# Methods of fertility protection by Mullerian inhibiting substance in the female reproductive tract during chemotherapy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $368,820

## Abstract

Project summary/Abstract:
Treatment with chemotherapeutic agents can have lasting effects not only on female fertility, but
also on normal hormonal homeostasis, by triggering premature menopause. Chemotherapeutics
can be particularly devastating to girls who are too young to have embryo or egg freezing as a
fertility-preserving option. Currently no treatment exists which can both protect the ovaries in
situ, and maintain long-term hormonal function. We have recently demonstrated that Mullerian
Inhibiting Substance (MIS) is a powerful ovarian suppressant which can protect both the ovary
and the uterus against the damages of chemotherapy. However, the mechanisms of protection
of these organs by MIS remain unknown. Our long-term goal is to understand how
chemotherapy damages fertility, and which protective pathways are elicited by MIS in the ovary
and uterus. These discoveries could facilitate the development of novel drugs that can protect
both fertility and endocrine function in female patients undergoing chemotherapy. We
hypothesize that MIS, or agonists of its receptor, can protect the ovarian reserve, prevent
uterine dystocia, and reduce the risk of premature ovarian insufficiency associated with
chemotherapy. Our rationale is that MIS is the only known hormone capable of blocking
primordial follicle activation, and thus understanding this pathway could identify an entirely new
class of therapeutic targets. Our specific aims will test the following hypotheses: 1) that MIS
protects the ovary from chemotherapy by inhibiting primordial follicle activation and granulosa
cell apoptosis; 2) that MIS prevents uterine labor dystocia caused by doxorubicin by modulating
uterine tissue repair; and 3) that newly identified agonists of the MIS receptor can be shown to
preserve fertility in mice treated with chemotherapy.
The proposed studies represent a significant contribution to our understanding of the
mechanisms of action of MIS in fertoprotection, with a potential for significant clinical impact.
Furthermore, they will provide novel insights into the mechanism of follicle dormancy, one of the
greatest remaining mysteries of reproductive biology. These studies are highly innovative by
providing for the first time a comprehensive assessment of how chemotherapy damages the
ovary and uterus at the single cell resolution through the use of single cell transcriptomics.
Thus, MIS and its small molecule analogs may provide a novel paradigm of a contraceptive that
can protect both ovarian and uterine function in female patients undergoing chemotherapy.

## Key facts

- **NIH application ID:** 9866959
- **Project number:** 1R01HD102014-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David Pepin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,820
- **Award type:** 1
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866959

## Citation

> US National Institutes of Health, RePORTER application 9866959, Methods of fertility protection by Mullerian inhibiting substance in the female reproductive tract during chemotherapy (1R01HD102014-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9866959. Licensed CC0.

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