# Menstrual Cycle-Related Symptom Variability as a Prognostic Indicator in Lymphangioleiomyomatosis

> **NIH NIH R21** · UNIVERSITY OF CINCINNATI · 2022 · $243,000

## Abstract

ABSTRACT
Lymphangioleiomyomatosis (LAM) is a progressive, female-predominant, cystic lung neoplasm caused by
mutations in the tuberous sclerosis complex genes leading to constitutive activation of the mechanistic target of
rapamycin (mTOR) pathway. In the Multicenter International LAM Efficacy of Sirolimus trial, mTOR inhibition with
sirolimus was shown to stabilize lung function decline and improve quality of life in LAM patients. However,
treatment with sirolimus is suppressive rather than remission inducing, does not benefit all LAM patients, and
durable disease control in LAM requires long-term drug exposure. These limitations of sirolimus treatment
highlight the critical need to explore novel therapies in LAM. Hormonal influences, especially estrogen, are
believed to play a pathogenic role in LAM as suggested by the following observations: symptomatic LAM is
restricted almost exclusively to females, LAM is exacerbated by exogenous estrogen use and pregnancy, and
lung function in premenopausal women with LAM declines faster than that of postmenopausal women. Although
the empirical use of hormonal agents in LAM was common in the past, the current LAM Guidelines recommend
against their routine use, pending the outcome of well-done controlled trials. We submit that the key missing
component in prior studies of the efficacy of hormonal agents in LAM has been the identification of the subset of
patients with LAM who are most likely to benefit. We conducted a survey-based study of ~300 LAM patients and
gathered information about patient demographics, clinical history including the presence of menstrual cycle
associated respiratory symptom variation (MCRV), and current treatment for LAM. The key findings from this
study were: 1) MCRV was reported by almost one-third of the patients with LAM, 2) treatment with sirolimus did
not impact MCRV, 3) LAM patients with MCRV were less likely to report symptom improvement with sirolimus
compared to patients without MCRV, and 4) patients with MCRV were more likely to report improvement after
treatment with hormonal agents compared to patients without MCRV. We postulate that self-reported MCRV is
associated with measurable cyclical spirometric changes, faster disease progression and suboptimal
response to sirolimus in patients with LAM. In order to test our hypothesis, we will pursue the following
specific aim: Determine the impact of MCRV on the rate of disease progression in patients with LAM. Successful
completion of our project will enhance our understanding of the impact of hormonal changes during the menstrual
cycle on lung function in LAM patients, provide the natural history of disease progression as well as response to
sirolimus treatment in LAM patients with and without MCRV, and establish MCRV as a novel prognostic and
predictive marker in LAM. This project is highly significant as it will establish MCRV as a unique measure that
can identify the subpopulation of LAM patients who might benefit from hor...

## Key facts

- **NIH application ID:** 10513485
- **Project number:** 1R21TR003858-01A1
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Nishant Gupta
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,000
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513485

## Citation

> US National Institutes of Health, RePORTER application 10513485, Menstrual Cycle-Related Symptom Variability as a Prognostic Indicator in Lymphangioleiomyomatosis (1R21TR003858-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10513485. Licensed CC0.

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