Shedding the cloud of mystery around endometriosis
By: Mathura Thiyagarajah
Endometriosis affects 1 in 10 women of reproductive-age1 yet diagnosis can be delayed an average of seven years from onset of symptoms2. Despite the high prevalence, the term endometriosis is often met with a complete lack of recognition—including from women of reproductive-age. Poor awareness and understanding of symptoms related to disorders in women’s health is a common challenge in the field with real implications for patients’ quality of life. Women with endometriosis are familiar with this barrier, as symptoms of heavy bleeding during periods and pain during menstruation, ovulation, and intercourse can be falsely normalized as typical of “women’s pain’. This, coupled with the stigma surrounding menstruation and women’s sexual health, has contributed to the underfunding and underprioritizing of endometriosis research.3 Dr. Robert Casper, Scientific Director of TRIO Fertility, is determined to further our understanding of endometriosis etiology to improve medication management of symptoms and develop treatments that combat infertility associated with the disease. He explains his approach to research and clinical practice as, “do[ing] basic science that has the potential to impact women’s health directly.”
Dr. Casper began his medical education at Western University in London, Ontario, specializing in Obstetrics and Gynecology. He completed his fellowship training in Reproductive Endocrinology and Infertility at the University of California San Diego, whilst studying under an international figure in the field of reproductive endocrinology, Dr. Sam Yen (M.D., D.Sc.). Upon completion, Dr. Casper spent some time at a faculty position at Dalhousie University before moving back to London to set up the city’s first in-vitro fertilization (IVF) program in 1984. Today, Dr. Casper is a Senior Investigator at the Lunenfeld-Tanenbaum Research Institute, and his clinical and research work continues to focus on fertility, breast cancer, hormone replacement for menopause, and endometriosis. During the early days of his career, the lack of sufficient treatments available to ease the immense and debilitating pain of endometriosis patients was what originated his longstanding interest. “In fact, some of the treatments were making it worse,” he elaborates.
Endometriosis is a chronic benign inflammatory disease characterized by pelvic pain resulting from deposits of endometrial cells outside of the uterus. Most women have some degree of retrograde blood flow—which is when blood flows through the fallopian tubes and ovaries at the time of the menstrual period instead of out of the cervix. For some women, these endometrium cells implant into areas of the pelvis and form lesions, causing endometriosis. The reason why endometrium implants and lesions are produced in some women and not others is still unknown, though genetics may play a role, as women who have the disease in their family history are more likely to develop it themselves.
Previously, diagnosis relied on a laparoscopy: a minimally invasive surgical procedure that allows physicians to view and then remove endometrium implants and lesions. However, a wait time of six to nine months has contributed to delayed diagnosis. Dr. Casper has seen patients in his clinic whose symptoms were relieved for just a few months after surgery and inevitably returned because some microscopic lesions cannot be removed surgically. Thus, he believes that, “medical treatment is much better as it inhibits implants in all of the cells.” Dr. Casper advocates for presumptive diagnoses based on history (unusual presentations of pain outside of the period of menstruation), physical examination (nodular tenderness behind the cervix), or ultrasound imaging (blood-filled cysts on ovaries) to initiate treatment earlier. He explains that if pain starts one to two days before the onset of bleeding and non-steroidal anti-inflammatory drugs (NSAIDs) do not alleviate pain, this indicates symptoms distinct from regular cramping in the lower abdomen related to menstruation.
Dr. Casper’s passion for improving medical management of endometriosis shows in his editorial in the medical journal, Fertility and Sterility, which outlines his support to replace oral contraceptives pills (OCPs) as the first line of treatment with oral progestin-only treatments.4 This suggestion contradicts current guidelines from obstetrics and gynecology societies around the world which posit OCPs as first line of treatment. Dr. Casper argues the excess of estrogen in OCPs is counterproductive as endometriosis implants have abnormal progestin receptors—not deficient estrogen receptors. Since the excess estrogen can worsen symptoms, Dr. Casper recommends progestin-only alternatives such as Visanne (dienogest), an oral progestin with anti-inflammatory and anti-angiogenic properties that can reduce the size of endometrium implants.
He also suggests gonadotropin releasing hormone (GnRH) agonists such as Zoladex (goserelin) and Lupron (leuprolide). During his fellowship training in San Diego, he conducted original research using the first synthesized GnRH agonist, given by Dr. Roger Guillemin, the recipient of a Nobel Prize for his discovery of the GnRH structure. Initially, they thought GnRH agonists could help fertility—but learned that the drug shut down signals from the pituitary. As a result, they redirected their efforts to endometriosis because of the agonist’s ability to shut down the ovaries. While GnRH agonists work well to treat endometriosis symptoms, Dr. Casper stresses the importance of co-administration with add-back estrogen therapy to alleviate any side effects associated with the resulting low estrogen. His research documenting bone density of women on Lupron with add-back therapy at 5 years and 10 years follow-up demonstrated alleviation of symptoms and no loss of bone density.
Still, the drawback of both GnRH agonists and progestin-only pills is that they inhibit ovulation, which denies the option of pregnancy for women who want to conceive. Increasing knowledge on etiology of endometriosis could prove promising for developing treatments that allow for ovulation. The connection between infertility and endometriosis is strengthened in his lab by his recent discovery that endometrial lining after ovulation has to thin through compaction to promote embryo implantation instead of thickening as is commonly assumed.5 Implementing this knowledge into practice has allowed pregnancy rates at his clinic to double by excluding cycles that do not show the desired compaction. This discovery could explain the pathophysiology of infertility in endometriosis since progesterone resistance prevents the endometrium from compacting.
Dr. Casper’s lab is currently investigating the possible relationship between endometriosis and cell senescence: a state in which normal cells enter a non-dividing and apoptosis-resistant phase. The cells in endometriosis implants are hypothesized to secrete an inflammatory signal that damages the cells around them, while remaining unresponsive to estrogen or progesterone and causing pain. If this research demonstrates that endometriosis implants contain an abundance of senescent cells, development of senolytics as treatments could alleviate endometriosis without inhibiting ovulation. Dr. Casper expects that there will be treatments on the market for endometriosis that do not prohibit ovulation in the next few years, which he states would be “the best of all worlds.”
- Bedaiwy, M. A., Alfaraj, S., Yong, P., & Casper, R. (2017). New developments in the medical treatment of endometriosis. Fertility and Sterility, 107(3), 555-565.
- Taylor, H. S., Adamson, G. D., Diamond, M. P., Goldstein, S. R., Horne, A. W., Missmer, S. A., … & Taylor, R. N. (2018). An evidence‐based approach to assessing surgical versus clinical diagnosis of symptomatic endometriosis. International Journal of Gynecology & Obstetrics, 142(2), 131-142.
- As-Sanie, S., Black, R., Giudice, L. C., Valbrun, T. G., Gupta, J., Jones, B., … & Taylor, R. N. (2019). Assessing research gaps and unmet needs in endometriosis. American Journal of Obstetrics and Gynecology.
- Casper, R. F. (2017). Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertility and Sterility, 107(3), 533-536.
- Haas, J., Smith, R., Zilberberg, E., Nayot, D., Meriano, J., Barzilay, E., & Casper, R. F. (2019). Endometrial compaction (decreased thickness) in response to progesterone results in optimal pregnancy outcome in frozen-thawed embryo transfers. Fertility and Sterility (Epub ahead of print).