

  28. Kim, McGee, Czeczor, Walker, Kale, Kouzani, Walder, Berk, Tye (2016): Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects. Transl Psychiatry. 2016 Jun 21;6(6):e842. doi: 10.1038/tp.2016.84.

  29. López-Calderón, Ariznavarreta, Chen (1991): Influence of chronic restraint stress on proopiomelanocortin mRNA and β-endorphin in the rat hypothalamus, J Mol Endocrinol 1991:7:197-204.

  30. Young, Akil (1985): Corticotropin-Releasing Factor Stimulation of Adrenocorticotropin and β-Endorphin Release: Effects of Acute and Chronic Stress, Endocrinology, Volume 117, Issue 1, 1 July 1985, Pages 23–30, https://doi.org/10.1210/endo-117-1-23

  31. Hashimoto, Suemaru, Takao, Sugawara, Makino, Ota (1988): Corticotropin-releasing hormone and pituitary-adrenocortical responses in chronically stressed rats; Regulatory Peptides; Volume 23, Issue 2, November 1988, Pages 117-126; https://doi.org/10.1016/0167-0115(88)90019-5

  32. Uehara, Habara, Kuroshima, Sekiya, Takasugi, Namiki (1989): Increased ACTH response to corticotropin-releasing factor in cold-adapted rats in vivo; Am J Physiol 1989:257: E336-E339. 1 SEP 1989 https://doi.org/10.1152/ajpendo.1989.257.3.E336

  33. Marti, Gavaldà, Gómez, Armario (1994): Direct Evidence for Chronic Stress-Induced Facilitation of the Adrenocorticotropin Response to a Novel Acute Stressor. Neuroendocrinology 1994;60:1-7

  34. Armario, Hidalgo, Giralt (1988): Evidence that the Pituitary-Adrenal Axis Does Not Cross-Adapt to Stressors: Comparison to Other Physiological Variables. Neuroendocrinology 1988;47:263-267

  35. Martí, Octavi, Jolín, Armario (1993): Effect of regularity of exposure to chronic immobilization stress on the circadian pattern of pituitary adrenal hormones, growth hormone, and thyroid stimulating hormone in the adult male rat; Psychoneuroendocrinology, Volume 18 , Issue 1 , 67 – 77

  36. Chappell, Smith, Kilts, Bissette, Ritchie, Anderson, Nemeroff (1996): Alterations in corticotropin-releasing factor-like immunoreactivity in discrete rat brain regions after acute and chronic stress; Journal of Neuroscience 1 October 1986, 6 (10) 2908-2914