Mineralocorticoid antagonists in the treatment of central serous chorioetinopathy: Review of the pre-clinical and clinical evidence
Introduction
Central Serous Chorioretinopathy (CSCR) remains a subject of debate and research. No consensus exists regarding the clinical classification of the different forms of the disease (Singh et al., 2018), the causative factors, the physiopathogenic mechanisms and the optimal treatment options (Daruich et al., 2015a). The hypothesis has been raised that a potential mechanism, being a plausible explanation for the aggravating rather than curative effect of glucocorticoids, could be the overactivation of the mineralocorticoid pathway in the retina and/or choroid of patients with CSCR (Zhao et al., 2012). Indeed, the glucocorticoids can exert either anti-inflammatory and anti-edematous effects or rather pro-inflammatory and pro-edematous effects depending on whether they activate the gluco or the mineralocorticoid receptor (MR) pathways (Behar-Cohen, 2018). The deleterious effects of MR pathway activation have been well studied in the heart and the vessels (Davel et al., 2017; Sztechman et al., 2018) as well as in the kidney (Belden et al., 2017). Based on cellular (Zhao et al., 2010) and preclinical animal studies (Zhao et al., 2012), the use of oral mineralocorticoid receptor antagonists (MRA), which are old drugs indicated for heart failure after myocardial infarction, has been proposed for the treatment of non-spontaneously resolutive CSCR, showing in a cross-over controlled study a drug effect on the short term resorption of the subretinal fluid (Bousquet et al., 2015a). Since then, several studies have shown that oral MRA can benefit to patients with various forms of CSCR. In this review, we will summarize the preclinical and clinical evidence for using MRA in CSCR and related diseases, expose the limitation of oral MRA for ocular diseases and open new perspective to deepen our understanding on the role of gluco and mineralocorticoid pathways in ocular pathology.
Section snippets
Clinical description of CSCR
CSCR is a chorioretinal disease characterized by serous retinal detachment usually associated with pigment epithelium detachments and an increased choroidal thickness. CSCR belongs to the recently described pachychoroid spectrum disorder characterized by dilated choroidal vessels in the Haller layer, called pachyvessels, associated with a thinning of choriocapillaris and Sattler's layer (Cheung et al., 2018). CSCR is the fourth most common retinal disease among non-surgical retinopathy after
Risk factors
Although the precise etiology remains unknown, several risk factors have been identified. The most consistent is the use of corticosteroid medication even through systemic, local or topic administrations (Haimovici et al., 2004; Nicholson et al., 2013). Additional association have been reported, such as stress life event,(Bousquet et al., 2016), Type A and narcissist personalities (Yannuzzi, 1987), sleep disturbances (Ji et al., 2018), shift work (Bousquet et al., 2016; Setrouk et al., 2016)
MR overactivation in CSCR pathophysiology: preclinical evidence
Although CSCR associates many features of ocular inflammation, such as rupture of the outer retinal barrier and edema, CSCR is aggravated or even triggered by use of glucocorticoids (GCs) (Nicholson et al., 2018). Endogenous hypercortisolism has also been associated with CSCR (van Haalen et al., 2018). It seems that, at least in a subgroup of patients, glucocorticoids do not restore the retinal pigment epithelium defect, but instead aggravate it. This paradoxical effect of GCs can be related to
MR overactivation in choroidal neovascularization: preclinical evidence
About one third of chronic CSCR cases are complicated by choroidal neovascularization (CNV) (Bonini Filho et al., 2015). While aldosterone stimulated the proliferation and tubulogenesis in bovine retinal endothelial cells, MR antagonists inhibited retinal neovascularization in oxygen-induces retinopathy rat model through anti-inflammatory and anti-oxydant mechanisms (Wilkinson-Berka et al., 2009). We recently showed that specific MR antagonists reduced choroidal neovascular leakage and
Treatments
Many treatments for CSCR have been proposed with few prospective randomized controlled studies resulting in an absence of international consensus on the more optimal management. One of the major difficulties in designing CSCR trials is that episodes of subretinal fluid spontaneously resorbs in more than 83% of the cases within 6 months and around 50% at 6 months (Daruich et al., 2017) and recurrence can occur in about 40% of the cases, mostly in the first 7 months after resolution of the first
Conclusions and perspectives
To date, the only objective of treatment in CSCR is to reduce subretinal fluid duration. MRA not only can contribute to reach this objective, but MRA have also the potential, if used on the long-term, to limit the underlying vasculopathy and epitheliopathy. Genetic studies have shown that CSCR is not a simple disease, but rather a multigenic and multifactorial disease, which mechanisms still remain poorly understood. As MRA act on transcriptional regulations, they act of multiple pathways, but
Acknowledgment
ANR Agence Nationale de la Recherche grant ROCK-SUR-MeR, ANR-15-CE18-0032
References (114)
- et al.
Shift work: a risk factor for central serous chorioretinopathy
Am. J. Ophthalmol.
(2016) - et al.
Predictive factors of response to mineralocorticoid receptor antagonists in nonresolving central serous chorioretinopathy
Am. J. Ophthalmol.
(2019) - et al.
Half-dose verteporfin photodynamic therapy for acute central serous chorioretinopathy: one-year results of a randomized controlled trial
Ophthalmology
(2008) - et al.
Central serous chorioretinopathy: recent findings and new physiopathology hypothesis
Prog. Retin. Eye Res.
(2015) - et al.
Central serous chorioretinopathy: recent findings and new physiopathology hypothesis
Prog. Retin. Eye Res.
(2015) - et al.
Chronic central serous chorioretinopathy is associated with genetic variants implicated in age-related macular degeneration
Ophthalmology
(2015) - et al.
A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule
J. Biol. Chem.
(2010) - et al.
One-year outcomes with half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy
Ophthalmology
(2015) - et al.
Risk factors for central serous chorioretinopathy: a case-control study
Ophthalmology
(2004) - et al.
Fundus autofluorescence and visual acuity in central serous chorioretinopathy
Ophthalmology
(2011)
A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy
J. Diabetes Complicat.
The incidence of central serous chorioretinopathy in Olmsted County, Minnesota, 1980-2002
Ophthalmology
Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics
Mol. Cell. Endocrinol.
A multicenter study on the long-term outcomes of half-dose photodynamic therapy in chronic central serous chorioretinopathy
Am. J. Ophthalmol.
Subfoveal choroidal thickness after treatment of central serous chorioretinopathy
Ophthalmology
The 45-year story of the development of an anti-aldosterone more specific than spironolactone
Mol. Cell. Endocrinol.
Central serous chorioretinopathy associated with administration of sympathomimetic agents
Am. J. Ophthalmol.
Common variants in the complement factor H gene confer genetic susceptibility to central serous chorioretinopathy
Ophthalmology
Long-term visual outcomes and causes of vision loss in chronic central serous chorioretinopathy
Ophthalmology
Relative inhibitory potency of five mineralocorticoid antagonists on aldosterone biosynthesis in vitro
Biochem. Pharmacol.
Central serous chorioretinopathy: update on pathophysiology and treatment
Surv. Ophthalmol.
Central serous chorioretinopathy and glucocorticoids: an update on evidence for association
Surv. Ophthalmol.
Inhibition of hormonal-induced cAMP and steroid production by inhibitors of pregnenolone metabolism in adrenal and Leydig cells
Mol. Cell. Endocrinol.
Direct, indirect, and sham laser photocoagulation in the management of central serous chorioretinopathy
Am. J. Ophthalmol.
[Eplerenone treatment in chronic central serous chorioretinopathy]
J. Fr. Ophtalmol.
Cerebral uptake of a 3 H-labelled spirolactone compound in the dog
Eur. J. Pharmacol.
Oral eplerenone for the management of chronic central serous chorioretinopathy
Int. J. Ophthalmol.
Half-dose photodynamic therapy versus high-density subthreshold micropulse laser treatment in patients with chronic central serous chorioretinopathy: the PLACE trial
Ophthalmology
Towards an optimized use of ocular corticosteroids: EURETINA award lecture 2017
Ophthalmologica
The role of the mineralocorticoid receptor in inflammation: focus on kidney and vasculature
Am. J. Nephrol.
Association of choroidal neovascularization and central serous chorioretinopathy with optical coherence tomography angiography
JAMA Ophthalmol
Spironolactone for nonresolving central serous chorioretinopathy: a randomized controlled crossover study
Retina
Mineralocorticoid receptor antagonism in the treatment of chronic central serous chorioretinopathy: a pilot study
Retina
Clinical experience with eplerenone to treat chronic central serous chorioretinopathy
Graefes Arch. Clin. Exp. Ophthalmol.
New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure
J. Nephrol.
Long-term follow-up of central serous retinopathy in 150 patients
Doc. Ophthalmol.
Multifocal electroretinogram abnormalities persist following resolution of central serous chorioretinopathy
Arch. Ophthalmol.
Pachychoroid disease
Eye (Lond)
Oral mineralocorticoid antagonists for recalcitrant central serous chorioretinopathy
Clin. Ophthalmol.
Vascular consequences of aldosterone excess and mineralocorticoid receptor antagonism
Curr. Hypertens. Rev.
CHOROIDAL THICKNESS IN PATIENTS WITH CENTRAL SEROUS CHORIORETINOPATHY: assessment of haller and sattler layers
Retina
Oral mineralocorticoid-receptor antagonists: real-life experience in clinical subtypes of nonresolving central serous chorioretinopathy with chronic epitheliopathy
Transl Vis Sci Technol
Acute central serous chorioretinopathy: factors influencing episode duration
Retina
The endothelial mineralocorticoid receptor: mediator of the switch from vascular health to disease
Curr. Opin. Nephrol. Hypertens.
30 Years of the Mineralocorticoid Receptor: the role of the mineralocorticoid receptor in the vasculature
J. Endocrinol.
Indocyanine green angiography of pachychoroid pigment epitheliopathy
Retina
Visual and anatomical outcomes of spironolactone therapy in patients with chronic central serous chorioretinopathy
J. Ophthalmic Vis. Res.
Long-term follow-up of a prospective trial of argon laser photocoagulation in the treatment of central serous retinopathy
Br. J. Ophthalmol.
30 years of the mineralocorticoid receptor: mineralocorticoid receptor activation and specificity-conferring mechanisms: a brief history
J. Endocrinol.
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