Effect of glucocorticoid excess on the cortisol/cortisone ratio

OBJECTIVE: The conversion of cortisol, which binds avidly to the mineralocorticoid receptor, to cortisone, which no longer has mineralocorticoid function, is predominantly catalyzed by the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD 2). It was the objective of the present study to examine the impact of different forms of glucocorticoid excess on the cortisol/cortisone ratio and to differentiate their role in the genesis of hypertension. DESIGN AND METHODS: Plasma cortisol and cortisone levels were determined in 12 adults with Cushing's disease, 12 adults with hypercortisolism due to an adrenal tumor, and 20 healthy volunteers before and after an intravenous ACTH test, using specific radioimmunoassays after automated Sephadex LH 20 chromatography. RESULTS: The cortisol/cortisone ratios were significantly higher in patients with Cushing's disease (13.9 +/- 1.1), adrenal tumors (11.5 +/- 2.3), and in healthy volunteers after ACTH stimulation (14.1 +/- 2.0) than in untreated controls (6.0 +/- 0.5) (P < 0.001, P < 0.05, and P < 0.001, respectively). Similar differences were seen for cortisol plasma concentrations, whereas cortisone concentrations did not differ among the groups. CONCLUSIONS: Our data suggest that the excessive mineralocorticoid effects in patients with hypercortisolism are inflicted by elevated cortisol/cortisone ratios possibly due to an insufficient conversion of cortisol to cortisone by 11beta-HSD 2. This may provide a possible explanation for the occurrence of hypertension. This effect seems to be independent of the role of ACTH in the mechanism of hypercortisolism.     

The serum cortisol:cortisone ratio in the postoperative acute-phase response

OBJECTIVE: In a previous cross-sectional pilot investigation, an increase in the ratio of active cortisol to inactive cortisone in serum has been found as a general phenomenon during the acute-phase response. The aim of the present study was to further characterize this alteration of cortisol metabolism in patients undergoing elective cardiac bypass surgery. METHODS: Cortisol and cortisone were quantified by use of liquid-chromatography tandem mass spectrometry in sera that were sampled preoperatively and on the first 4 postoperative days (POD) from 16 patients undergoing aortocoronary bypass grafting (7.00 a.m.). RESULTS: The median serum cortisol concentration peaked on the first POD and then decreased statistically significantly until the end of the observation period: preoperatively, 245 nmol/l (IQR 198-331); 1st POD, 532 nmol/l (IQR 409-678 ); 4th POD, 373 nmol/l (IQR 306-493); p for trend = 0.019. In contrast, the cortisol:cortisone ratio was constantly increased approximately twofold on all POD compared to preoperative sampling: preoperatively, 5.4 (IQR 5.0-7.2); 1st POD, 11.3 (IQR 9.2-13.6); 4th POD, 9.9 (IQR 7.7-11.0), with no significant trend of normalization. CONCLUSION: Following major surgery, the substantial increase in the serum cortisol:cortisone ratio - reflecting a shift in the overall set-point of 11beta-hydroxysteroid dehydrogenase activity - is more sustained than the increase in serum cortisol; the increase in the cortisol:cortisone ratio seems to be a long-term phenomenon of the activation of the hypothalamic-pituitary-adrenocortical system by surgical stress and systemic inflammation.     

Increased ratio of serum cortisol to cortisone in acute-phase response

BACKGROUND/OBJECTIVES: 11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes convert cortisol into inactive cortisone and vice versa. While 11beta-HSD type 2 (mainly localized in the kidney) unidirectionally inactivates cortisol to cortisone, type I isoform (mainly localized in the liver) acts bidirectionally and can thus potentially restore cortisone to active cortisol. The aim of this pilot study was to investigate whether the serum cortisol:cortisone ratio is altered during the acute-phase response, possibly due to altered modulation of 11beta-hydroxysteroid dehydrogenase isoforms. METHODS: Using liquid chromatography electrospray tandem mass spectrometry, cortisol and cortisone were measured in the serum of hospitalized patients with normal and abnormal CRP concentrations, the latter indicating acute-phase response. Fifteen unselected samples were analyzed, all with a CRP concentration within one of the following ranges to cover a wide range of CRP concentrations evenly: <5, 5-20, 21-50, 51-100, 101-200, and >200 mg/l. RESULTS: In the heterogeneous study population, increased CRP concentrations significantly correlated with an increased cortisol:cortisone ratio (p < 0.001; r = 0.65, Spearman correlation coefficient). This correlation was independent of increased serum cortisol concentrations found by multivariate regression analysis. The median ratio was 6.4 (interquartile range 5.5-7.4; n = 30) in patients with a CRP concentration < or =20 mg/l, and 11.2 (interquartile range 8.8-13.9; n = 60) in patients with CRP >20 mg/l (p < 0.01). CONCLUSION: The balance between serum cortisol and cortisone is altered during acute-phase response with a shift towards active cortisol, suggesting that 11beta-HSD isoenzymes play a role in the modulation of systemically available cortisol during acute illness.     

Changes in human EEG caused by low level modulated microwave stimulation

This study focuses on the effect of low level microwave radiation on human EEG alpha and theta rhythms. During the experiment, 20 healthy volunteers were exposed to a 450 MHz microwaves with 7 Hz on-off modulation. The field power density at the scalp was 0.16 mW/cm2. Signals from the following EEG channels were used: FP1, FP2, P3, P4, T3, T4, O1, and O2. The experimental protocol consisted of one cycle of short term photic and ten cycles of the repetitive microwave stimulation. The changes caused by photic as well as microwave stimulation were more regular on the alpha rhythm. In the majority of cases, photic stimulation caused changes in the EEG energy level in the occipital and microwave stimulation in the frontal region. Our experimental results demonstrated that microwave stimulation effects became apparent, starting from the third stimulation cycle. Changes varied strongly from subject to subject. Therefore, photic and microwave exposure did not cause statistically significant changes in the EEG activity level for the whole group. For some subjects, clear tendencies of changes in microwave on-off cycles were noticeable.     

Acne conglobata; use of cortisone and corticotropin in therapy

Six patients with acne conglobata were treated with cortisone and adrenocorticotropic hormone. Definite immediate improvement was observed in all of them. In three cases control of the disease was maintained on relatively low doses of steroid. In one case there was response to superficial x-ray therapy after the acute phase of the disease had subsided in response to steroids. Resistance to steroid therapy apparently developed in one patient after approximately 18 months of treatment. One patient responded to treatment and then remained well (for two months when last observed) although steroids and all other treatment were discontinued. The combined use of antibiotics and steroids in the patients treated gave the best results.     

Uptake and metabolism of cortisone and cortisol by the fetal rabbit lung

Lungs of rabbit fetuses at 28 days of gestation were incubated with tritium-labeled cortisone (17α,21-dihydroxy-4-pregnene-3,11,20-trione) or Cortisol (11β,17α,21-trihydroxy-4-pregnene-3,20-dione). The fetal lungs metabolized efficiently cortisone yielding cortisol as the major product (64–71% conversion). Cortisol was poorly metabolized, only 10–14% being converted to cortisone and 68–75% of the substrate being recovered unchanged. A small amount of cortisone (5–7% of tissue radioactivity) was also found in the lungs twenty minutes after injection of labeled cortisol to the fetus $\text{in utero}$. Incubation of fetal lungs with labeled cortisone at 37° resulted in specific uptake and binding of radioactivity (predominantly cortisol) to nuclear macromolecules. The amount of cortisol bound to nuclear macromolecules was similar whether the tissue was incubated with cortisol or cortisone. These results demonstrate that the lungs of the rabbit fetus have the capacity to convert the biologically inactive cortisone to the biologically active cortisol, the reverse reaction occurring only to a limited extent.     

Production of cortisol from cortisone by the isolated,perfused fetal rabbit lung

Perfusion of the isolated 26 day fetal rabbit lung with ³H-cortisone resulted in its conversion to ³H-cortisol and release into the perfusate. Little conversion of ¹⁴C-cortisol to ¹⁴C-cortisone occurred. Quantitative study of homogenized fetal rabbit lung revealed the development of both the cofactor and the enzyme for 11β-hydroxy steroid dehydrogenase activity between 21 and 29 days gestation. These results suggest increasing production of cortisol from cortisone by the fetal rabbit lung as a function of gestational age. This conversion may be of significance with respect to both lung development and parturition, both events being accelerated by cortisol treatment.     

A new defect in the peripheral conversion of cortisone to cortisol

A steroid disorder is described in two sisters, aged 13 and 17 years, in which the metabolism of cortisol results almost exclusively in urinary excretion of tetrahydro-cortisone (11-keto) derivatives. The evidence implies the existence of a deficiency in the peripheral enzymatic conversion of cortisone to cortisol.     

Leukemia; duration of life in children treated with corticotropin and cortisone

The average duration of survival of 15 cases of childhood leukemia treated with corticotropin and cortisone was 6.8 months. This survival was the same as observed among 59 children who received no treatment, or treatment with x-ray, or blood transfusion alone. Despite the fact that objective evidence of remission was observed in 7 of 15 children treated with corticotropin and cortisone, the remissions were not reflected by a longer duration of life. Treatment of childhood leukemia with corticotropin and cortisone appears to be a palliative measure, without significant effect on the duration of life.     

Neurodegeneration in humans caused by prions.

Prion diseases include kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia of humans as well as scrapie and bovine spongiform encephalopathy of animals. For many years, the prion diseases were thought to be caused by viruses despite evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve aberrant metabolism of the prion protein. In many cases, the cellular prion protein is converted into the scrapie variant by a process after translation that involves a conformational change. Often the human prion diseases are transmissible experimentally to animals, and all of the inherited prion diseases segregate with prion protein gene mutations.