Abstract
Context
Fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular ...disease in later life.
Objective
To develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesized placental 11-β-hydroxysteroid dehydrogenase-type 2 (11β-HSD2) would be the major rate-limiting step in maternal cortisol transfer to the fetus.
Design
We used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modeling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus.
Participants
Term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery.
Intervention
Maternal artery of the isolated perfused placenta was perfused with D4-cortisol.
Main Outcome Measures
D4-cortisol, D3-cortisone, and D3-cortisol were measured in maternal and fetal venous outflows.
Results
D4-cortisol, D3-cortisone, and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11-β-hydroxysteroid dehydrogenase (11β-HSD) activity was inhibited. At the highest inlet concentration, only 3.0% of the maternal cortisol was transferred to the fetal circulation, whereas 26.5% was metabolized and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, whereas 92.7% exited via the maternal vein.
Conclusions
Our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major “barrier” to cortisol transfer to the fetus.
Placental cortisol metabolism and transfer was studied using tracers and computational modeling. This indicated that the placenta presents both metabolic and physical barriers to cortisol transfer.
LINKED ARTICLES
This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit ...http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The stress, labor, and workload of diversity, equity, and inclusion (DEI) staff and administrators in higher education never seem to end. On the one hand, colleges and universities require new and ...innovative infrastructures to support growing diversity on campus. On the other hand, the war against DEI wages on. DEI leaders and staff are forced into conversations about unit name changes, removing DEI rhetoric from strategic planning documents, or planning for their unit to be dissolved altogether. DEI and its workers are perpetually between a rock and a hard place. The purpose of this conceptual article is to outline precisely how DEI work is inherently shaped by White neoliberalism forces from outside but also within higher education. The premise of our argument is hegemonic Whiteness and White supremacy are at the heart of anti-DEI movements but also inherent in DEI work itself. We offer a contemporary perspective of the racialized tensions involved in doing DEI work and invite critical discussion around ways DEI practitioners might reify or challenge White logics of higher education. (PsycInfo Database Record (c) 2024 APA, all rights reserved) (Source: journal abstract)
Full text
Available for:
CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
This study shows that during critical illness, reduced cortisol breakdown, related to suppressed activity of cortisol-metabolizing enzymes, contributes to hypercortisolemia and hence corticotropin ...suppression, which may have clinical implications.
Critical illness, an example of severe acute physical stress, is often accompanied by hypercortisolemia that is proportionate to the severity of illness.
1
,
2
This observation has traditionally been attributed to stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis and increased corticotropin-driven cortisol production.
3
However, this stress response may not be sufficient for a good prognosis in patients with relative adrenal insufficiency.
4
–
7
Moreover, Vermes et al.
8
reported only transiently elevated levels of corticotropin during critical illness, whereas cortisol levels remained high, a paradoxical dissociation between cortisol and corticotropin levels that has also been observed in other stress conditions.
9
In addition to . . .
Glucocorticoids are powerful anti-inflammatory drugs, but are associated with many side-effects. Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal ...suppression. 5α-Tetrahydrocorticosterone (5αTHB) is a potential selective anti-inflammatory with reduced metabolic effects. Here, the efficacy and side-effect profile of 5αTHB were compared with hydrocortisone in preclinical models of irritant dermatitis.
Acute irritant dermatitis was invoked in ear skin of male C57BL/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5αTHB and hydrocortisone. Side-effects of 5αTHB and hydrocortisone were assessed following chronic topical steroid treatment (28 days) to non-irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5αTHB and hydrocortisone were measured following intravenous and oral administration.
5αTHB suppressed ear swelling in mice, with ED
similar to hydrocortisone (23 μg vs. 13 μg). Chronic application of 5αTHB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5αTHB (8× ED
). 5αTHB was rapidly cleared from the systemic circulation.
Topical 5αTHB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Aims
Portopulmonary hypertension (POPH) was previously associated with a single‐nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 ...CYP19A1). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH.
Approach and Results
We performed a multicenter case‐control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn‐sec/cm−5, and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome‐wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio OR, 2.36; 95% confidence interval CI, 1.12‐4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2‐hydroxyestrogen/16‐α‐hydroxyestrone (OR per 1‐ln decrease = 2.04; 95% CI, 1.16‐3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone‐sulfate (OR per 1‐ln decrease = 2.38; 95% CI, 1.56‐3.85; P < 0.001), and higher plasma levels of 16‐α‐hydroxyestradiol (OR per 1‐ln increase = 2.16; 95% CI, 1.61‐2.98; P < 0.001) were associated with POPH.
Conclusions
Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces ...tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11β-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11β-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11β-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucocorticoids are potent inhibitors of angiogenesis in the rodent in vivo and in vitro but the mechanism by which this occurs has not been determined. Administration of glucocorticoids is used to ...treat a number of conditions in horses but the angiogenic response of equine vessels to glucocorticoids and, therefore, the potential role of glucocorticoids in pathogenesis and treatment of equine disease, is unknown. This study addressed the hypothesis that glucocorticoids would be angiostatic both in equine and murine blood vessels.The mouse aortic ring model of angiogenesis was adapted to assess the effects of cortisol in equine vessels. Vessel rings were cultured under basal conditions or exposed to: foetal bovine serum (FBS; 3%); cortisol (600 nM), cortisol (600nM) plus FBS (3%), cortisol (600nM) plus either the glucocorticoid receptor antagonist RU486 or the mineralocorticoid receptor antagonist spironolactone. In murine aortae cortisol inhibited and FBS stimulated new vessel growth. In contrast, in equine blood vessels FBS alone had no effect but cortisol alone, or in combination with FBS, dramatically increased new vessel growth compared with controls. This effect was blocked by glucocorticoid receptor antagonism but not by mineralocorticoid antagonism. The transcriptomes of murine and equine angiogenesis demonstrated cortisol-induced down-regulation of inflammatory pathways in both species but up-regulation of pro-angiogenic pathways selectively in the horse. Genes up-regulated in the horse and down-regulated in mice were associated with the extracellular matrix. These data call into question our understanding of glucocorticoids as angiostatic in every species and may be of clinical relevance in the horse.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Aromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a ...commonly prescribed therapy for postmenopausal breast cancer.
Objective
We hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer.
Design
Case-control study.
Setting
University teaching hospital.
Participants
Patients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects.
Main outcome measures
The primary outcome measure was insulin sensitivity index – Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively).
Results
Aromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035).
Conclusion
Women who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.
We demonstrate increased insulin resistance, adiposity, and plasma leptin in patients with breast cancer treated with aromatase inhibitors, compared with control subjects matched for age and body mass index.
PDF
