Cortisol metabolites

Chronic liver disease reduces cortisol clearance and the production of urinary metabolites. Cortisol concentrations are elevated by acute ingestion of alcohol. Individuals with alcoholic cirrhosis have normal to elevated basal cortisol concentrations, blunted circadian rhythms, and prolonged clearance rates. 

The groups of steroids present will be discussed under the following headings 3j8-hydroxy-A steroids, progesterone and progesterone metabolites, cortisol and its metabolites, testosterone and the 17-OS, and the estrogens. 

Although MR also binds glucocorticoids, its main ligand in classical mineralocorticoid target tissues such as kidney and colon is aldosterone ( d 1.3 nM). This can be granted to the ability of 11 (3-hydioxysteroid dehydrogenase type II (11 (3-HSD II) to convert active cortisol into its inactive metabolite cortisone in these tissues. Since aldosterone is no substrate for this enzyme it can readily bind to MR, leading to exclusive occupation of the receptor by aldosterone. In contrast, no such mechanism exists in brain and presumably... 

Theory Cortisol (or hydrocortisone) was introduced in the year 1951, for the treatment of rheumatoid arthritis. It has a significant effect on protein metabolism. It also exerts widespread effects on carbohydrates, lipid and protein synthesis (or anabolism). The cardinal side effects such as excessive potassium excretion and sodium retention, enhanced gastric acidity, oedema, psychosis and negative nitogen balance are some of the exaggerated manifestations of the normal metabolite functions of cortisol. 

M12. Morey, K. S., and Litwack, G., Isolation and properties of cortisol metabolite binding proteins of rat liver cytosol. Biochemistry 8, 4813-4821 (1969). 

The slight conformational modification of the A ring (revealed by X-ray diffraction), which probably comes from an interaction between the fluorine on C-9 and the axial OH on C-1, could contribute to the differences of affinity. However, X-ray structure of the cocrystallized form of fluorocortisol with the glucocorticoid receptor does not explain the impact of fluorine on the increase in affinity (cortisol = 0.67 pM versus 9a-fluorocortisol Xj = 0.027 The fluorine at C-9 can reduce the oxidative metabolism of hydroxyl-11. Oxidation of OH-11 into ketone is fast for the cortisol and is accompanied by the loss of biological activity. However, this hypothesis would imply metabolites to contribute to the mineralocorticoid activity. 

Cortisone and hydrocortisone (cortisol) are enzymatically interconvertible, and so one finds metabolites from both. Glucocorticoids having a ketone group at Cn (e.g., cortisone, prednisone, and meprednisone) must be reduced in the liver to their corresponding 11 J-hydroxyl analogs (hydrocortisone, prednisolone, and meprednisolone) in order to be pharmacologically active. 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

Table 5.3.2 The gas chromatography (GC)-MS urinary free cortisol (UFFj and metabolite panel internal standards, monitored ions, and normal excretions...

The synthesis of adrenal steroids and major excreted metabolites is illustrated in Fig. 5.3.1. Little secreted steroid product is excreted unchanged and most of the catabolism takes place in the liver, although cortisol metabolism by the kidney is clinically important and microbial metabolism in the gut can be quantitatively significant. The major metabolic transformations of hormonal steroids and precursors are detailed by Makin [54] and summarized in Fig. 5.3.2. GC-MS steroid profiling is the technique of choice for measurement of important urinary constituents. 

Profile analysis is very useful for diagnosing patients with the mild, nonclassical, late-onset form of the disorder. They can have normal cortisol metabolite excretion, but ratios of 17-OHP and 21-dihydrocortisol metabolite to cortisol metabolite excretions are elevated. Typically, if the PT + 17HP Fs ratio is > 0.34 and the PTONE Fs ratio is greater than 0.05, nonclassical 21-hydroxylase disorder should be considered [85]. 

HD 21 -Hydroxylase deficiency 5PT 5-pregnene-3/ ,17a,20a-triol, 160HDHEA 16a-hydroxyDHEA, 17HP 17a-hydroxy-pregnanolone, d days, Fs cortisol metabolites, m months, yrs years, Pat patient, PTONE pregnanetriolone... 

P represents mean values for nine patients, C are normal values for different age groups, as follows Cl 2 months—5 years C2 5-10 years C3 11-16 years C4 2 months—16 years C5 2 months—10 years, C6 2 months-16 years. The first ratio focuses on 17,20-lyase activity (andro-gens/C21-precursors), which is suppressed in the condition compared to normal controls. The remaining ratios illustrate precursor metabolites increased by attenuated 17- and 21-hydroxyl-ation, relative to metabolites of the product cortisol. 

Abbreviations Bs corticosterone metabolites, Fs cortisol metabolites, 17HP 17a-Hydroxypreg-nenolone, 5-PD pregnenediol, PTONE pregnanetriolone... 

Patients with a complete block have almost undetectable excretions of cortisol metabolites. The major urinary steroids are androsterone, etiocholanolone, tetrahydro-... 

Attenuated conversion of cortisol to cortisone in AME causes inhibition of cortisol synthesis (negative feedback), and excretion of total cortisol metabolites is typically 50% lower than normal. The condition is most commonly diagnosis by determining... 

The THEiTHF + 5aTHF ratio is commonly greater than 15 in these disorders, the opposite to AME syndrome. While the ratio of saturated steroids demonstrates a high 11-oxo l 1/1-hydroxy ratio, this is not the case for steroids retaining a - -4-ene structure. The F E ratio is normal or elevated (i.e., > 1 Table 5.3.9). Steroid profile analysis also typically reveals an elevated excretion of DHEA and other androgen metabolites. Clearly the excessive ACTH production resultant from an apparent cortisol deficiency is responsible for the elevated adrenal androgen production, which in turn is responsible for female virilization and other manifestations of polycystic ovary syndrome. 

Overall, with the exception of 18-oxygenated cortisol metabolites, the patients with GRA we ve studied have normal excretions of all cortisol metabolites. THAldo excretion is almost always elevated (> 50 pg/24 h), as expected. 

---