Ignite Creation Date:
2024-05-06 @ 2:20 PM
Last Modification Date:
2024-10-26 @ 1:28 PM
Study NCT ID:
NCT04280523
Status:
COMPLETED
Last Update Posted:
2024-03-01
First Post:
2020-01-15
Brief Title:
TranspulmonarY Estrogen Gradient and Estrogen Receptors TYEGER in PAH
Sponsor:
Vanderbilt University Medical Center
Organization:
Vanderbilt University Medical Center
Study Overview
Official Title:
TranspulmonarY Estrogen Gradient and Estrogen Receptors TYEGER in PAH
Status:
COMPLETED
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TYEGER
Brief Summary:
Pulmonary arterial hypertension PAH is a disease characterized by elevated pressures in the blood vessels of the lungs that is not caused by another disease processes More specifically it is defined by a mean pulmonary artery pressure 25 mm Hg a pulmonary vascular resistance 3 Wood Units WU and a normal pulmonary capillary wedge pressure in the absence of other etiology of pulmonary hypertension The underlying mechanism of the disease in still unknown but marked changes to the small arteries in the lungs have been observed These changes include thickening of vessel walls and clot formation -- making the vessels less capable of gas exchange Currently PAH therapies focus on dilating the good remaining vessels that havent been altered by this disease process however this therapy does not cure the disease Survival remains low despite progress
There is growing human and experimental evidence supporting the concept that estrogens and estrogen receptors in the lungs are involved in the process that leads to PAH
As mentioned above no current therapies attack the cause of PAH they only act to dilate remaining good vessels which can reduce the burden of the disease but not cure it Thus there is a critical need for novel therapeutics as recently highlighted by a National Institute of Health workshop on pulmonary vascular diseases which called for the exploration of novel therapeutic approaches None of the current FDA-approved treatments for PAH target estrogen or estrogen receptors
Despite the evidence supporting the concept that estrogens and estrogen receptors in the lungs contribute to PAH no human studies investigate the estrogen level and the amount of estrogen receptors within the lungs of patients with PAH and their potential associations with current disease severity or 1 year outcomes including survival after 1 year functional status etc Investigators hypothesize that a subset of PAH patients will have higher levels of estrogen and estrogen receptors in their lungs which would make them good candidates for novel therapies that block estrogen in hopes of halting the disease process
There is growing human and experimental evidence supporting the concept that estrogens and estrogen receptors in the lungs are involved in the process that leads to PAH
As mentioned above no current therapies attack the cause of PAH they only act to dilate remaining good vessels which can reduce the burden of the disease but not cure it Thus there is a critical need for novel therapeutics as recently highlighted by a National Institute of Health workshop on pulmonary vascular diseases which called for the exploration of novel therapeutic approaches None of the current FDA-approved treatments for PAH target estrogen or estrogen receptors
Despite the evidence supporting the concept that estrogens and estrogen receptors in the lungs contribute to PAH no human studies investigate the estrogen level and the amount of estrogen receptors within the lungs of patients with PAH and their potential associations with current disease severity or 1 year outcomes including survival after 1 year functional status etc Investigators hypothesize that a subset of PAH patients will have higher levels of estrogen and estrogen receptors in their lungs which would make them good candidates for novel therapies that block estrogen in hopes of halting the disease process
Detailed Description:
The strongest established risk factor for the progressively fatal disease pulmonary arterial hypertension PAH is female sex 31 femalemale ratio Investigators and others have found higher circulating estrogen levels and enhanced estrogen signaling in PAH patients Evidence suggests that exuberant estrogen signaling causes a perturbation of mitochondrial function and energy substrate utilization in both sexes However systemic estrogen level elevation is not uniform among patients and the affinity of the pulmonary vascular bed for estrogens is unknown In preliminary studies of prevalent PAH patients estradiol E2 levels dropped across the pulmonary vasculature suggestive of E2 uptake by the lungs those patients with a high transpulmonary gradient pre- minus post-capillary had a higher mean pulmonary artery pressure at diagnosis
Investigators previously confirmed that urine 16α-hydroxyestrone 16αOHE1 is elevated at least 2-fold in females and males with PAH consistent with data from other groups that estrogens are elevated in PAH 16αOHE1 is an estrogen metabolite with high affinity for the canonical estrogen receptors ESRα and ESRβ and thus an active estrogen Investigators published that in a transgenic mouse model of PAH administration of 16αOHE1 significantly increased PAH penetrance concomitant with features of oxidant stress including elevated isoprostanes IsoPs and isofurans IsoFs Those animals also developed insulin resistance and mitochondrial dysfunction characteristics investigators have described during the current PPG in humans with PAH Concomitantly through ESR signaling 16αOHE1 reduced PPARγ expression via reduction in PGC1α By co-administering drugs to block extra-gonadal estrogen synthesis and receptor signaling investigators were able to prevent or reverse the cellular metabolic defects and pulmonary vascular phenotype in investigators transgenic model system
The capacity for enhanced estrogen signaling represented by elevated blood E2 levels elevated urinary 16αOHE1 and specific genetic variants is a characteristic of PAH patients of both sexes in several studies Experimental data from investigators group and others support the concept that estrogen antagonism may be beneficial for humans with PAH However investigators recognize that not all subjects will benefit from estrogen antagonism making a one size fits all approach too narrow
Investigators and others have shown that estrogens directly alter pulmonary vascular cell homeostasis and gene expression including reduction in BMPR2 expression and signaling via ESR and experimental PAH models demonstrate increased expression of aromatase an enzyme which converts androgens to estrogens in the lungs But no human studies investigate the direct contribution of the pulmonary circulation to estrogen avidity ESR density and outcomes Investigators propose to evaluate the influence of estrogens on the pulmonary vasculature and cardiac function using incident and prevalent PAH cases to reduce confounding by disease course Findings from this study should help determine patients most likely to have a beneficial response to estrogen antagonism supporting the overall project goal to improve precision medicine approaches in PAH
Investigators hypothesize that blood-based and radiologic markers of estrogen burden will support the determination of a phenotype profile of subjects with PAH for whom estrogen antagonism will be an effective therapeutic approach In a cohort of PAH patients investigators will determine if transpulmonary change pre- to post-pulmonary capillary bed E2 levels andor lung ESR density associate with disease severity at cardiac catheterization functional capacity time to clinical worsening and oxidant stress
Specific Aim 1 To test the hypothesis that among PAH patients transpulmonary TP E2 gradient associates with a more severe hemodynamic profile and worse 1 year outcomes
Specific Aim 2 To test the hypothesis that among PAH patients higher lung ESR density associates with a more severe hemodynamic profile and worse 1 year outcomes
These studies may ultimately lead to novel discoveries in the transpulmonary gradient of sex hormones investigate a novel imaging approach in PAH optimize the ability to precisely determine the correct patient for sex hormone modification and potentially support the development of novel therapeutic targets in PAH The data collected in this study will also synergize with an ongoing NIH-supported clinical trial to investigate the use of sex hormone modification as a therapeutic approach for PAH
ClinicalTrialsgov Identifier NCT03528902
Investigators previously confirmed that urine 16α-hydroxyestrone 16αOHE1 is elevated at least 2-fold in females and males with PAH consistent with data from other groups that estrogens are elevated in PAH 16αOHE1 is an estrogen metabolite with high affinity for the canonical estrogen receptors ESRα and ESRβ and thus an active estrogen Investigators published that in a transgenic mouse model of PAH administration of 16αOHE1 significantly increased PAH penetrance concomitant with features of oxidant stress including elevated isoprostanes IsoPs and isofurans IsoFs Those animals also developed insulin resistance and mitochondrial dysfunction characteristics investigators have described during the current PPG in humans with PAH Concomitantly through ESR signaling 16αOHE1 reduced PPARγ expression via reduction in PGC1α By co-administering drugs to block extra-gonadal estrogen synthesis and receptor signaling investigators were able to prevent or reverse the cellular metabolic defects and pulmonary vascular phenotype in investigators transgenic model system
The capacity for enhanced estrogen signaling represented by elevated blood E2 levels elevated urinary 16αOHE1 and specific genetic variants is a characteristic of PAH patients of both sexes in several studies Experimental data from investigators group and others support the concept that estrogen antagonism may be beneficial for humans with PAH However investigators recognize that not all subjects will benefit from estrogen antagonism making a one size fits all approach too narrow
Investigators and others have shown that estrogens directly alter pulmonary vascular cell homeostasis and gene expression including reduction in BMPR2 expression and signaling via ESR and experimental PAH models demonstrate increased expression of aromatase an enzyme which converts androgens to estrogens in the lungs But no human studies investigate the direct contribution of the pulmonary circulation to estrogen avidity ESR density and outcomes Investigators propose to evaluate the influence of estrogens on the pulmonary vasculature and cardiac function using incident and prevalent PAH cases to reduce confounding by disease course Findings from this study should help determine patients most likely to have a beneficial response to estrogen antagonism supporting the overall project goal to improve precision medicine approaches in PAH
Investigators hypothesize that blood-based and radiologic markers of estrogen burden will support the determination of a phenotype profile of subjects with PAH for whom estrogen antagonism will be an effective therapeutic approach In a cohort of PAH patients investigators will determine if transpulmonary change pre- to post-pulmonary capillary bed E2 levels andor lung ESR density associate with disease severity at cardiac catheterization functional capacity time to clinical worsening and oxidant stress
Specific Aim 1 To test the hypothesis that among PAH patients transpulmonary TP E2 gradient associates with a more severe hemodynamic profile and worse 1 year outcomes
Specific Aim 2 To test the hypothesis that among PAH patients higher lung ESR density associates with a more severe hemodynamic profile and worse 1 year outcomes
These studies may ultimately lead to novel discoveries in the transpulmonary gradient of sex hormones investigate a novel imaging approach in PAH optimize the ability to precisely determine the correct patient for sex hormone modification and potentially support the development of novel therapeutic targets in PAH The data collected in this study will also synergize with an ongoing NIH-supported clinical trial to investigate the use of sex hormone modification as a therapeutic approach for PAH
ClinicalTrialsgov Identifier NCT03528902
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None