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The pachychoroid disease spectrum (PDS) includes several chorioretinal diseases that share specific choroidal abnormalities. Although their pathophysiological basis is poorly understood, diseases that are part of the PDS have been hypothesized to be the result of venous congestion. Within the PDS, central serous chorioretinopathy is the most common condition associated with vision loss, due to an accumulation of subretinal fluid in the macula. Central serous chorioretinopathy is characterized by distinct risk factors, most notably a high prevalence in males and exposure to corticosteroids. Interestingly, sex differences and corticosteroids are also strongly associated with specific types of arteriovenous anastomoses in the human body, including dural arteriovenous fistula and surgically created arteriovenous shunts. In this manuscript, we assess the potential of such arteriovenous anastomoses in the choroid as a causal mechanism of the PDS. We propose how this may provide a novel unifying concept on the pathophysiological basis of the PDS, and present cases in which this mechanism may play a role.

The choroid is a key player in maintaining ocular homeostasis and plays a role in a variety of chorioretinal diseases, many of which are poorly understood. Recent advances in the field of single-cell RNA sequencing have yielded valuable insights into the properties of choroidal endothelial cells (CECs). Here, we review the role of the choroid in various physiological and pathophysiological mechanisms, focusing on the role of CECs. We also discuss new insights regarding the phenotypic properties of CECs, CEC subpopulations, and the value of measuring transcriptomics in primary CEC cultures derived from post-mortem eyes. In addition, we discuss key phenotypic, structural, and functional differences that distinguish CECs from other endothelial cells such as retinal vascular endothelial cells. Understanding the specific clinical and molecular properties of the choroid will shed new light on the pathogenesis of the broad clinical range of chorioretinal diseases such as age-related macular degeneration, central serous chorioretinopathy and other diseases within the pachychoroid spectrum, uveitis, and diabetic choroidopathy. Although our knowledge is still relatively limited with respect to the clinical features and molecular pathways that underlie these chorioretinal diseases, we summarise new approaches and discuss future directions for gaining new insights into these sight-threatening diseases and highlight new therapeutic strategies such as pluripotent stem cell‒based technologies and gene therapy.

Purpose: The aim of the study was to assess the role of sex hormones in male and female patients with central serous chorioretinopathy (CSC), a disease with a pronounced male predilection. Methods: A total of 206 chronic CSC patients (183 males, 23 females) and 59 healthy controls (29 males, 30 females) were enrolled. Serum testosterone, estradiol, albumin, and sex hormone-binding globulin levels were determined using immunoassays. The free fraction of testosterone and the free testosterone/estradiol ratio were calculated. Results: No differences in the levels of total testosterone and estradiol were observed between CSC patients and healthy controls. Albumin levels were found to be lower in male CSC patients compared to controls (controls 47.8 g/L, patients 46.0 g/L, adj. p = 0.006). Only in females with CSC, sex hormone-binding globulin levels were found to be lower (controls 94.2 nmol/L, patients 50.4 nmol/L, adj. p = 0.001), together with a higher free testosterone/estradiol ratio (controls 0.06, patients 0.18, adj. p = 0.018). Conclusions: In this study, we did not find evidence for a disturbance in sex hormone levels in males with CSC. The lower levels of sex hormone-binding globulin in females with CSC, leading to a disturbed free testosterone/estradiol ratio, warrant further investigation into the role of androgens in females with CSC.

Multiple case series have provided evidence for a relatively high incidence of central serous chorioretinopathy (CSC) in patients with active Cushing’s syndrome (CS). We describe the ophthalmological status in detail of consecutive patients with active endogenous CS (either de novo or recurrent active endogenous CS) in this prospective cohort study. All patients underwent complete ophthalmological examination, including multimodal imaging, which was performed shortly after establishing the diagnosis of active CS in hypercortisolemic state. Eleven CS patients (4 men, 7 women) with active hypercortisolism were included. Abnormalities reminiscent of (subclinical) CSC were found in 3 patients. Optical coherence tomography (OCT) revealed macular subretinal fluid in 1 patient, who was diagnosed as having active CSC and was successfully treated with half-dose photodynamic therapy. Two other patients showed CSC-like abnormalities: an unilateral pseudovitelliform lesion on OCT and hyperfluorescent changes on fluorescein angiography in one patient, and unilateral leakage on fluorescein angiography in the other patient. Mean subfoveal choroidal thickness on enhanced depth imaging OCT was 270 ± 40 μm (range, 178 – 357 μm). Retinal abnormalities resembling (subclinical) CSC may be more common than previously thought in patients with active CS, and may exist even in patients without visual complaints. Clinicians should have a low threshold for ophthalmological evaluation in case of a CS patient with visual symptoms since there may be therapeutic opportunities to prevent vision loss.

Purpose: Central serous chorioretinopathy (CSC), a distinct form of macular degeneration, has been associated with glucocorticoid use and possibly also with an increased endogenous activity of the hypothalamic-pituitary-adrenal (HPA) axis. To estimate long-term glucocorticoid exposure, measurement of hair cortisol concentrations (HCC) has emerged. This cross-sectional study aimed to investigate HCC, as a reflection of chronic endogenous steroid exposure, in a cohort of patients with chronic CSC (cCSC).Methods: Hair cortisol concentrations (HCC) were determined in 48 patients with cCSC and 230 population-based controls (Lifelines cohort study), not using exogenous corticosteroids.Results: Increased HCC (defined as >10.49 pg/mg) were present in 2 (4%) patients with cCSC and 13 (6%) controls. Mean HCC values were not different between patients and controls, and no difference in HCC was found between patients with active cCSC disease and patients with inactive disease. No correlation between HCC and urinary free cortisol (UFC) levels in patients with cCSC was found.Conclusions: This study shows that HCC in patients with cCSC are not elevated compared to population-based controls, and no association between HCC and cCSC severity was found. This finding questions the previous suggestion that cCSC is associated with increased HPA axis activity. In line, HCC do not seem useful in monitoring cCSC disease activity.

This study describes the clinical, genetic, and histopathological features in patients with RPGR-associated retinal dystrophies. Nine male patients from eight unrelated families underwent a comprehensive ophthalmic examination. Additionally, the histopathology of the right eye from a patient with an end-stage cone-rod-dystrophy (CRD)/sector retinitis pigmentosa (RP) phenotype was examined. All RPGR mutations causing a CRD phenotype were situated in exon ORF15. The mean best-corrected visual acuity (BCVA, decimals) was 0.58 (standard deviation (SD)): 0.34, range: 0.05&ndash, 1.13), and the mean spherical refractive error was &minus, 4.1 D (SD: 2.11, range: &minus, 1.38 to &minus, 8.19). Hyperautofluorescent rings were observed in six patients. Full-field electroretinography responses were absent in all patients. The visual field defects ranged from peripheral constriction to central islands. The mean macular sensitivity on microperimetry was 11.6 dB (SD: 7.8, range: 1.6&ndash, 24.4) and correlated significantly with BCVA (r = 0.907, p = 0.001). A histological examination of the donor eye showed disruption of retinal topology and stratification, with a more severe loss found in the peripheral regions. Reactive gliosis was seen in the inner layers of all regions. Our study demonstrates the highly variable phenotype found in RPGR-associated retinal dystrophies. Therapies should be applied at the earliest signs of photoreceptor degeneration, prior to the remodeling of the inner retina.

Purpose To isolate, culture, and characterize primary human choroidal endothelial cells, and to assess their responsiveness to corticosteroids, in order to enable knowledge gain on the pathogenesis of central serous chorioretinopathy. Methods Choroidal endothelial cells were isolated from cadaveric human donors. Magnetic-activated cell sorting with anti-human CD31 was performed for choroidal endothelial cell isolation. Primary cultures of purified choroidal endothelial cells were treated with several regimens of corticosteroids and analyzed for effects on primary corticosteroid responsive genes. Results Isolated choroidal endothelial cell cultures had a cobblestone appearance in monolayer cultures and stained positive for vascular endothelial cadherin. Moreover, on a 3D-Matrigel matrix, these cells formed capillary-like structures, characteristic of in vitro endothelial cells. Primary cultures of purified choroidal endothelial cells treated with several regimens of corticosteroids demonstrated significant transcriptional upregulation of primary corticosteroid responsive genes (FKBP5, PER1, GILZ, and SGK1). Further pharmacologic analysis using specific agonists (dexamethasone, aldosterone) and antagonists (mifepristone, spironolactone) for either the glucocorticoid receptor or the mineralocorticoid receptor showed that this response was exclusively mediated by the glucocorticoid receptor in our model. Conclusions With this optimized choroidal endothelial cell isolation and culturing protocol, we have established an in vitro model that appears very suitable for research on both central serous chorioretinopathy and other diseases in which corticosteroids and choroidal endothelial cells are involved. Our model proves to be suitable for studying effects mediated through the glucocorticoid receptor. The role of mineralocorticoid receptor-mediated effects needs further research, both in vivo and in cell model development.