{"id":4848,"date":"2026-08-23T13:56:32","date_gmt":"2026-08-23T13:56:32","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=4848"},"modified":"2026-08-24T23:01:52","modified_gmt":"2026-08-24T23:01:52","slug":"summary-pge2-hypothesis-article","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=4848","title":{"rendered":"Summary PGE2 hypothesis article"},"content":{"rendered":"\t\t<div data-elementor-type=\"wp-page\" data-elementor-id=\"4848\" class=\"elementor elementor-4848\">\n\t\t\t\t<div class=\"elementor-element elementor-element-b821526 e-flex e-con-boxed e-con e-parent\" data-id=\"b821526\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-2d57179 elementor-widget elementor-widget-spacer\" data-id=\"2d57179\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"spacer.default\">\n\t\t\t\t\t\t\t<div class=\"elementor-spacer\">\n\t\t\t<div class=\"elementor-spacer-inner\"><\/div>\n\t\t<\/div>\n\t\t\t\t\t\t<\/div>\n\t\t\t\t<div class=\"elementor-element elementor-element-baf0d57 elementor-widget elementor-widget-heading\" data-id=\"baf0d57\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"heading.default\">\n\t\t\t\t\t<h2 class=\"elementor-heading-title elementor-size-default\">Summary PGE2 hypothesis article<\/h2>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-049aba3 e-flex e-con-boxed e-con e-parent\" data-id=\"049aba3\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-9fb45e3 elementor-widget elementor-widget-text-editor\" data-id=\"9fb45e3\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t<h3><br \/>Persistent Prostaglandin E2 Upregulation as an Integrative Framework for Long COVID and Related Fatigue Syndromes<\/h3><p><em>A concise overview of a testable hypothesis<\/em><\/p><p>Vjera Ramer<sup>1<\/sup>, Gert A. van Montfrans<sup>2 <br \/><\/sup><br \/><sup>1 <\/sup>Independent Researcher, Amsterdam, corresponding author (<a href=\"mailto:the.PGE2hypothesis@proton.me\">the.PGE2hypothesis@proton.me<\/a>) <br \/><sup>2 <\/sup>Academic Medical Centre, University of Amsterdam, Department of Internal Medicine<\/p><p><strong>Background<\/strong><\/p><p>Fundamental questions about Long COVID (LC) and related post-infectious conditions, including post-acute infection syndrome (PAIS) and myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS), remain unanswered. It is unclear why diverse triggering events can lead to similar chronic disease phenotypes and why patients with the same diagnosis may develop markedly different clinical presentations.<\/p><p>Numerous pathophysiological abnormalities have been described in LC, including cognitive impairment, mitochondrial dysfunction, autonomic dysregulation, viral persistence, autoimmunity, and abnormalities affecting multiple organ systems. In our recently published hypothesis article, <em>\u201cPersistent Prostaglandin E2Upregulation and Hormonal Multiresistance: A Hypothesis for Long COVID\u201d<\/em>, we propose a possible biological framework that may explain the development and persistence of these processes.<\/p><p>The hypothesis is experimentally testable and may also apply to related fatigue syndromes. If confirmed, it could provide leads for patient stratification and a more targeted use of already investigated Long COVID treatments. This summary aims to make these potential new insights accessible to a broader medical audience. Further information and references are available in our publication<sup>1<\/sup>.<\/p><p><strong>A new perspective on a familiar inflammatory mediator: Prostaglandin E2 (PGE2)<\/strong><\/p><p>PGE2 is one of the most biologically active members of the prostaglandin family, a group of paracrine signalling molecules. Through its broad effects on immune and physiological processes, PGE2 contributes to the systemic manifestations of acute illness, including fever, inflammation, pain, and fatigue, collectively known as the sickness syndrome.<\/p><p>Remarkably elevated PGE2 concentrations have been reported in COVID-19. Based on an extensive review of the literature, we propose that increased PGE2 activity is also involved in numerous pathophysiological processes observed in LC. We hypothesize that persistent PGE2 overactivity may represent a mechanistic bridge between acute inflammation and chronic post-infectious fatigue syndromes.<\/p><p>In the following sections, we summarize the key findings supporting a central role for PGE2 and describe the underlying mechanism proposed in our hypothesis.<\/p><p><strong>Why PGE2 is a plausible candidate<\/strong><\/p><p>Five observations from the literature support a possible central role for PGE2 in LC, PAIS, and ME\/CFS:<\/p><ul><li>All types of infections, as well as other triggers associated with post-infectious fatigue syndromes, including major surgery, burns, traumatic brain injury, and childbirth, increase PGE2 production. Although this does not establish causality, PGE\u2082\u2019s immunoregulatory properties make it a plausible link between acute and chronic disease processes.<\/li><li>Elevated PGE2 concentrations have been reported in patients with LC and related conditions, including ME\/CFS.<\/li><li>Literature searches addressing individual LC-associated mechanisms, symptoms, and comorbidities repeatedly identify evidence for a relevant role of PGE2<\/li><li>Several partially successful interventions investigated for LC have been shown to reduce PGE2 activity.<\/li><li>Independent studies have identified four recognizable clinical subphenotypes of LC. PGE2 signals through four EP receptors whose functional spectrum corresponds with the reported symptom clusters and cytokine profiles. Differences in EP receptor expression may help explain both clinical heterogeneity and variation in treatment response.<\/li><\/ul><p><strong>Why has a central role for PGE2 not been proposed before?<\/strong><\/p><p>Prostaglandins are short-lived paracrine signalling molecules that act locally and are therefore not generally considered potential drivers of systemic disease processes. Nevertheless, PGE2 produces body-wide effects, including fever. To understand how this transient signalling molecule could generate such persistent and widespread effects, we integrated findings from different medical disciplines into a broader framework. We hypothesize that the explanation may lie in the extensive interactions between PGE2 and the many endocrine hormones, growth factors, and cytokines that can stimulate PGE2 production in a dose-dependent manner throughout the body and brain.<\/p><p><strong>PGE2 and its four receptors<\/strong><\/p><p>PGE2 exerts its effects through four E-prostanoid (EP) receptors (EP1 &#8211; EP4), which are expressed on most cell types and have also been detected in the nucleus and mitochondria. EP receptor expression varies between tissues and individuals and is influenced by multiple biological factors, including age, sex hormones, and, importantly, PGE2 concentrations themselves. EP3 and EP4 are widely expressed and fulfil essential but often opposing functions.<\/p><p>Through EP3, PGE2 promotes the production of pro-inflammatory cytokines, which can in turn further stimulate PGE2 synthesis. This creates positive feedback loops that may contribute to cytokine storms, amplifying fever and inflammation. We therefore hypothesize that relatively high EP3 expression may increase the risk of severe acute disease, particularly in groups known to have higher baseline PGE2 activity, including older individuals, men, and people with obesity or underlying disease.<\/p><p>At higher PGE2 concentrations, signalling through EP4 becomes increasingly relevant and promotes anti-inflammatory processes. The possibility that some individuals experience mild or asymptomatic infections may therefore be related to a receptor profile characterized by relatively low EP3 and high EP4 expression.<\/p><p>During prolonged PGE2 overactivity, both EP receptor expression and downstream signalling pathways may change. Evidence suggests that EP3 can become downregulated, possibly as a protective response against excessive inflammation, while the relative influence of EP1, EP2, and EP4 increases. Thus, an individual with initially high EP3 expression may, following severe acute disease, develop a relatively EP3-deficient receptor profile.<\/p><p>At the same time, chronic PGE2 exposure may alter EP4 signalling towards pathways associated with pro-inflammatory cytokine production, chronic inflammation, and autoimmunity. EP2 and EP1 may contribute to these processes as well. We therefore hypothesize that low EP3 expression may increase susceptibility to chronic inflammation and autoimmunity by allowing the combined influence of EP1, EP2, and EP4 to become pathologically dominant.<\/p><p><strong>The proposed mechanism underlying persistent PGE2 overactivity<\/strong><\/p><p>Persistent PGE2 overactivity may interfere with the actions of other signalling molecules through several mechanisms, including competition for shared signalling pathways (via EP1\u2013EP4), inhibition of their production or secretion (via EP3), and reduced receptor responsiveness through processes such as phosphorylation and antibody-mediated receptor modulation (via EP4, EP2, and EP1).<\/p><p>Importantly, many signalling molecules that are functionally inhibited by PGE2 also stimulate PGE2 production themselves. This may represent a homeostatic feedback mechanism designed to limit excessive activity of these pathways. A well-studied example is the antidiuretic hormone arginine vasopressin (AVP), which stimulates PGE2 production while also being inhibited by PGE2<\/p><p>We hypothesize that, under normal conditions, balanced EP receptor expression allows these opposing effects to remain in equilibrium. However, when this balance becomes disrupted, persistently elevated PGE2 activity may progressively reduce the effectiveness of multiple signalling pathways. PGE\u2082-stimulating hormones and other mediators may then become functionally resistant, as their concentrations increase in an attempt to restore homeostasis, while simultaneously maintaining PGE2 production. This compensatory response may therefore fail to reduce PGE2 activity, resulting in persistent inflammation and chronic symptoms.<\/p><p>Rather than representing a biological \u201cflaw\u201d, this process may reflect an initially protective and reversible adaptation that becomes maladaptive when homeostatic imbalance exceeds a certain threshold. The acute sickness syndrome appears to conserve energy for immune defence and recovery. Chronic disease states may similarly involve conserved survival mechanisms that were originally adaptive under prolonged extreme conditions. Consistent with this concept, both PGE2 overactivity and resistance phenomena have been described in the physiological adaptations underlying hibernation.<\/p><p><strong>How could Long COVID develop after both severe and mild infection?<\/strong><\/p><p>Within this framework, different EP receptor profiles may contribute to different disease trajectories. High EP3 expression may facilitate a stronger acute inflammatory response and a more severe initial infection. Even after subsequent EP3 downregulation, residual EP3 dominance may continue to influence the inflammatory response. Conversely, a relatively EP4-dominant profile may contribute to a milder acute infection.<\/p><p>However, in both situations, excessive PGE2 upregulation could disrupt receptor balance and homeostasis. Through the mechanisms described above, this may ultimately result in persistent PGE2 overactivity and chronic symptoms.<\/p><p><strong>A possible explanation for sex differences<\/strong><\/p><p>The higher frequency of severe acute infection in men compared with women may reflect differences in EP receptor expression, particularly the balance between EP3 and EP4. Men also more frequently develop Long COVID symptoms associated in the literature with EP3-mediated pathways. In addition, oestrogen and progesterone have been reported to reduce EP3 expression.<\/p><p>However, because sex differences in susceptibility to infectious and autoimmune diseases are already apparent before puberty, genetic influences on EP receptor expression may also contribute.<\/p><p><strong>Testable predictions<\/strong><\/p><p>A major strength of this hypothesis is that it generates specific, experimentally testable predictions. PGE2 concentrations can be measured in blood and urine. In addition, EP receptor profiles can be assessed using different techniques in relevant tissues, peripheral blood cells, and mitochondria. These receptor profiles can subsequently be correlated with clinical symptom clusters and cytokine patterns, potentially providing biomarkers for patient stratification.<\/p><p><strong>Conclusion<\/strong><\/p><p>The PGE2 hypothesis provides a possible framework in which existing partial explanations for fatigue syndromes can be integrated. Given the broad biological effects of PGE2, persistent overactivity could contribute to the more than 200 reported symptoms, potentially manifesting as recognizable clinical subphenotypes associated with distinct EP receptor profiles.<\/p><p>If confirmed, this hypothesis may provide leads for biomarker development and a more targeted application of existing and future treatments. Further validation through laboratory studies and clinical research will be required to determine its relevance for diagnosis and therapy.<br \/><br \/>Reference<\/p><p>1\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Ramer, V. &amp; van Montfrans, G. A. Persistent prostaglandin E2 upregulation and hormonal multi-resistance: A hypothesis for long COVID. <em>Biochemistry and Biophysics Reports<\/em> <strong>46<\/strong>, 102518 (2026). <a href=\"https:\/\/doi.org\/https:\/doi.org\/10.1016\/j.bbrep.2026.102518\">https:\/\/doi.org\/https:\/\/doi.org\/10.1016\/j.bbrep.2026.102518<\/a><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"<p>Summary PGE2 hypothesis article Persistent Prostaglandin E2 Upregulation as an Integrative Framework for Long COVID and Related Fatigue Syndromes A [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"site-sidebar-layout":"no-sidebar","site-content-layout":"","ast-site-content-layout":"full-width-container","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"disabled","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"class_list":["post-4848","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/4848","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=4848"}],"version-history":[{"count":22,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/4848\/revisions"}],"predecessor-version":[{"id":5573,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/4848\/revisions\/5573"}],"wp:attachment":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=4848"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}