# Sex Hormones in Pulmonary Arterial Hypertension

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $626,833

## Abstract

Project Summary
The strongest established risk factor for the progressively fatal disease pulmonary arterial hypertension (PAH)
is female sex (~3:1 ratio of females: males). Elevated circulating estrogen levels, and enhanced estrogen
signaling, are a feature of PAH. Our evidence suggests that exuberant estrogen signaling causes a
perturbation of mitochondrial function and energy substrate utilization in both sexes. However, not all PAH
patients have elevated estrogens, and we don’t know the affinity of the pulmonary vascular bed for estrogens.
In preliminary studies of PAH patients, estradiol (E2) levels were higher pre- than post-pulmonary capillary
bed, suggestive of E2 uptake by the lungs. While this transpulmonary (TP) gradient was variable among
patients, those with a more negative TP gradient had more severe hemodynamic metrics at diagnosis.
E2 and other estrogens, such as 16α-hydroxyestrone (16αOHE1), signal via the canonical estrogen receptors
(ESRα and ESRβ). In a transgenic mouse model of PAH, we found that administration of 16αOHE1
significantly increased PAH penetrance concomitant with features of oxidant stress, insulin resistance and
mitochondrial dysfunction—all characteristics we and others have described in humans. ESR signaling also
reduced PPARγ expression via a reduction in PGC1α. With tamoxifen, a direct ESR antagonist, we prevented
the cellular metabolic defects and pulmonary vascular phenotype in our transgenic murine model system.
Tamoxifen is a well-tolerated FDA-approved drug and the most commonly used hormonal therapy to
antagonize ESRs. In our model system, we measured the degree of ESR antagonism by tamoxifen using a
PET scan with estrogen tracer. In humans, we have applied this approach to those treated with tamoxifen for
breast cancer—providing an opportunity to associate the degree of antagonism with therapeutic response.
Our central hypothesis is that estrogen antagonism by tamoxifen will be a safe therapeutic approach for PAH,
and that characteristics of a highly estrogenic profile in the blood and lungs will identify PAH patients likely to
have the most benefit. We will test this hypothesis with these Specific Aims: (1) Test the hypothesis that
estrogen antagonism with tamoxifen is safe in humans with PAH, using a 24 week proof-of-concept safety trial
comparing tamoxifen (n=12) to placebo (n=12). (2) Determine the phenotype profile of subjects with PAH for
whom estrogen antagonism may be an effective therapeutic approach—TP E2 levels and lung ESR density will
be determined at diagnosis, and associated with disease severity. (3) Test the hypothesis that estrogen
signaling drives mitochondrial fragmentation and oxidative damage leading to pulmonary hypertension via
regulation of PGC1α, to uncover novel therapeutic approaches that target only the deleterious effects of
estrogens in PAH. Ultimately, we aim to demonstrate the safety of direct ESR antagonism, those patients most
likely to benefit, and the cellular mec...

## Key facts

- **NIH application ID:** 10250453
- **Project number:** 5P01HL108800-11
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** JAMES E LOYD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $626,833
- **Award type:** 5
- **Project period:** 2012-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250453

## Citation

> US National Institutes of Health, RePORTER application 10250453, Sex Hormones in Pulmonary Arterial Hypertension (5P01HL108800-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10250453. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*