Association between Anticardiolipin Antibody Positivity and Increased 17‐Beta‐Estradiol Levels in Premenopausal Women with Rheumatoid Arthritis<sup>a</sup>

Seriolo, Bruno; Accardo, S; Garnero, A.; Fasciolo, D.; Cutolo, Maurizio

doi:10.1111/j.1749-6632.1999.tb07635.x

Cited by 7 publications

(4 citation statements)

References 17 publications

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“…In conclusion, these results might suggest that persistent high 17β-estradiol levels, observed at least in premenopausal patients with RA, may predispose to a more efficient immune response, including the enhanced expression of aCL antibodies. This correlation between 17β-estradiol levels and aCL antibodies might contribute to the higher mortality risk for female patients during the reproductive years [54].…”

Section: Apl Antibodies and Atherosclerosis In Ramentioning

confidence: 94%

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

Olech

Merrill²

2006

Curr Rheumatol Rep

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Published data were reviewed to evaluate the occurrence of antiphospholipid antibodies (aPL) in rheumatoid arthritis (RA) patients and to investigate their clinical relevance in this population. The mean prevalence was calculated at 28% and the median was 22%. Few studies have found a relationship between aPL antibodies and thrombosis, particularly in combination with other risk factors. Conflicting results have been reported on the association of anticardiolipin (aCL) antibody positivity and neurologic symptoms, Reynaud's phenomenon, disease activity, radiographic erosions, extra-articular RA manifestations, rheumatoid factor, and atherosclerosis. Some studies, however, suggest that there is a correlation present between those antibodies and C-reactive protein levels, rheumatoid nodules, and antinuclear antibodies. TNF-alpha blocking agents may cause an induction of aCL antibodies, but it seems like they do not cause any clinical features related to the antiphospholipid syndrome. Higher 17beta-estradiol levels were observed in aCL antibody-positive RA patients than in aCL antibody-negative patients and especially in premenopausal women, which may predispose to a more efficient immune response.

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Section: Apl Antibodies and Atherosclerosis In Ramentioning

confidence: 94%

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

Olech

Merrill²

2006

Curr Rheumatol Rep

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“…Both elevated levels of pro-inflammatory cytokines (69) and the presence of inflammatory cells around plexiform lesions, including macrophages and T and B lymphocytes, have been reported in patients with PAH (70). Inflammatory cells such as macrophages and lymphocytes and pro-inflammatory cytokines such as TNFα, and IL-6 strongly induce aromatase activity (71-73) and peripheral E2 synthesis (74). Notably, estriol (16α-hydroxyestradiol; E3) strongly stimulates the expression of TNFα and IL-6 (75), and thus the shift toward the 16α-hydroxylation pathway should be expected to increase peripheral E2 synthesis.…”

Section: Estradiol Metabolism and Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Tofovic

2010

Journal of Cardiovascular Pharmacology

102

113

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Severe pulmonary arterial hypertension (PAH) is characterized by clustered proliferation of endothelial cells in the lumina of small size pulmonary arteries resulting in concentric obliteration of the lumina and formation of complex vascular structures known as plexiform lesions. This debilitating disease occurs more frequently in women, yet both animal studies in classical models of PAH and limited clinical data suggest protective effects of estrogens: the estrogen paradox in pulmonary hypertension. Little is known about the role of estrogens in PAH, but one line of evidence strongly suggests that the vascular protective effects of 17β-estradiol (estradiol; E2) are mediated largely by its downstream metabolites. Estradiol is metabolized to 2-hydroxyestradiol (2HE) by CYP1A1/CYP1B1, and 2HE is converted to 2-methoxyestradiol (2ME) by catechol-Omethyl transferase. 2ME is extensively metabolized to 2-methoxyestrone, a metabolite that lacks biologic activity but which may be converted back to 2ME. 2ME has no estrogenic activity and its effects are mediated by estrogen receptors-independent mechanism(s). Notably, in systemic and pulmonary vascular endothelial cells, smooth muscle cells, and fibroblasts 2ME exerts stronger anti-mitotic effects than E2 itself. E2 and 2ME, despite having similar effects on other cardiovascular cells, have opposing effects on endothelial cells; that is, in endothelial cells, E2 is pro-mitogenic, pro-angiogenic and anti-apoptotic, whereas 2ME is antimitogenic, anti-angiogenic and pro-apoptotic. This may have significant ramifications in severe PAH that involves uncontrolled proliferation of monoclonal, apoptosis resistant endothelial cells. Based on its cellular effects, 2ME should be expected to attenuate the progression of disease and provide protection in severe PAH. In contrast, E2, due to its mitogenic, angiogenic, and anti-apoptotic effects (otherwise desirable in normal, quiescent endothelial cells), may even adversely affect endothelial remodeling in PAH and this may be even more significant if the E2's effects on injured endothelium are not opposed by 2ME (e.g., in the event of reduced E2 conversion to 2ME due to hypoxia, inflammation, drugs, environmental factors, or genetic polymorphism of metabolizing enzymes). This review focuses on the effects of estrogens and their metabolites on pulmonary vascular pathobiology and the development of experimental PAH, and offers potential explanation for the estrogen paradox in PAH. Furthermore, we propose that unbalanced estradiol metabolism may lead to the development of PAH. Recent animal data and studies in patients with PAH support this concept.Corresponding Author: Stevan P. Tofovic M.D., Ph.D. FAHA FASN Division of Pulmonary, Allergy and Critical Care Medicine and Vascular Medicine Institute, Department of Medicine University of Pittsburgh School of Medicine Bridge side 542 100 Technology Drive, Pittsburgh, PA 15219 FAX +412-624-5070 Phone +412-648-3363 tofovic@dom.pitt.edu. This is a PDF file of an unedited manuscript that ...

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“…Pulmonary vascular remodeling in HPH requires the recruitment of circulating mesenchymal precursors of the monocyte/macrophage lineage (185), which is essential for the late onset of HPH (186). Studies investigating links between estrogen and inflammation in other diseases have revealed that proinflammatory cytokines such as TNFα, IL-1 and IL-6 stimulate the activity of fibroblast aromatase and increase the level of estrogen (187,188). Upregulation of CYP1B1 leads to increased estrogen catabolism to 4-OHE and 16α-OHE1, which have significant angiogenic, pro-inflammatory and mitogenic properties, and thus promote the development of PAH (46).…”

Section: Immunomodulationmentioning

confidence: 99%

Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension

Sun

Sangam

Guo

et al. 2021

Front. Cardiovasc. Med.

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Pulmonary arterial hypertension (PAH) is a complex and devastating disease with a poor long-term prognosis. While women are at increased risk for developing PAH, they exhibit superior right heart function and higher survival rates than men. Susceptibility to disease risk in PAH has been attributed, in part, to estrogen signaling. In contrast to potential pathological influences of estrogen in patients, studies of animal models reveal estrogen demonstrates protective effects in PAH. Consistent with this latter observation, an ovariectomy in female rats appears to aggravate the condition. This discrepancy between observations from patients and animal models is often called the “estrogen paradox.” Further, the tissue-specific interactions between estrogen, its metabolites and receptors in PAH and right heart function remain complex; nonetheless, these relationships are essential to characterize to better understand PAH pathophysiology and to potentially develop novel therapeutic and curative targets. In this review, we explore estrogen-mediated mechanisms that may further explain this paradox by summarizing published literature related to: (1) the synthesis and catabolism of estrogen; (2) activity and functions of the various estrogen receptors; (3) the multiple modalities of estrogen signaling in cells; and (4) the role of estrogen and its diverse metabolites on the susceptibility to, and progression of, PAH as well as their impact on right heart function.

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Association between Anticardiolipin Antibody Positivity and Increased 17‐Beta‐Estradiol Levels in Premenopausal Women with Rheumatoid Arthritis^a

Cited by 7 publications

References 17 publications

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension

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Association between Anticardiolipin Antibody Positivity and Increased 17‐Beta‐Estradiol Levels in Premenopausal Women with Rheumatoid Arthritisa

Cited by 7 publications

References 17 publications

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension

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Association between Anticardiolipin Antibody Positivity and Increased 17‐Beta‐Estradiol Levels in Premenopausal Women with Rheumatoid Arthritis^a