Assessing systemic 11[beta ]-hydroxysteroid dehydrogenase with serum cortisone/cortisol ratios in healthy subjects and patients with diabetes mellitus and chronic renal failure

doi:10.1053/meta.2001.24213

Metabolism

Volume 50, Issue 7, July 2001, Pages 801-804

https://doi.org/10.1053/meta.2001.24213 Get rights and content

Abstract

11[beta ]-hydroxysteroid dehydrogenase (11[beta ]-HSD), an enzyme regulating mineralocorticoid like action of glucocorticoid, oxidizes active cortisol to inactive cortisone. Impaired activity of this enzyme is associated with apparent mineralocorticoid excess (AME) syndrome and is characterized by hypertension and hypokalemia. Recent investigations suggest the presence of hypertensive subjects with low activity of 11[beta ]-HSD. The blood concentration ratio of cortisone/cortisol reflects the overall conversion of cortisol to cortisone and may be an index to assess the systemic activity of 11[beta ]-HSD. We evaluated the peripheral blood concentration ratio of cortisone/cortisol as a possible marker to identify subjects with hypertension thought to represent impaired 11[beta ]-HSD activity. We compared this ratio in healthy subjects and patients with diabetes mellitus (DM) or chronic renal failure (CRF). Peripheral blood samples were collected from 69 healthy subjects, 44 DM, and 36 CRF patients in the morning (9:00 to 11:00 AM). Twenty-six DM patients (59%) and 32 CRF patients (89%) met the criteria for having hypertension. Serum cortisol and cortisone concentrations were determined by high performance liquid chromatography (HPLC). All values for serum cortisone and cortisol levels were within the normal range. Serum cortisone/cortisol ratio in the healthy subjects was distributed with a range of 0.113 to 0.494 (median, 0.243). Compared with healthy subjects, DM and CRF patients had significantly low (P [lt ] .01) serum cortisone/cortisol levels (median, 0.188 [range, 0.092 to 0.313] in DM and 0.088 [range, 0.031 to 0.140] in CRF). Bimodal distribution of cortisone/cortisol, found in DM patients with hypertension, represntby Presented high- and low-ratio groups around the border of the ratio 0.2. Kidney function, DM duration, and complications varied between the high- and low-ratio groups. The low ratio group ([lt ]0.2), whose 11[beta ]-HSD activity was considered low, had an increase in blood urea nitrogen (BUN) levels and experienced nephropathy, neuropathy, retinopathy, and prolonged DM duration when compared with the group with a ratio greater than 0.2. The data suggest that the serum cortisone/cortisol ratio reflects the change in 11[beta ]-HSD activity and is dependent kidney function. This is a possible marker to evaluate glucocorticoid excess hypertension observed in DM and CRF patients.

References (0)

Cited by (40)

Prolactin and Other Pituitary Disorders in Kidney Disease
2021, Seminars in Nephrology
Citation Excerpt :
As a result, circulating cortisol does not normally activate mineralocorticoid receptors. In patients with CKD, it has been reported that there is ineffective deactivation of cortisol by 11 β-hydroxysteroid dehydrogenase 2,48 which may lead to exaggerated activation of the mineralocorticoid receptors and, eventually, hypertension.49 In addition to changes in metabolism of endogenous glucocorticoid in patients with CKD, there is prolongation of the half-life of hydrocortisone and prednisolone owing to a reduced metabolic clearance rate, but a shortening of the half-life of dexamethasone owing to an increased metabolic clearance rate, highlighting the differences in the metabolism of exogenous steroids in CKD.50
Summary: Prolactin levels are increased in chronic kidney disease (CKD) as a result of reduced clearance and increased secretion. Hyperprolactinemia manifests as galactorrhea and hypogonadism. Treatment of hyperprolactinemia should focus on improving bothersome galactorrhea or hypogonadism by using dopamine agonists and/or replacement of sex hormone(s). Changes in the hypothalamic–pituitary–adrenal axis in CKD are characterized by increases in adrenocorticotropic hormone (ACTH) and cortisol levels, largely preserved circadian rhythms of ACTH and cortisol, and a normal response of cortisol to ACTH, metyrapone, and insulin-induced hypoglycemia. However, the hypothalamic–pituitary–adrenal axis is less inhibited by 1 mg dexamethasone but retains normal suppression by higher-dose dexamethasone. Diagnosis of adrenal insufficiency in CKD patients, as in normal subjects, usually is made by finding a subnormal cortisol response to ACTH. The mainstay of treatment of adrenal insufficiency is to replace glucocorticoid hormone. Cushing's disease in CKD is difficult to diagnose and relies on the dexamethasone suppression test and the midnight salivary cortisol test because the 24-hour urine free cortisol test is not useful because it is increased already in CKD. Treatment of Cushing's disease involves surgery, complemented by radiation and/or medical therapy if necessary. Growth hormone levels are increased and insulin-like growth factor 1 levels are normal in patients with CKD. In a normal patient with CKD, as in one with acromegaly, there can be a paradoxic increase in growth hormone after an oral glucose load. Therefore, diagnosis of acromegaly in renal insufficiency is challenging. The treatment of choice for acromegaly is surgery, although data for medical treatment for acromegaly in CKD are rare. In patients with renal impairment, arginine vasopressin levels are increased as a result of decreased clearance, and there also is impairment of arginine vasopressin signaling in renal tubules. Diabetes insipidus can be masked in advanced kidney disease until kidney transplantation. Diagnosis of the syndrome of inappropriate antidiuretic hormone is similar in mild or moderate kidney disease as in normal subjects, but is challenging in patients with advanced kidney disease owing to the impairment in urine dilution.
Quantitative MALDI-MS/MS assay for serum cortisol through charged derivatization
2020, Journal of Pharmaceutical and Biomedical Analysis
Citation Excerpt :
Based on these results, steroids present in the adrenal venous serum were not abundant enough to seriously interfere with the CRT quantification. The serum concentration of cortisone, which is a hormonally-inactive glucocorticoid, has been reported to be a fraction of that of CRT [9,11,25]. In the adrenal venous serum sample, the aldosterone concentration is sometimes over 10 ng/mL [25,26].
Cortisol (CRT), the main glucocorticoid in humans, plays a crucial role in many physiological processes, therefore, the measurement of its serum level is of great clinical significance. Matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS) might be an effective approach for the quantification of CRT in serum due to its attractive properties, i.e., high specificity, ease of use, ruggedness and rapid analysis. In this study, we developed a method to quantify the serum CRT by MALDI-MS/MS. This method employed the derivatization using a Girard-type reagent, 1-(hydrazinocarbonylmethyl)isoquinolinium chloride, which compensated for the lack of sensitivity. This method enabled the reproducible quantification of the serum CRT using a 20-μL sample (intra- and inter-assay relative standard deviations, 7.4% or lower), and the measurable range was 25–500 ng/mL. The serum CRT concentrations determined by the newly-developed MALDI-MS/MS method agreed well with those by liquid chromatography/electrospray ionization-MS/MS or electrochemiluminescence immunoassay. The MALDI-MS/MS method was used for the analysis of peripheral venous serum samples of healthy subjects and adrenal venous serum samples of patients with primary aldosteronism, and satisfactory results were obtained.
Tandem mass spectrometry determined maternal cortisone to cortisol ratio and psychiatric morbidity during pregnancy-interaction with birth weight
2016, Psychoneuroendocrinology
Citation Excerpt :
This finding is in line with a number of studies suggesting no difference in gestational cortisol levels between women with antenatal depression, anxiety, or stress and healthy controls (Hellgren et al., 2013; Iliadis et al., 2015) A non-pregnant individual’s serum cortisone to cortisol ratio has been proposed to be set by the total 11β-HSD type 1 and type 2 activity combined (Heilmann et al., 1999; Homma et al., 2001) and a low cortisol to cortisone conversion has been found to be associated with renal disease and hypertension (Homma et al., 2001). We found a mean cortisone to cortisol quotient that was at least three times higher than what has been previously reported in healthy non-pregnant controls (Homma et al., 2001; Simunkova et al., 2008).
Maternal serum cortisol has been suggested to be influenced by psychiatric morbidity, and may also influence fetal growth. However, several studies found equal cortisol levels in depressed and healthy pregnant women. Placental 11-β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) shields the fetus from maternal cortisol by conversion to cortisone, a function that may be compromised by maternal stress. We aimed to compare the serum ratio of cortisone to cortisol, in women with and without psychiatric morbidity during pregnancy. A secondary aim was to investigate whether fetal growth, approximated by infant birth weight, was associated with the cortisone to cortisol ratio.
We performed tandem mass spectrometry analysis of serum cortisol and cortisone in late pregnancy in 94 women with antenatal psychiatric morbidity and 122 controls (cohort 1). We also compared the placental gene expression of HSD11B1 and 2 in another group of 69 women with psychiatric morbidity and 47 controls (cohort 2).
There were no group differences in cortisol to cortisone ratio, absolute levels of cortisone and cortisol (cohort 1), or expression of HSD11B1 or 2 (cohort 2). However, cortisone to cortisol ratio was positively associated with birth weight in women with psychiatric morbidity, also after adjustment for gestational length, fetal sex, maternal height, smoking, SSRI use, and time of blood sampling (standardized β = 0.35, p < 0.001), with no association in the healthy controls
Thus, the maternal serum cortisone to cortisol ratio does not seem to be affected by psychiatric morbidity, but psychiatric morbidity may increase fetal exposure to cortisol or other metabolic factors influencing fetal growth.
Hypertension in Small Animal Kidney Disease
2011, Veterinary Clinics of North America - Small Animal Practice
Citation Excerpt :
The syndrome of apparent mineralocorticoid excess occurs when there is decreased conversion of hormonally active cortisol to inactive cortisone within mineralocorticoid-target tissues, such as those of the kidney. This conversion is catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase type 2, and activity of this enzyme is impaired in human patients with CKD.115 Cortisol has great affinity for mineralocorticoid receptors and its concentration is much higher than that of aldosterone; therefore, if conversion of cortisol to cortisone is reduced, signs of mineralocorticoid excess (hypokalemia and hypertension) develop.
Urinary cortisol/cortisone ratios in hypertensive and normotensive cats
2009, Journal of Feline Medicine and Surgery
Hypertension is a common problem in older cats, particularly associated with chronic kidney disease (CKD). Reduced activity of 11β-hydroxysteroid dehydrogenase type 2 predisposes to hypertension in human patients by allowing excessive stimulation of the mineralocorticoid receptor by cortisol. This study was designed to test the hypothesis that reduced conversion of cortisol to cortisone contributes to the development of systemic hypertension in some cats with CKD and idiopathic hypertension (iHT). The study included 60 client-owned cats: 21 clinically normal, 16 normotensive cats with CKD (NTCKD), 14 hypertensive cats with CKD (HTCKD) and nine iHTs. Urine cortisol and cortisone were extracted into dichloromethane and chloroform, respectively, prior to analysis by radioimmunoassay. Data are reported as median and range. The Kruskall–Wallis test was used to compare cortisol:cortisone ratios between groups with post-hoc testing using the Mann–Whitney U test. Wilcoxon signed-ranks test was used to compare results before and after treatment of hypertensive cats with amlodipine. The urinary cortisol:cortisone ratio was significantly higher in clinically normal cats (0.87; 0.46–1.39) when compared to NTCKD (0.60; 0.35–1.20; P < 0.001), HTCKD (0.62; 0.34–1.00; P = 0.002) and cats with iHT (0.65; 0.46–0.85; P = 0.015). No statistical difference was detected between NTCKD, HTCKD and iHT groups. No effect of anti-hypertensive treatment on the urinary cortisol–cortisone ratio was detected (P = 0.327). Reduced urinary cortisol to cortisone conversion does not appear to be associated with systemic hypertension in cats. In fact, the cortisol to cortisone shuttle appears to be more effective in cats with CKD (hypertensive and normotensive) and iHT than clinically normal cats. The mechanism for this potentially adaptive response to kidney disease is not clear.
Continuous positive airway pressure therapy decreases evening cortisol concentrations in patients with severe obstructive sleep apnea
2009, Metabolism: Clinical and Experimental
Patients with obstructive sleep apnea syndrome (OSAS) show recurrent episodes of nightly hypoxic stress. The purpose of this study is the detection of alterations of the hypothalamic-pituitary-adrenal stress axis in OSAS patients before and after continuous positive airway pressure (CPAP) therapy. An activation of the hypothalamic-pituitary-adrenal axis was proposed because of the nightly hypoxic stress in these patients, but previous studies were not conclusive. Here we hypothesize that CPAP therapy decreases salivary cortisol concentrations in patients with severe OSAS. We performed a clinical within-subject study including 50 patients with newly diagnosed OSAS and an apnea-hypopnea index greater than or equal to 40 h⁻¹. Diurnal profiles of salivary cortisol concentrations were compiled before and after 3 months of treatment with CPAP. Therefore, 6 cortisol samples were collected: before and after lunch, in the evening, the next morning after awakening, and before and after breakfast. Thirty-eight patients returned after 3 months of CPAP therapy for follow-up. According to the reference range for healthy subjects, cortisol values were not pathologically increased. Analysis of variance revealed a significant effect of CPAP therapy on diurnal cortisol profiles (P = .048). Subjects with severe OSAS showed a decrease (3.04 ± 0.55 nmol L⁻¹ pre-CPAP vs 2.48 ± 0.78 nmol L⁻¹ post-CPAP, P = .038) of evening cortisol levels after CPAP treatment, whereas prelunch levels were increased after CPAP therapy (7.18 ± 0.83 nmol L⁻¹ pre-CPAP vs 10.22 ± 1.10 nmol L⁻¹ post-CPAP, P = .044). Our results show that CPAP therapy decreases evening cortisol concentrations in patients with severe OSAS. These data suggest that OSAS may increase the cortisol nadir that is reversed after CPAP therapy.

View all citing articles on Scopus

^☆: Supported by the Ministry of Education in Japan (Grant in Aid No. 08772175).

View full text

ArticlesAssessing systemic 11[beta ]-hydroxysteroid dehydrogenase with serum cortisone/cortisol ratios in healthy subjects and patients with diabetes mellitus and chronic renal failure☆

Abstract

Articles
Assessing systemic 11[beta ]-hydroxysteroid dehydrogenase with serum cortisone/cortisol ratios in healthy subjects and patients with diabetes mellitus and chronic renal failure☆