ABSTRACT
BACKGROUND & AIMS: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins. METHODS: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61). RESULTS: Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSRmax was negatively correlated with CP score (r = -0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min-1) compared with that in the CP ≤8 group (0.21 ± 0.21 min-1), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p <0.001) was observed. CONCLUSIONS: CSRmax and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSRmax estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis. LAY SUMMARY: We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis.
ABSTRACT
Considering that stress condition associated with osteoporosis, the hypothalamic-pituitary-adrenal (HPA) axis, which is essential for central stress response system, is implicated in regulating bone mass accrual. Melanocortin 2 receptor (MC2R), the receptor of adrenocorticotropic hormone is expressed in both adrenal gland cells and bone cells. To elucidate the role of HPA axis in bone metabolism, we assessed the skeletal phenotype of MC2R deficient mice (MC2R -/- mice). We first examined bone mineral density and cortical thickness of femur using dual x-ray absorptiometry and micro-computed tomography. We then conducted histomorphometric analysis to calculate the static and dynamic parameters of vertebrae in MC2R -/- mice. The levels of osteoblastic marker genes were examined by quantitative PCR in primary osteoblasts derived from MC2R -/- mice. Based on these observations, bone mineral density of femur in MC2R -/- mice was increasing relative to litter controls. Meanwhile, the thickness of cortical bone of femur in MC2R -/- mice was remarkably elevated. Moreover, serum osteocalcin level was drastically raised in MC2R -/- mice. However, bone histomorphometry revealed that static and dynamic parameters reflecting bone formation and resorption were unchanged in vertebrae of MC2R -/- mice compared to the control, indicating that MC2R function may be specific to appendicular bone than axis bone. Taken together, the HPA axis due to deletion of MC2R is involved in bone metabolism.
ABSTRACT
Allopregnanolone (3α,5α-tetrahydroprogesterone; pharmaceutical formulation: brexanolone) is a neurosteroid that has recently been approved for the treatment of postpartum depression, promising to fill part of a long-lasting gap in the effectiveness of pharmacotherapies for depressive disorders. In this review, we explore the experimental research that characterized the antidepressant-like effects of allopregnanolone, with a particular focus on the neurotrophic adaptations induced by this neurosteroid in preclinical studies. We demonstrate that there is a consistent decrease in allopregnanolone levels in limbic brain areas in rodents submitted to stress-induced models of depression, such as social isolation and chronic unpredictable stress. Further, both the drug-induced upregulation of allopregnanolone or its direct administration reduce depressive-like behaviors in models such as the forced swim test. The main drugs of interest that upregulate allopregnanolone levels are selective serotonin reuptake inhibitors (SSRIs), which present the neurosteroidogenic property even in lower, non-SSRI doses. Finally, we explore how these antidepressant-like behaviors are related to neurogenesis, particularly in the hippocampus. The protagonist in this mechanism is likely the brain-derived neurotrophic factor (BFNF), which is decreased in animal models of depression and may be restored by the normalization of allopregnanolone levels. The role of an interaction between GABA and the neurotrophic mechanisms needs to be further investigated.
ABSTRACT
Human aldo-keto reductase (AKR) 1C3, type 2 3α-hydroxysteroid dehydrogenase (HSC)/ type 5 17ß-HSD, is known to be involved in steroids, prostaglandins, and lipid aldehydes metabolism. The expression of AKR1C3 has been demonstrated in hormone-dependent normal tissues such as breast, endometrium, prostate, and testis; and de -regulated AKR1C3 expression has been shown in breast carcinoma, endometrial hyperplasia, endometrial carcinoma, and prostate carcinoma. AKR1C3 expression has also been demonstrated in hormone-independent normal tissues (renal tubules and urothelium) and neoplastic tissues (renal cell carcinoma, Wilm's tumor, and urothelial cell carcinoma). Extensive expression of AKR1C3 in normal and neoplastic as well as hormone-dependent and hormone-independent tissues indicates that AKR1C3 may have functions beyond steroid hormone metabolism. In this report, we describe a widespread expression of AKR1C3 in glial neoplasms and meningiomas, with limited expression in medulloblastoma and no expression in Schwannoma. These tumors, except meningioma, are not classically considered to be sex hormone-dependent or related brain tumors. The current results corroborate our earlier observations that AKR1C3 is expressed in both sex hormone-dependent and hormone-independent malignancies. Similar to AKR1C3 distribution in Wilm's tumor, we also demonstrate that expression of AKR1C3 is reduced in tumors with embryonic phenotypes.