Cortisol

Antalarmin is a CRH/CRF antagonist, developed as an anxiety treatment: it blocks pro-cortisol signaling to the pituitary. Comparison with other identified CRH antagonists (PMID 22033745) suggests adenylosuccinate may be a physiologic CRH antagonist.

Other anti-cortisols (top row) may share active sites with CRH antagonists.

CBZ and lamotrigine, both of which are expected to act via adenosine deaminase inhibtion, inhibit CRH PMID 21947356?

While guanfacine and clonidine are anti-cortisol and used to treat ADHD, atomoxetine (also for ADHD) increases cortisol PMID 17446206.

Add lofexidine?

I recently attended a case of chronic treatment-resistant hypersexual psychotic mania with physical exam and lab findings consistent with excess cortisol: a microadenoma/ growth was found on pituitary MRI. 

Chronic inhibited adenylosuccinate synthase may lead to inadequate inhibition of pro-cortisol pituitary cell growth.

The patient’s complaints clinically responded to anti-cortisol ziprasidone PMID 16120074, clonidine PMID 6302442, and amlodipine PMID 8501151. Hypersexuality is sometimes attributed to testosterone excess, but did not respond to anti-DHT spironolactone or finasteride in this case.

Anti-cortisols (e.g. clonidine, guanfacine) may also help non-psychotic sexual compulsions/ complaints while preserving sexual function.

In normal physiology, cortisol is pulsed, consistent with interrupted feedback via adenylosuccinate synthase:

• Stress (e.g. before a test) temporarily decreases need for sleep, (inhibits adenosine production). After the test, excess inosine metabolites are metabolized into extra adenosine, resulting in catch-up sleep

• Sexual arousal temporarily decreases need for sleep while IMP increases engorgement via PDE5, followed by release, then afterglow (PMID 28485699), possibly the experience of a pulse of CRH inhibition via conversion of a pulse of IMP to adenylosuccinate, often followed by sleep/ conversion to adenosine.

Testing can be difficult, especially if symptoms are already partially controlled with anti-cortisol ziprasidone, clonidine, or guanfacine.  There is no way to adjust test results for concurrent therapies. Consulting with expert endocrinologists, I have repeatedly been told that there is no definitive testing for hypercortisolism: that all tests relating to hypercortisolism, but that hospitalization or psychiatric distress will be seen as skewing the results/ making them uninterpretable. In cases in which (likely pituitary) tumors are found, treatment can be definitive, but symptoms may persist following resection for months. PMID XXXX. Alternatively, symptomatic treatment may affect purine balance, inhibiting adenoma growth.

Consistent with immune-modulating effects of purine disturbances, patients with hypercortisolism are particularly succeptible to fungal infections PMID 24470886, which may have led to the surprising discovery of ketoconazole, an antifungal, as a treatment for hypercortisolism. However, due to hepatotoxicity, ketoconazole is no longer first-line. IMG

I have noticed a clinical association between patients with evidence of hypercortisolism and listed chlorpromazine allergy: the apparent mechanism suggests that chlorpromazine would increase IMP by inhibiting Io-i conversion.

Ziprasidone seems to perform well when paired with CBZ/OXC, which is expected to activate PNP, reducing manic psychosis.

Gout is a listed side effect of anti-cortisol ziprasidone. 

Gout’s natural history connects gout flares to cortisol’s daily nadir: PMID 25504842.

In my clinical experience, anti-cortisols can cause gout flare-ups, guanfacine more frequently than clonidine. 

This is consistent with cortisol inhibition of adenylosuccinate synthase and IMP’s similar structure to allopurinol/ likely similar mechanism as a xanthine oxidase inhibitor.

In patients with a history of gout, start allopurinol 300mg QHS with first-dose at least a few hours prior to anti-cortisol initiation, lean towards clonidine rather than guanfacine.

Increased dietary purines are considered problematic for gout, however, ketogenic diet, expected to be high in purines due to high frequency of high-purine meat, is shown to decrease the inflammatory process associated with gout PMID 28249154, is hypothesized to be helpful for gout 32810124 despite increase in uric acid associated with higher purine intake 2661288.

Allopurinol is metabolized into oxypurinol, xanthine analogue, indicating competitive inhibition at the first XO reaction. 5658870, 22300439

There is a recognized phenomenon attributed to a history of alcohol dependence that results in chronic elevated levels of cortisol, but not to the extent that it would be concerning for adrenal or pituitary tumor. The central obesity colloquially referred to as a beer belly is consistent with this finding.  IMG

Alcohol is known to increase hypoxanthine (i) and xanthine (x) production PMID XXXX, with significantly increased risk of gout suggesting that HGPRT salvage is bypassed in this case. Cortisol may be consistently suppressed by adenylosuccinate, intermediate between IMP and AMP. Increased conversion from Io to i, with subsequent decrease in IMP (bypassed HGPRT) would result in decreased IMP and decreased adenylosuccinate, increasing cortisol.  IMG

Clinically, I have seen recovered alcoholics, years since their most recent admitted use, who continue to demonstrate signs and symptoms of psuedocushing's until treated by an anti-cortisol. More commonly, the increased anxiety, decreased need for sleep associated with excess cortisol seem to contribute to discomfort being sober and subsequent relapse. IMG

Excess cortisol reduces AMP/SAM-e, which reduces testosterone, which may contribute to traditionally recognized muscle wasting.

PTSD and depression are closely linked to cortisol, specifically characterized by insomnia (often until 3am, the cortisol's accepted nadir) and anxiety. Lack of adenosine as a peripheral vasodilator may contribute to HTN: in my clinical experience, diastolic and HR tend to be tightly correlated, within 5-7 points.

Naltrexone has a pro-cortisol effect: mechanism unknown.

Sertraline, despite its use as an antidepressant, has a pro-cortisol effect, consistent with adenosine-analogue product suppression of adenylosuccinate synthase open-label PMID 11979064, placebo-controlled dexamethasone suppression PMID 21617914.

In contrast, fluoxetine decreases free cortisol PMID 22429479, 20466437, an effect correlated with CRH receptor polymorphisms and response 25086452, despite competing with cortisol for binding to albumin PMID 24250455.

Fluphenazine also increases cortisol 17126974: when patients on long-term fluphenazine show increased PMA, nightmares, or racing thoughts, decreasing dose of fluphenazine and/or adding clonidine can be helpful.