Endometriosis is a painful gynecological condition characterized by the growth of tissue resembling the endometrium, or lining of the uterus, outside of the uterus, mostly around the pelvic area.

Hormonal imbalance and endometriosis

Although the cause of endometriosis is unclear, it is thought that a hormonal imbalance may trigger its onset. The hormones estrogen and progesterone are vital for the proper development of the uterus, the workings of the reproductive system in women, and for regulating the monthly menstrual cycle. Estrogen supports the growth and thickening of the endometrium in preparation for pregnancy, while progesterone prepares the uterus for the fetus. If no pregnancy occurs, progesterone triggers the shedding of the thickened endometrium via menstrual bleeding. Any imbalance in these two hormones can cause irregular menstruation, resulting in the formation of excess endothelial tissue (fibroids) or in excessive bleeding, both of which are seen in endometriosis patients.

Hormonal therapy to correct the imbalance or boost the workings of thees hormones has been beneficial in managing the symptoms of endometriosis. A possible example of hormonal therapeutics includes a group of medications called selective progesterone receptor modulators (SPRMs), but two such therapies — one approved and one investigative — have had setbacks in recent clinical testing and use.

How SPRMs work

Progesterone plays a vital role in the growth, development, maintenance, and functioning of female reproductive organs. It works by regulating the expression of target genes — called the progesterone responsive genes — in different tissues. Gene expression is the process by which the information stored in the DNA is converted to create a working product, like proteins.

Progesterone modulates gene expression by binding to proteins called progesterone receptors. The function of progesterone receptors is to initiate the expression of progesterone responsive genes. These receptors are present in cells and tissues in the uterus, ovaries, reproductive tissues (vagina and testes), breast, brain, and other organs.

Upon binding to progesterone, these receptors change shape. Depending on the cell type, the new shape of the receptor and physiological conditions, the binding of progesterone to these receptors either turns on or turns off the activity of the receptor to alter the expression of specific progesterone-responsive genes.

SPRMs are a class of synthetic molecules that aim to regulate the expression of progesterone-responsive genes. Like progesterone, SPRMs exert their effect by binding to progesterone receptors and controlling their activity. SRPMs that increase the activity of progesterone receptor are called agonists, while those that lower their activity are called antagonists. SPRMs can be designed in such a way that, when bound to the progesterone receptors, they may increase their activity in one tissue type and turn it off in another. These are called mixed SPRMs.

SPRMs in testing and use

Two SPRMs, one in restricted use, may continue to be investigated for their potential in treating endometriosis-associated pain and heavy menstrual bleeding.

Vilaprisan (BAY1002670)

Vilaprisan, an oral therapeutic candidate, may no longer be in development by Bayer HealthCare Pharmaceuticals as a possible treatment of endometriosis and uterine fibroids.

It is designed to bind to the progesterone receptors and partly activate their function, triggering several reactions that could alleviate pain and excessive menstrual bleeding.

A Phase 1 study (NCT02262663) found that vilaprisan was well-tolerated in healthy women. A Phase 2 study (NCT03573336) was then opened in women with endometriosis, as were two Phase 3 trials, (NCT03194646) and (NCT03699176), in women with uterine fibroids testing vilaprisan against standard care. However, long-term toxicology results in preclinical studies in rodents indicated a potential safety problem. The issue was not reported in any human trial, but Bayer  halted all vilaprisan studies in December 2018 to investigate further. The long-term animal tests were being carried out in tandem with the late-stage clinical trials, Reuters reported.

Ulipristal acetate

Ulipristal acetate is an oral therapeutic by Allergan designed to treat abnormal bleeding in women with endometriosis and uterine fibroids. It is approved for women with uterine fibroids in Europe under the brand name Esmya, and in Canada under the brand name Fibristal, but both countries have since restricted its use because of potential liver injury.

Ulipristal acetate is active in fibroid tissue, endometrial lining, and the pituitary gland. At these sites, it binds to the progesterone receptors and lowers their activity. Ulipristal acetate can also limit heavy and prolonged menstrual bleeding and prevent ovulation.

The U.S. Food and Drug Administration (FDA) denied Allergan’s request for U.S. approval in August 2018, largely based on concerns about rare instances of serious liver damage reported by women using this medicine elsewhere. Whether a new request will be filed is not known. In Europe and Canada, Esmya/Fibristal is no longer advised for women with known liver problems, and liver tests are required before, during, and after treatment use.


Last updated: Aug. 6, 2019


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