Modulation by Ozone of Glucocorticoid-Regulating Factors in the Lungs in Relation to Stress Axis Reactivity

Exposure to air pollutants increases levels of circulating glucocorticoid stress hormones that exert profound effects relevant to health and disease. However, the nature and magnitude of tissue-level effects are modulated by factors that regulate local glucocorticoid activity; accordingly, inter-individual differences could contribute to susceptibility. In the present study, we characterized effects of ozone (O3) inhalation on glucocorticoid-regulating factors in the lungs of rat strains with contrasting hypothalamic–pituitary–adrenal stress axis responses. Hyper-responsive Fischer (F344) and less responsive Lewis (LEW) rats were exposed to air or 0.8 ppm O3 for 4 h by nose-only inhalation. Levels of the high-specificity and -affinity corticosteroid-binding globulin protein increased in the lungs of both strains proportional to the rise in corticosterone levels following O3 exposure. Ozone reduced the ratio of 11β-hydroxysteroid dehydrogenase type 1 (HSDB1)/HSDB2 mRNA in the lungs of F344 but not LEW, indicating strain-specific transcriptional regulation of the major glucocorticoid metabolism factors that control tissue-level action. Intercellular adhesion molecule (ICAM)-1 and total elastase activity were increased by O3 in both strains, consistent with extravasation and tissue remodeling processes following injury. However, mRNA levels of inflammatory markers were significantly higher in the lungs of O3-exposed LEW compared to F344. The data show that strain differences in the glucocorticoid response to O3 are accompanied by corresponding changes in regulatory factors, and that these effects are collectively associated with a differential inflammatory response to O3. Innate differences in glucocorticoid regulatory factors may modulate the pulmonary effects of inhaled pollutants, thereby contributing to differential susceptibility.

Steroid Metabolism in Children and Adolescents With Obesity and Insulin Resistance: Altered SRD5A and 20α/20βHSD Activity

Alterations in glucocorticoid metabolism may contribute to the development of obesity and insulin resistance (IR). Obesity in turn affects the androgen balance. The peripheral metabolism of steroids is equally an important determinant of their bioavailability and activity. The aim of this study was to evaluate steroid metabolism in obese children and to define which enzyme alterations are associated with IR. Clinical characteristics and anthropometric measurements were determined in 122 obese children and adolescents (72 girls, 50 boys) aged 8 – 18 years. 26 of them (21.3%) were diagnosed with IR (13 boys, 13 girls). Routine laboratory tests were performed and 24h urinary steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Positive relationship between 5α-reductase (SRD5A) activity and IR was found. According to the androsterone to etiocholanolone (An/Et) ratio the activity of SRD5A was significantly increased in obese children with IR, but the difference remained insignificant once the 5α-dihydrotestosterone to testosterone (5αDHT/T) ratio was considered. Furthermore, this relationship persisted in boys but was not observed in girls. The activity of 20α-hydroxysteroid dehydrogenase (20αHSD) and 20β-hydroxysteroid dehydrogenase (20βHSD) was reduced only in obese girls with IR. Conclude, in the context of obese children and adolescents with IR, we surmise that increased SRD5A represents a compensatory mechanism to reduce local glucocorticoid availability. This phenomenon is probably different in the liver (restriction) and in the adipose tissue (expected increase in activity). We show significant changes in 20αHSD and 20βHSD activity in obese girls with IR, but it is difficult to clearly determine whether the activity of these enzymes is an indicator of the function in their ovaries or adrenal glands.

Endogenous Glucocorticoid Metabolism in Bone: Friend or Foe

The role of tissue specific metabolism of endogenous glucocorticoids (GCs) in the pathogenesis of human disease has been a field of intense interest over the last 20 years, fuelling clinical trials of metabolism inhibitors in the treatment of an array of metabolic diseases. Localised pre-receptor metabolism of endogenous and therapeutic GCs by the 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes (which interconvert endogenous GCs between their inactive and active forms) are increasingly recognised as being critical in mediating both their positive and negative actions on bone homeostasis. In this review we explore the roles of endogenous and therapeutic GC metabolism by the 11β-HSD enzymes in the context of bone metabolism and bone cell function, and consider future strategies aimed at modulating this system in order to manage and treat various bone diseases.

Glucocorticoid induced adrenal insufficiency

ABSTRACTSynthetic glucocorticoids are widely used for their anti-inflammatory and immunosuppressive actions. A possible unwanted effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal axis, which can lead to adrenal insufficiency. Factors affecting the risk of glucocorticoid induced adrenal insufficiency (GI-AI) include the duration of glucocorticoid therapy, mode of administration, glucocorticoid dose and potency, concomitant drugs that interfere with glucocorticoid metabolism, and individual susceptibility. Patients with exogenous glucocorticoid use may develop features of Cushing’s syndrome and, subsequently, glucocorticoid withdrawal syndrome when the treatment is tapered down. Symptoms of glucocorticoid withdrawal can overlap with those of the underlying disorder, as well as of GI-AI. A careful approach to the glucocorticoid taper and appropriate patient counseling are needed to assure a successful taper. Glucocorticoid therapy should not be completely stopped until recovery of adrenal function is achieved. In this review, we discuss the factors affecting the risk of GI-AI, propose a regimen for the glucocorticoid taper, and make suggestions for assessment of adrenal function recovery. We also describe current gaps in the management of patients with GI-AI and make suggestions for an approach to the glucocorticoid withdrawal syndrome, chronic management of glucocorticoid therapy, and education on GI-AI for patients and providers.

Targeting glucocorticoid metabolism in prostate cancer

In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through the androgen receptor (AR), the primary driver of prostate cancer, some malignancies are able take advantage of the closely related glucocorticoid receptor (GR). Escape from AR-dependency often involves a simple functional switch from one steroid receptor to another. Recent research efforts have outlined the mechanism enabling this switch, which involves alterations in glucocorticoid metabolism that occur with antiandrogen therapy to increase tumor tissue glucocorticoids and enable GR signaling. Targeting this mechanism pharmacologically by blocking hexose-6-phosphate dehydrogenase shows promise in normalizing glucocorticoid metabolism and restoring responsiveness to antiandrogen therapy. This perspective reviews what we have learned about this resistance mechanism, examines potential implications, and considers how this knowledge might be harnessed for therapeutic benefit.

Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation

Prostate cancer resistance to next-generation hormonal treatment with enzalutamide is a major problem and eventuates into disease lethality. Biologically active glucocorticoids that stimulate glucocorticoid receptor (GR) have an 11β-OH moiety, and resistant tumors exhibit loss of 11β-HSD2, the oxidative (11β-OH → 11-keto) enzyme that normally inactivates glucocorticoids, allowing elevated tumor glucocorticoids to drive resistance by stimulating GR. Here, we show that up-regulation of hexose-6-phosphate dehydrogenase (H6PD) protein occurs in prostate cancer tissues of men treated with enzalutamide, human-derived cell lines, and patient-derived prostate tissues treated ex vivo with enzalutamide. Genetically silencing H6PD blocks NADPH generation, which inhibits the usual reductive directionality of 11β-HSD1, to effectively replace 11β-HSD2 function in human-derived cell line models, suppress the concentration of biologically active glucocorticoids in prostate cancer, and reverse enzalutamide resistance in mouse xenograft models. Similarly, pharmacologic blockade of H6PD with rucaparib normalizes tumor glucocorticoid metabolism in human cell lines and reinstates responsiveness to enzalutamide in mouse xenograft models. Our data show that blockade of H6PD, which is essential for glucocorticoid synthesis in humans, normalizes glucocorticoid metabolism and reverses enzalutamide resistance in mouse xenograft models. We credential H6PD as a pharmacologic vulnerability for treatment of next-generation androgen receptor antagonist–resistant prostate cancer by depleting tumor glucocorticoids.

A Prospective Cross-Over Study of Tissue Glucocorticoid Metabolism in Patients With Adrenal Insufficiency: The Effects of Dual-Release Hydrocortisone Therapy

Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that GC metabolism is altered in patients with AI due to the non-physiological pattern of current immediate-release hydrocortisone (IR-HC) replacement therapy. The use of once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®) offers a more physiological cortisol profile and may alter GC metabolism in vivo.Study Design and Methods: Prospective cross-over study assessing impact of 12 weeks of DR-HC on tissue GC metabolism (using urinary steroid metabolomics, serum cortisol generation curves and adipose tissue biopsies) in 51 patients with AI (primary and secondary) and compared to age-and BMI-matched controls. Results: Patients with AI (n=51) receiving immediate-release HC (IR-HC) had a higher median 24-hour excretion of urinary cortisol compared to healthy controls [72.1µg/24hrs (IQR 43.6–124.2) vs 51.85 (35.5–72.3), p=0.02],with a lower global activity of 11β-HSD2 and higher activity of 5-alpha reductase. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary F and total GC metabolite excretion, which was most significant in the evening on diurnal urine sampling. There was an increase in global 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered post-DR-HC but there was a significant reduction in gene expression of 11β-HSD1 in subcutaneous adipose tissue. Conclusion: Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in glucocorticoid metabolism in patients with AI. This is driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability, which can be improved following treatment with DR-HC.