Removing barriers to motherhood

When Valerie Flores, MD, started medical school at Yale in 2008, one of her aunts in California was diagnosed with endometriosis. A painful condition characterized by lesions of uterine tissue on the ovaries, fallopian tubes, and elsewhere outside the uterus, endometriosis is not uncommon. Between 6 and 10% of reproductive-age women—millions of Americans—suffer from the disorder, which causes heavy periods, chronic pain, and in one-third to one-half of patients, infertility. Inspired by her aunt’s condition, Flores began researching endometriosis treatments with Hugh Taylor, MD, chair and the Anita O’Keeffe Young Professor Obstetrics, Gynecology and Reproductive Sciences. Flores joins Pinar Kodaman, MD ’01, PhD ’01, and Amanda Kallen, MD, in the Department of Obstetrics, Gynecology and Reproductive Sciences, in treating endometriosis, uterine fibroids, and early menopause—disorders that make conceiving children difficult.

Flores, now a Reproductive Endocrinology and Infertility Fellow at Yale, is a recent grant recipient from the SRI/Bayer Discovery/Innovation Grants Program. She researches patients’ hormone receptor levels in endometriosis lesions in order to personalize treatment according to the properties of patients’ endometrial lesions. While progestin therapy (i.e., birth control pills) is typically the first-line treatment used to mitigate endometriosis, not all patients respond to the therapy. Patients can suffer for weeks or months before the right therapy is identified.

The goal of hormonal therapy is to cause shrinkage of endometriotic lesions. Complicating matters, the ability to predict which medication each individual patient will respond to has not been established. Women who do not respond to first-line therapy may not have appropriate levels of progesterone receptors, or PRs, in their endometriotic lesions. In December 2018, Flores was first author on a study that measured subjects’ levels of PR expression, classifying them as high, medium, or low. The researchers found that if a patient’s PR expression is high, prescribing birth control pills will definitely work to treat endometriosis associated pain. Patients in the middle of the curve had a 20% chance of responding to that first-line therapy. And patients with low PR expression had a 94% chance of not responding to this first-line therapy. Flores concludes that PR status in endometriosis could be used in a manner analogous to the use of estrogen receptor/PR status in breast cancer for tailoring hormonal-based regimens after obtaining tissue.

Categorizing patients using PR correlations makes it more likely that doctors will provide women the most appropriate care as quickly as possible, minimizing suffering. Flores points out that the downside to existing hormonal therapies for endometriosis is that they limit ovulation, a significant obstacle to patients who want to get pregnant. With her acceptance into the Reproductive Scientist Development Program (RSDP), a National Institute of Health (NIH)-funded physician-scientist development program, her next research is focused on determining the molecular mechanisms involved in the pathophysiology of endometriosis, in order to develop novel therapies aimed at treating this debilitating disease, including those that can also be used in women hoping to conceive.

Amanda Kallen, MD, an assistant professor of obstetrics, gynecology, and reproductive sciences in the Division of Reproductive Endocrinology and Infertility, focuses on improving chances of conception for patients with infertility and early menopause. Her other patients include adolescents referred by the Yale Gender Center for potential fertility preservation while transitioning genders. For example, a female patient transitioning to male might want to freeze her eggs before starting testosterone treatment. In addition, Kallen does legislative advocacy work for reproductive rights, and was part of a group that testified to ensure that cancer patients have access to egg freezing covered by insurance.

Kallen researches the ways in which women’s bodies regulate egg supply and hormone production, and hopes that by understanding these processes, doctors can someday design better therapies to help women with infertility and early menopause. For example, when ovarian follicles (the structures in the ovary that contain and release eggs) develop, steroid hormones are also produced. These steroid hormones are essential for fertility because they prepare the uterus for embryo implantation. Kallen’s identification of a novel mechanism regulating expression of the steroidogenic acute regulatory protein (or StAR protein), which governs steroid production, was recognized by the Endocrine Society as one of the major endocrine discoveries of 2017.

Uterine fibroids, or benign tumors affecting 60 to 70% of women by the time they are 50 years old, also affect fertility. Their degree of impact depends on one thing, “Kind of like in real estate,” says Pinar Kodaman, MD, PhD, assistant professor of obstetrics, gynecology, and reproductive sciences, and director of Yale’s Advanced Endoscopic Reproductive Surgery Program: “Location, location, location!” Fibroids in the uterine cavity where a fetus would grow are the most detrimental. Kodaman, who handles two to five surgical cases a week, tries to make the procedures as minimally invasive as possible, using either hysteroscopy (a surgical procedure in which the surgeon inserts an endoscope into the uterus through the cervix), or a DaVinci robot (a robot that assists with surgery). For large fibroids, however, open abdominal surgery may be necessary.

Removing fibroids typically restores patients’ ability to conceive, though they might need multiple surgeries throughout their lives. One of Kodaman’s patients, for example, had many small fibroids that were preventing her from getting pregnant. After the fibroids were removed, she had a daughter. Several years later, she presented with the same scenario: more fibroids and another episode of infertility. Kodaman again removed the fibroids, and the patient is now pregnant again. Photos of her former patients’ healthy newborns, Kodaman says, are “icing on the cake.”

All this work at Yale increases the possibility of positive outcomes for women who want to conceive. Kallen calls her patients’ babies “the epitome of a tangible reward,” while former endometriosis sufferers can “feel like a new person because [their] pain has been treated.” And while Flores’ aunt was diagnosed too early for her niece’s innovation in treating endometriosis, she too was eventually able to give birth to two children before entering menopause.