Rhythm of Fetoplacental 11ß-Hydroxysteroid Dehydrogenase Type 2 - Fetal Protection From Morning Maternal Glucocorticoids.

CONTEXT: Excess glucocorticoids impact fetal health. Maternal glucocorticoids peak in early morning. Fetoplacental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) inactivates cortisol to cortisone, protecting the fetus from high glucocorticoids. However, time-specific alterations of human fetoplacental 11ß-HSD2 have not been studied. OBJECTIVE: We hypothesized that fetoplacental 11ß-HSD2 activity shows time-specific alteration and acute affective or anxiety disorders impact fetoplacental 11ß-HSD2 activity. METHODS: In this observational study we investigated 78 pregnant European women undergoing amniocentesis (15.9 ± 0.9 weeks of gestation). Amniotic fluid was collected (8:00 to 16:30 hours) for analysis of fetoplacental 11ß-HSD2 activity, using cortisol (F):cortisone (E) ratio in amniotic fluid, E/(E + F). Fetoplacental 11ß-HSD2 rhythm and association with "acute affective or anxiety disorder" (patients with at least one of: a major depressive episode, specific phobia, panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder) and "acute anxiety disorder" (one of: panic disorder, generalized anxiety disorder, mixed anxiety, depressive disorder), assessed using Mini International Neuropsychiatric Interview, were investigated. RESULTS: Activity of 11ß-HSD2 correlated with time of amniocentesis, peaking in the morning (r = -0.398; P < 0.001) and increased with acute affective or anxiety disorder (mean [M] = 0.70 vs M = 0.74; P = 0.037) and acute anxiety disorder (M = 0.70 vs M = 0.75; P = 0.016). These associations remained significant when controlling for confounders. 11ß-HSD2 activity correlated negatively with pre-pregnancy body mass index (r = -0.225; P = 0.047). CONCLUSION: Our study indicates a time-specific alteration of fetoplacental 11ß-HSD2 activity with peaking levels in the morning, demonstrating a mechanism of fetal protection from the morning maternal glucocorticoid surge.

Increased cortisol metabolism in women with pregnancy-related hypertension.

PURPOSE: The diminished function of 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) was found in placentae from preeclamptic pregnancies. Here, we examine the overall maternal glucocorticoid balance in pregnancy-related hypertension. We aim to answer the question if the functions of primary enzymes involved in cortisol metabolism: 11ß-HSD1 and 11ß-HSD2 and 5-reductases (both 5α- and 5ß) are altered in the course of hypertensive pregnancy. METHODS: We determined plasma and urinary cortisol and cortisone as well as their urinary tetrahydro- and allo-tetrahydrometabolites, both in free and conjugated forms in samples obtained from 181 Polish women in the third trimester of pregnancy. We compared steroid profiles in women with preeclampsia (PE), gestational hypertension (GH), chronic hypertension (CH) and in normotensives (controls). RESULTS: We found significant differences in glucocorticoid balance in pregnancy-related hypertension. Plasma cortisol to cortisone was significantly lower in PE than in controls (3.00 vs. 4.79; p < 0.001). Increased function of renal 11ß-HSD2 in PE and GH was manifested by significantly lower urinary free cortisol to cortisone ratio (0.169 and 0.206 vs. 0.277 in controls; p < 0.005). Markedly enhanced metabolism of cortisol was observed in pregnancy-related hypertension, with no significant alterations in CH, and the changes were more clearly expressed in PE than in GH. CONCLUSIONS: The glucocorticoid balance in PE and GH is shifted towards decreasing cortisol concentration either due to intensified conversion to cortisone or enhanced production of tetrahydro and allo-tetrahydrometabolites.

Apparent systemic 11ß-dehydroxysteroid dehydrogenase 2 activity is increased in preeclampsia but not in intrauterine growth restriction.

OBJECTIVE: The enzyme 11ß-dehydroxysteroid dehydrogenase 2 (11ß-HSD2) converts active cortisol (F) to inactive cortisone (E). A reduced 11ß-HSD2 activity in the placenta has been demonstrated for prematurity, low birth weight, and preeclampsia. We hypothesized that disturbed placental function rather than a maternal response contributes to decreased 11ßHSD2 activity as reflected by a diminished conversion of F to E. Hence, the aim of the present study was to estimate the systemic activity of 11ß-HSD2 throughout gestation and in pregnancies complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR) by calculating maternal serum F/E ratios. METHODS: A total of 188 maternal serum samples were analyzed for nine glucocorticoid metabolites by gas chromatography-mass spectrometry (GC-MS) and F/E ratios were calculated. Study Group A: In a longitudinal set 33 healthy pregnant women were analyzed at three different time points throughout gestation and one postpartum. Study Group B: Cross-sectionally additional 56 patients were enrolled. We compared patients with PE (N = 14) and IUGR (N = 14) with gestational age matched healthy controls (CTRL = 28). RESULTS: Group A: The apparent 11ß-HSD2 activity dropped in the second trimester being restored to first trimester levels (P value = 0.016). Group B: The 11ß-HSD2 activity was high in PE (P value < 0.05) but not in the IUGR group as compared to CTRL. CONCLUSION: The increased apparent serum 11ß-HSD2 activity observed with advancing gestation in normal pregnancy may reflect an elevated general increase in enzyme activity due to a higher placental mass. The high systemic 11ß-HSD2 activity in PE but not in IUGR however suggests an increased F deactivation in maternal tissue in PE rather than in the placenta since placental insufficiency in the absence of PE does not significantly alter F/E ratio.

Itraconazole induced hypertension and hypokalemia: Mechanistic evaluation.

We describe a case of apparent mineralocorticoid excess (hypertension, hypokalemia, metabolic alkalosis and low plasma renin activity) secondary to itraconazole therapy. Inhibition of 11ß-hydroxysteroid dehydrogenase 2 was demonstrated, and withholding itraconazole led to resolution of adverse effects that did not recur with voriconazole. This report adds to a growing body of evidence linking apparent mineralocorticoid excess with certain triazoles.

11ß-hydroxysteroid dehydrogenase type-II activity is affected by grapefruit juice and intense muscular work

ABSTRACT Objective The enzymatic activity of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) is key to protecting mineral corticoid receptors from cortisol and has been implicated in blood pressure regulation. Grapefruit juice (GFJ) and acidity are thought to inhibit this enzyme in vitro. This study examines the effect of GFJ and intense exercise on 11β-HSD2 enzyme activity in vivo. Subjects and methods Eighteen subjects ingested GFJ or apple juice (CON) on separate days prior to reporting to the laboratory in a randomized order. Saliva (Sal) samples were obtained at baseline, 15 and 45 minutes post-treadmill stress test; Sal cortisone (E) and cortisol (F) levels were determined, and the Sal cortisone:cortisol (E:F) ratio was used as an index of 11β-HSD2 enzyme activity at rest and after intense muscular work. Results GFJ treatment decreased baseline 11β-HSD2 enzyme activity (44%) and Sal-E (28%) compared to CON (both, p < 0.05). Sal-E (r = 0.61, p < 0.05) and Sal-F (r = 0.66, p < 0.05) were correlated with diastolic blood pressure (DBP) in GFJ-treated individuals. Treadmill stress significantly increased Sal-E and Sal-F but did not alter 11β-HSD2 enzyme activity regardless of treatment. When treatments were examined separately, CON 11β-HSD2 enzyme activity decreased by 36% (p < 0.05) from baseline to 15 post-treadmill exercise. Conclusion Our findings suggest that GFJ and intense muscular work decrease 11β-HSD-2 activity independently, and no additive effect was noted. The association between DBP and the levels of Sal-F and Sal-E during the GFJ trial should be interpreted cautiously and warrants further investigation.

11ß-hydroxysteroid dehydrogenase type-II activity is affected by grapefruit juice and intense muscular work.

OBJECTIVE: The enzymatic activity of 11ß-hydroxysteroid dehydrogenase-2 (11ß-HSD2) is key to protecting mineral corticoid receptors from cortisol and has been implicated in blood pressure regulation. Grapefruit juice (GFJ) and acidity are thought to inhibit this enzyme in vitro. This study examines the effect of GFJ and intense exercise on 11ß-HSD2 enzyme activity in vivo. SUBJECTS AND METHODS: Eighteen subjects ingested GFJ or apple juice (CON) on separate days prior to reporting to the laboratory in a randomized order. Saliva (Sal) samples were obtained at baseline, 15 and 45 minutes post-treadmill stress test; Sal cortisone (E) and cortisol (F) levels were determined, and the Sal cortisone:cortisol (E:F) ratio was used as an index of 11ß-HSD2 enzyme activity at rest and after intense muscular work. RESULTS: GFJ treatment decreased baseline 11ß-HSD2 enzyme activity (44%) and Sal-E (28%) compared to CON (both, p < 0.05). Sal-E (r = 0.61, p < 0.05) and Sal-F (r = 0.66, p < 0.05) were correlated with diastolic blood pressure (DBP) in GFJ-treated individuals. Treadmill stress significantly increased Sal-E and Sal-F but did not alter 11ß-HSD2 enzyme activity regardless of treatment. When treatments were examined separately, CON 11ß-HSD2 enzyme activity decreased by 36% (p < 0.05) from baseline to 15 post-treadmill exercise. CONCLUSION: Our findings suggest that GFJ and intense muscular work decrease 11ß-HSD-2 activity independently, and no additive effect was noted. The association between DBP and the levels of Sal-F and Sal-E during the GFJ trial should be interpreted cautiously and warrants further investigation.

Reciprocal Regulation of 11ß-HSDs May Predict Steroid Sensitivity in Childhood Nephrotic Syndrome.

Childhood nephrotic syndrome, in which steroid-dependence occurs concurrently with steroid-resistance, requires aggressive therapy to prevent relapse. Predictive biomarkers that can be used to stratify treatment are urgently needed. Here we report that reciprocal regulation of the glucocorticoid metabolizing enzymes, 11ß-hydroxysteroid dehydrogenase types 1 and 2, is associated with steroid-responsiveness and disease remission in childhood nephrotic syndrome, potentially providing a marker to identify patients in which aggressive therapy is required.

Serial changes in plasma total cortisol, plasma free cortisol, and tissue cortisol activity in patients with septic shock: an observational study.

Published data on adrenocortical function in septic shock have enrolled patients at various stages of critical illness and predominantly used plasma total cortisol, with minimal information on serial changes. Moreover, plasma free cortisol and tissue corticosteroid activity may not be strongly associated; however, few published data exist. The aim of this prospective observational study was to investigate serial changes in plasma total and free cortisol and tissue cortisol activity in septic shock. Twenty-nine adult patients admitted with septic shock to a tertiary-level intensive care unit were enrolled. A low-dose corticotropin test was performed on day 1. Plasma total and free cortisol, cortisone, transcortin, and urinary free cortisol and cortisone were analyzed on days 1 to 5, 7, and 10. Urinary and plasma cortisol-cortisone ratios (F:E ratio) were calculated as indices of 11-ß hydroxysteroid dehydrogenase 2 and global 11-ß hydroxysteroid dehydrogenase activity, respectively. Baseline total and free plasma cortisol values from 10 healthy control subjects were obtained for comparative analysis. Baseline plasma total and free cortisol levels were significantly higher than controls (457.8 ± 193 vs. 252 ± 66 nmol/L, P = 0.0002; and 50.83 ± 43.19 vs. 6.4 ± 3.2, P < 0.0001, respectively). Plasma free cortisol rose proportionately higher than total cortisol (124% ± 217.3% vs. 40% ± 33.2%, P = 0.007) following corticotropin. Baseline plasma and urinary F:E ratios were elevated over the reference ranges (13.13 ± 1.5, 1.69 ± 2.8) and were not correlated with plasma free cortisol values (r = 0.2, 0.3 respectively). Over the study period, total cortisol levels and plasma F:E ratios remained elevated, whereas plasma free cortisol levels and urinary F:E ratio declined. At baseline, plasma free cortisol levels were higher in patients who subsequently survived (23.7 ± 10.5 vs. 57.9 ± 45.8 nmol/L, P = 0.04). In septic shock, there is a differential response of plasma total and free cortisol over time and in response to corticotropin. Changes in plasma and urinary F:E ratios suggest tissue modulation of 11-ß hydroxysteroid dehydrogenase activity. Total plasma cortisol measurements may not reflect the global adrenal response in septic shock.

Spironolactone effective hypertension in the elderly due to 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) impairment: contributory role of determining serum cortisol/cortisone ratio as a marker of 11beta-HSD2 activity.

Two elderly patients with mineralocorticoid excess state due to 11 beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) impairment are described. Moreover, the role of the precursor-product ratios of the steroids reflecting 11beta-HSD2 activity was estimated in 5 patients, including 3 patients reported previously by us. Significant elevations of urinary cortisol/cortisone ratios were observed, whereas urinary tetrahydrocortisol (THF)+allo-THF/tetrahydrocortisone (THE) ratios were not elevated significantly. Furthermore, an even more distinct elevation of serum cortisol/cortisone ratio was evident in all instances of 5 patients, suggesting a significant clinical role of the serum cortisol/cortisone ratio in the diagnosis of 11beta-HSD2 impairment.

Hypertension and circulating mRNA for 11beta-hydroxysteroid dehydrogenase type II.

Circulating DNA and mRNA for 11beta-hydoxysteroid dehydrogenase (HSD) type II were measured in patients with hypertension and in healthy subjects. DNA and RNA levels in hypertensive patients and controls were quantified using real-time RT-PCR. Messenger RNA for 11beta-HSD type II was significantly lower in the hypertensive patients (median: 0.18) (P= 0.032) than in healthy subjects (median: 0.42). Plasma DNA was also significantly lower (P= 0.016) in hypertension. It is suggested that measurement of mRNA for 11beta-HSD type II in hypertension may identify subjects who may be salt-sensitive.

Two elderly patients with mineralocorticoid excess due to 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) impairment.

A 75-year-old woman had a low circulating level of aldosterone, despite the mineralocorticoid excess state. These abnormalities were improved by spironolactone administration. The distinct elevation of urinary cortisol/cortisone ratio revealed 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) impairment. Moreover, slight but distinct elevation of the ratio was found in a 95-year-old woman with normotension and normopotassemia. The mineralocorticoid excess state with reduced aldosterone level appeared following with vomiting and diarrhea, exaggerating asymptomatic impairment of 11beta-HSD2 to induce apparent mineralocorticoid excess (AME)-like condition.

Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology.

Epidemiological evidence suggests that an adverse prenatal environment permanently 'programs' physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)--the fetoplacental barrier to maternal glucocorticoids--reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11beta- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming. In human pregnancy, severe maternal stress affects the offspring's HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function. The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly, some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.

Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure.

OBJECTIVE: The conversion of cortisol (F) to cortisone (E) is catalyzed by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). Children suffering from chronic renal failure (CRF) have a decreased activity of 11beta-HSD2 contributing to increased arterial blood pressure. The objective was to investigate whether a normal conversion of F to E is achieved after renal transplantation (TX) in children. METHODS: Fifteen children with CRF, 17 children with steroid-free immunosuppression after TX, and 18 healthy controls (CO) were enrolled. The activity of 11beta-HSD2 in plasma was calculated using the ratio of F/E determined by tandem mass spectrometry, the ratio of tetrahydrocortisol (THF) +5alpha-tetrahydrocortisol (5alphaTHF) in urine determined by gas chromatography/mass spectrometry, and the ratio of (THF +5alphaTHF)/tetrahydrocortisone (THE) in urine determined by tandem mass spectrometry. RESULTS: The F/E ratio (mean +/- S.D./S.E.M.) was significantly higher in CRF and TX (5.6 +/- 1.9/0.6, 7.12 +/- 3.1/0.9) than in CO (1.18 +/- 0.2/0.03, P < 0.0001) groups. The (THF + 5alphaTHF)/THE ratio in CRF (1.19 +/- 1.1/0.5) and TX (1.19 +/- 0.1/0.5) groups was significantly higher than in controls (0.21 +/- 0.05/0.18, P < 0.0001). Positive correlations between plasma and urinary ratios (P = 0.0004. R(2) = 0.73 in CRF, P = 0.0013, R(2) = 0.56 in TX, P < 0.0001, R(2) = 0.66 in CO) were found, whereas significant correlations between F/E or (THF + 5alphaTHF)/THE ratios and blood pressure, the number of antihypertensive drugs taken or creatinine clearance could not be found. CONCLUSIONS: In all children with chronic renal failure plasma and urinary cortisol/cortisone ratios are elevated and do not return to normal levels after renal allograft transplantation. This suggests that renal transplantation does not normalize 11beta-HSD2 activity.

GH effect on enzyme activity of 11betaHSD in abdominal obesity is dependent on treatment duration.

OBJECTIVE: In the past years the interaction of GH and 11beta hydroxysteroid dehydrogenase (11betaHSD) in the pathogenesis of central obesity has been suggested. DESIGN: We studied the effects of 9 months of GH treatment on 11betaHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48-66 years, in a randomised, double-blind, placebo-controlled trial. METHODS: Urinary steroid profile was used to estimate 11betaHSD type 1 and 2 (11betaHSD1 and 11betaHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic-hyperinsulinaemic glucose clamp was used to assess insulin sensitivity. RESULTS: In the GH-treated group the 11betaHSD1 activity decreased transiently after 6 weeks (P < 0.01) whereas 11betaHSD2 increased after 9 months of treatment (P < 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11betaHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11betaHSD1 and 11betaHSD 2 and changes in GDR. DISCUSSION: The study demonstrates that short- and long-term GH treatment has different effects on 11betaHSD1 and 11betaHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11betaHSD.

Activity of 11beta-hydroxysteroid dehydrogenase type 2 in normotensive blacks and whites.

BACKGROUND: Salt-sensitive hypertension occurs more commonly in Blacks than in Whites. A decrease in activity of the enzyme 11betaHSD2 that results in overstimulation of the mineralocorticoid receptor by cortisol could contribute to greater retention of sodium in Blacks. We tested the hypothesis that less activity of the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is present in Blacks than in Whites. METHODS: Eighty-nine subjects (42 Whites and 47 Blacks), ages 12 to 24 years were recruited from a young cohort that was followed longitudinally in a study of blood pressure regulation. For purposes of study, they were admitted to the General Clinical Research Center. Excretion of tetrahydrocortisol (THF), 5alpha-THF, and tetrahydrocortisone (THE) was measured in 12-hour overnight urine collections. In vivo 11betaHSD2 activity was estimated from the urinary (THF + 5alpha-THF)/THE) ratio. RESULTS: Blacks appeared to retain more sodium as evidenced by a lower level of 2-hour upright plasma aldosterone (P<.001) and marginally lower plasma renin activity (P=.06). The (THF + 5alpha-THF)/THE ratio in Blacks and Whites was similar: 0.91 +/- 0.41 (standard deviation), 0.86 +/- 0.52, 1.13 +/- 0.36, and 0.66 +/- 0.26, in White males, White females, Black males, and Black females, respectively; P=.35 for an overall effect of race. CONDUSION: 11betaHSD2 activity appears to be similar in Blacks and Whites and probably contributes minimally, if at all, to race differences in sodium retention.

Maternal asthma is associated with reduced female fetal growth.

Asthma during pregnancy is associated with a low birth weight, although the mechanisms contributing to this outcome remain unknown. The relationship between maternal asthma and its treatment, placental function, fetal sex, and low birth weight was examined to establish the effect of asthma on fetal growth. Glucocorticoid intake by women with asthma was assessed throughout pregnancy. The placenta was collected after delivery, and 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity was measured. Fetal cortisol and estriol were measured in the umbilical vein plasma at delivery. Those with asthma were compared with a nonasthmatic control group. In women with asthma who did not use inhaled steroids and were pregnant with a female fetus, we observed significantly reduced birth weights, whereas male birth weights were unaffected. The presence of a female fetus was associated with significantly increased maternal circulating monocytes, significantly reduced placental 11beta-HSD2 activity and fetal estriol, and a trend toward elevated fetal plasma cortisol. This study provides evidence that in pregnancies complicated by asthma there is a fetal sex-specific effect on the maternal immune system with adverse effects on placental function and female fetal growth.