Context:
Aberrant estrogen synthesis and metabolism have been suggested to increase local estradiol (E2) concentration in endometriosis and thus to promote the growth of the lesions. However, tissue ...estrogen concentrations within the endometrium and different types of endometriosis lesions have not been described.
Objective:
The aim of the study was to evaluate local E2 and estrone (E1) concentrations in the endometrium and different types of endometriosis lesions, and to correlate them with the expression of estrogen-metabolizing enzymes.
Patients:
Patients with endometriosis (n = 60) and healthy controls (n = 16) participated in the study.
Main Outcome Measures:
We measured serum and tissue concentrations of E2 and E1 as well as mRNA expression of the estrogen-metabolizing enzymes.
Results:
Endometrial or endometriotic intratissue E2 concentrations did not reflect the corresponding serum levels. In the proliferative phase, endometrial E2 concentration was five to eight times higher than in the serum, whereas in the secretory phase the E2 concentration was about half of that in the serum. Accordingly, a markedly higher E2/E1 ratio was observed in the endometrium at the proliferative phase compared with the secretory phase. In the endometriosis lesions, E2 levels were predominating over those of E1 throughout the menstrual cycle. Among the hydroxysteroid (17β) dehydrogenase (HSD17B) enzymes analyzed, HSD17B2 negatively correlated with the E2 concentration in the endometrium, and HSD17B6 was strongly expressed, especially in the deep lesions.
Conclusions:
Endometrial or endometriotic tissue E2 concentrations are actively regulated by local estrogen metabolism in the tissue. Thus, the inhibition of local E2 synthesis is a valid, novel approach to reduce local E2-dependent growth of endometriotic tissue.
► Local production of estrogens promotes endometriotic cell growth. ► Progesterone resistance leads to decreased inactivation of estradiol. ► Non-conventional estrogen signaling may participate in E2 ...action in endometriosis. ► Impaired ESR and coregulator action may influence endometriosis growth. ► Comparative analysis of E2 synthesizing enzymes in endometriosis subtypes is needed.
Endometriosis is an estrogen-dependent gynecological disease where endometrium-like tissue grows outside uterine cavity. Endometriotic cell proliferation is stimulated by estrogens acting predominantly via their nuclear receptors. Estrogen receptors (ESR1, ESR2) are ligand activated transcription factors whose activation is dependent on the cell-specific dynamic expression of the receptors, on the interacting proteins and on the ligand availability. The different types of endometriotic lesions, peritoneal, deep, and ovarian endometriosis, may respond to estrogens differentially due to differences in the expression of the receptors and interacting proteins, and due to potential differences in the ligand availability regulated by the local estrogen synthesis. This review summarizes the current knowledge of estrogen synthesizing enzymes and estrogen receptors in different types of endometriosis lesions. Further studies are still needed to define the possible differences in steroid metabolism in different types of endometriotic lesions.
Aims/hypothesis
Inflammation is a core component of residual cardiovascular risk in type 2 diabetes. With new anti-inflammatory therapeutics entering the field, accurate markers to evaluate their ...effectiveness in reducing cardiovascular disease are paramount. Gallium-68-labelled DOTATATE (
68
Ga-DOTATATE) has recently been proposed as a more specific marker of arterial wall inflammation than
18
F-fluorodeoxyglucose (
18
F-FDG). This study set out to investigate whether
68
Ga-DOTATATE uptake is amenable to therapeutic intervention in individuals with type 2 diabetes.
Methods
Individuals aged >50 years with type 2 diabetes underwent
68
Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) at baseline and after 3 months treatment with atorvastatin 40 mg once daily. Primary outcome was the difference in coronary
68
Ga-DOTATATE uptake, expressed as target-to-background ratio (TBR). The secondary outcome was difference in bone marrow and splenic uptake, expressed as the standardised uptake value (SUV).
Results
Twenty-two individuals with type 2 diabetes (mean age 63.2±6.4 years, 82% male, LDL-cholesterol 3.42±0.81 mmol/l, HbA
1c
55±12 mmol/mol 7.2%±3.2%) completed both
68
Ga-DOTATATE PET/CT scans. The maximum TBR was −31% (95% CI −50, −12) lower in the coronary arteries, and bone marrow and splenic
68
Ga-DOTATATE uptake was also significantly lower post statin treatment, with a mean percentage reduction of −15% (95% CI −27, −4) and −17% (95% CI −32, −2), respectively.
Conclusions/interpretation
68
Ga-DOTATATE uptake across the cardio–haematopoietic axis was lower after statin therapy in individuals with type 2 diabetes. Therefore,
68
Ga-DOTATATE is promising as a metric for vascular and haematopoietic inflammation in intervention studies using anti-inflammatory therapeutics in individuals with type 2 diabetes.
Trial registration
ClinicalTrials.gov NCT05730634
Graphical Abstract
Aims
Bariatric surgery is the most effective treatment to tackle morbid obesity and type 2 diabetes, but the mechanisms of action are still unclear. The objective of this study was to investigate the ...effects of bariatric surgery on intestinal fatty acid (FA) uptake and blood flow.
Materials and Methods
We recruited 27 morbidly obese subjects, of whom 10 had type 2 diabetes and 15 were healthy age‐matched controls. Intestinal blood flow and fatty acid uptake from circulation were measured during fasting state using positron emission tomography (PET). Obese subjects were re‐studied 6 months after bariatric surgery. The mucosal location of intestinal FA retention was verified in insulin resistant mice with autoradiography.
Results
Compared to lean subjects, morbidly obese subjects had higher duodenal and jejunal FA uptake (P < .001) but similar intestinal blood flow (NS). Within 6 months after bariatric surgery, obese subjects had lost 24% of their weight and 7/10 diabetic subjects were in remission. Jejunal FA uptake was further increased (P < .03). Conversely, bariatric surgery provoked a decrease in jejunal blood flow (P < .05) while duodenal blood flow was preserved. Animal studies showed that FAs were taken up into enterocytes, for the most part, but were also transferred, in part, into the lumen.
Conclusions
In the obese, the small intestine actively takes up FAs from circulation and FA uptake remains higher than in controls post‐operatively. Intestinal blood flow was not enhanced before or after bariatric surgery, suggesting that enhanced intestinal FA metabolism is not driven by intestinal perfusion.
Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum
F-labeled 1,4,7-triazacyclononane-
-triacetic acid conjugated folate (
...F-FOL) is a PET tracer targeting folate receptor β (FR-β), which is expressed on activated macrophages at sites of inflammation. We evaluated
F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR-β in human cardiac sarcoidosis specimens.
Myocarditis was induced by immunizing rats (
= 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats (
= 6) were injected with Freund adjuvant alone.
F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrast-enhanced high-resolution CT or
F-FDG PET images were used for coregistration. Rat tissue sections and myocardial autopsy samples from 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β.
The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial
F-FOL uptake colocalizing with inflammatory lesions (SUV
, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUV
, 0.4 ± 0.2 and 0.4 ± 0.1, respectively;
< 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of
F-FOL in myocardial inflammatory lesions. Uptake of
F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions.
In a rat model of autoimmune myocarditis,
F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.
Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study ...examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms. In low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR
ApoB
), VAP-1 was expressed on endothelial cells lining inflamed atherosclerotic lesions; normal vessel walls in aortas of C57BL/6N control mice were VAP-1-negative. Second, we discovered that the focal uptake of VAP-1 targeting sialic acid-binding immunoglobulin-like lectin 9 based PET tracer
GaDOTA-Siglec-9 in atherosclerotic plaques was associated with the density of activated macrophages (r = 0.58, P = 0.022). As a final point, we found that the inhibition of VAP-1 activity with small molecule LJP1586 decreased the density of macrophages in inflamed atherosclerotic plaques in mice. Our results suggest for the first time VAP-1 as a potential imaging target for inflamed atherosclerotic plaques, and corroborate VAP-1 inhibition as a therapeutic approach in the treatment of atherosclerosis.
Context:
Aberrant sex steroid signaling is suggested to promote endometriosis growth by several mechanisms, and the tissue concentrations of sex steroids are key determinants of the hormone action. ...However, their concentrations are only superficially known in the endometrium and endometriosis lesions.
Objective:
This study sought to evaluate whether the tissue steroid hormone concentrations in endometriosis differ from the endometrium or serum.
Main Outcome Measures:
Steroid analysis of serum and tissue specimens of women with endometriosis (n = 60) and healthy controls (n=16) was measured, and supporting data from quantitative RT-PCR for steroidogenic enzymes and explant cultures of a subset of specimens is provided.
Results:
Endometrial tissue progesterone (P4) concentrations reflected the serum P4 levels during the menstrual cycle, whereas in endometriosis lesions, the cycle-dependent change was missing. Remarkably high tissue T concentrations were measured in endometriosis lesions independent of the cycle phase, being 5–19 times higher than the corresponding serum levels. Tissue/serum ratio of T was further increased in patients with contraceptive medication. The altered tissue steroid concentrations in endometriosis were in line with the expression of various steroidogenic enzymes in the lesions, of which HSD3B2 showed constantly high expression, whereas CYP11A1 expression was low. Furthermore, the high concentration of sex steroids detected in the ovarian lesions involves their production by the lesion and by the adjacent ovarian tissue.
Conclusions:
Endometriosis lesions present with progestin and androgen metabolism, which are different from that of the endometrium, and the lesions are characterized by high tissue T and a loss of cyclical changes in tissue P4 concentration.
Dipeptidyl peptidase 4 (DPP-4) inhibitors have anti-inflammatory and atheroprotective effects. We evaluated the effects of the DPP-4 inhibitor linagliptin on atherosclerotic plaque and hepatic ...inflammation using histology and 2-deoxy-2-18F-fluoro-d-glucose (18F-FDG), a positron emission tomography tracer of inflammation, in a mouse model of hypercholesterolemia and type 2 diabetes.
Igf2/Ldlr−/−Apob100/100 mice were fed a high-fat diet (HFD) for 8 weeks and then randomly allocated to receive HFD (n = 14), or HFD with added linagliptin (n = 15) for additional 12 weeks. Five mice fed a chow diet were studied as an additional control. At the end of the study, glucose tolerance, aortic and liver uptake of 18F-FDG, and histology were studied.
Mice in linagliptin and HFD groups had similar fasting glucose concentrations, but linagliptin improved glucose tolerance. Aortas of linagliptin and HFD groups showed advanced atherosclerotic plaques with no difference in the mean intima-to-media ratio or number of macrophages in the plaques. Autoradiography showed similar 18F-FDG uptake by atherosclerotic plaques in linagliptin and HFD groups (plaque-to-wall ratio: 1.7 ± 0.25 vs. 1.6 ± 0.21; p = 0.24). In the liver, linagliptin reduced the histologic inflammation score but had no effect on 18F-FDG uptake. Compared with chow diet, uptake of 18F-FDG was similar in the aorta, but higher in the liver after HFD.
Linagliptin therapy improved glucose tolerance and reduced hepatic inflammation but had no effect on plaque burden or atherosclerotic inflammation, as determined by histology and 18F-FDG uptake, in atherosclerotic mice with type 2 diabetes.
Display omitted
•Potential anti-inflammatory effects of linagliptin were studied by a PET tracer 18F-FDG in a mouse model of atherosclerosis and diabetes.•Linagliptin treatment did not affect atherosclerotic plaque size or inflammation.•Linagliptin treatment, however, did reduce hepatic inflammation.
The
Gallium-labeled 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid conjugated radiolabelled arginine-glycine-aspartic acid peptide (
GaGa-NODAGA-RGD) is a positron emission tomography ...(PET) tracer binding to cell surface receptor α
β
integrin that is upregulated during angiogenesis and inflammation. We studied whether α
β
targeting PET imaging can detect myocardial inflammation in a rat model of autoimmune myocarditis. To induce myocarditis, rats (
= 8) were immunized with porcine cardiac myosin in complete Freund's adjuvant on days 0 and 7. Control rats (
= 8) received Freund's adjuvant alone. On day 21,
PET/CT imaging with
GaGa-NODAGA-RGD followed by
autoradiography and immunohistochemistry were carried out. Inflammatory lesions were detected histologically in the myocardium of 7 out of 8 immunized rats.
PET images showed higher
GaGa-NODAGA-RGD accumulation in the myocardium of rats with inflammation than the non-inflamed myocardium of control rats (SUV
0.4 ± 0.1 vs. 0.1 ± 0.02;
= 0.00006).
autoradiography and histology confirmed that
GaGa-NODAGA-RGD uptake co-localized with inflammatory lesions containing α
β
integrin-positive capillary-like structures. A non-specific
GaGa-DOTA-(RGE)
tracer showed 76% lower uptake than
GaGa-NODAGA-RGD in the inflamed myocardium. Our results indicate that α
β
integrin-targeting
GaGa-NODAGA-RGD is a potential PET tracer for the specific detection of active inflammatory lesions in autoimmune myocarditis.
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