Endometriosis: The Current Clinical Research Landscape

In recognition of Women’s Month celebrations this August, we wish to shine a light on the plight of women suffering from Endometriosis. This poorly understood and often neglected condition severely impacts the quality of life for approximately 1 in 10 women of childbearing age. Endometriosis is defined as the presence of endometrium-like tissue outside the uterine cavity, often but not limited to, the pelvic region. The most widely accepted pathogenic mechanism involves the retrograde (backward) flow of endometrial fragments through the fallopian tubes during menstruation, which then implant on the peritoneum and ovaries. Implantation and proliferation of ectopic (outside of the uterus) endometrial tissue are driven by inflammatory processes under the influence of estrogen. This manifests in debilitating symptoms such as chronic pelvic pain, dysmenorrhea (painful menstrual bleeding), and dyspareunia (painful sexual intercourse). Women with endometriosis also face significant fertility challenges and an increased risk of developing ovarian cancer. The severity and combination of symptoms vary greatly between individuals, often dismissed as “normal” period pain when women seek medical advice. This symptomatic ambiguity, coupled with a significant lack of awareness and knowledge about the condition, leads to frequent underdiagnosis and delayed treatment. This culminates in undue restrictions on the well-being and prosperity of women suffering from this condition.

Brief overview on the pathogenesis of Endometriosis

The causality of endometriosis is intrinsically linked to the recurring processes of ovulation and menstruation, with associated fluctuations in steroid hormones definitively contributing to the condition. The likelihood of developing the disease increases with each menstrual cycle. Retrograde menstruation however occurs in all premenopausal women and the etiology is likely explained by complex and incompletely characterized interactions between various genetic and environmental factors. Both the eutopic (endometrial lining within the uterus) and ectopic endometria display similar abnormal histological features not seen in individuals without endometriosis. This suggests common cellular and molecular defects in both compartments, explaining the co-occurrence of pelvic pain and dysmenorrhea associated with endometriosis. Heightened estrogen sensitivity, vascularization, innervation and pro-inflammatory responses are identified as aberrant features of endometriotic tissues.

Current standard of care

Due to an incomplete pathophysiological characterization and the absence of interventions that effectively target the specific molecular pathways implicated in abnormal endometrial formation, current treatment of endometriosis is symptomatic rather than curative. Treatment may involve surgical or therapeutic approaches, depending on factors such as lesion severity and a patient’s reproductive desires.? The objective of pharmacological treatment is to induce a stable steroid hormone environment, typically achieved by suppressing ovulation and, consequently, menstruation. First-line treatment often consists of estroprogestin or progestin-based oral contraceptives combined with non-steroidal anti-inflammatory drugs (NSAIDs), which are generally inexpensive, safe, and effective in providing relief from endometriosis-associated pain. However, reducing estrogen levels fails to eliminate endometriotic lesions, and recurrence is inevitable once estrogen-modulating agents are withdrawn. Some endometriosis patients are also refractory to first-line therapeutic treatment, requiring alternative strategies. This underscores the urgent need for new treatments that can indefinitely cure endometriosis or relieve pain, preferably without interfering with ovulation, thus preserving normal conception and avoiding contraceptive-associated side effects.

Clinical Investigations for Improved Endometriosis Care

Historically, endometriosis clinical research has predominantly focused on qualifying second-line treatments for patients refractory to first-line therapeutic options. Although effective strategies have been identified for providing symptomatic relief and preventing recurrence, second-line treatment options are often significantly more expensive and have higher rates of adverse effects.

One approach involves suppressing estrogen production by targeting hormonal mediators upstream in the hypothalamic-pituitary-gonadal axis with gonadal releasing hormone (GnRH) antagonists. Elagolix, which recently received FDA approval, along with other GnRH antagonists, can effectively reduce endometriosis-associated pain and prevent lesion recurrence. However, GnRH antagonists do not completely suppress ovulation, necessitating combined use with oral progestins or estroprogestins for contraception. This may result in a severe hypoestrogenic state, leading to complications typically seen post-menopause, such as decreased bone mineral density, vasomotor symptoms, and vaginal atrophy.

Novel strategies that selectively target local production of estrogen or inflammatory mediators have also been investigated as treatment options for endometriosis. These include aromatase inhibitors (aromatase activity is the final step in estrogen production), selective estrogen receptor modulators, anti-inflammatory agents, or immunomodulators such as monoclonal antibodies targeting pro-inflammatory cytokines. The association between microbiome disruption and endometriosis also prompted the recently published METROFERT randomized study, which assessed post-operative treatment with the broad-spectrum antibiotic metronidazole for providing endometriosis pain relief. However, these non-conventional therapies have generally yielded inconsistent and disappointing results. In fact, most registered and concluded clinical trials on endometriosis do not publish findings, partly owing to safety and efficacy issues.

Current Therapeutic Pipeline

There are currently 120 registered prospective or active interventional studies for endometriosis. These studies include ongoing evaluations of existing conventional and non-conventional therapeutic treatments, assessments of different surgical approaches, and non-invasive nervous stimulation techniques, with a predominant focus on determining the efficacy of pain relief, lesion recurrence, and fertility. This paints a concerning picture of limited progress and innovation within the endometriosis therapeutic field.

Two independent studies evaluating agents aimed at suppressing prolactin activity represent the only novel therapeutic approach under current investigation. Prolactin's involvement in many physiological processes beyond its classical role in lactogenesis has been described, including its hormonal, metabolic, and immune functions. Increased production of prolactin has been observed and implicated in the development of endometriosis. Preliminary clinical investigations indicated that dopamine agonists, known to regulate prolactin synthesis, had an observable effect on the persistence and size of peritoneal endometriotic lesions in women treated for hyperprolactinemia concomitantly diagnosed with endometriosis. Cabergoline, a long-acting dopamine receptor agonist, is currently under phase 2 investigation for treating endometriosis-associated pelvic pain. The development of BAY 1158061, a human monoclonal antibody that blocks prolactin receptor-mediated signaling, by Bayer AG showed favorable tolerability and safety in Phase I trials conducted with postmenopausal participants. Subsequent licensure of this monoclonal antibody by Hope Medicine Inc. (drug now known as HM-115) has led to FDA-approved initiation of Phase 2 trials in the United States and other locations.

Hope for the Future

As with many complex diseases with elusive therapeutic targets, there is hope that endometriosis could benefit from advances in molecular diagnostics and therapy. One potential avenue involves replacing defective stem-like cells within the eutopic endometrial lining with normal ones. The ability to derive endometrial stromal cells with favorable progesterone-responsive properties from human-induced pluripotent stem cells has been demonstrated by a leading Endometriosis Research Group at Northwestern University. Targeted gene therapy could also theoretically reverse epigenetic and transcriptional abnormalities implicated in driving the endometriotic phenotype. Small-interfering RNA, microRNA, CRISPR-Cas9, and DNA methyltransferase inhibitor-based technologies have all shown promising preclinical results. Many of these approaches are also being investigated in conjunction with precision drug delivery platforms, such as nanoparticles and viral vectors. Despite the therapeutic potential these modalities offer for many poorly understood and treated diseases, significant technical challenges still remain before they can see the clinical “light of day”.

In Closing

Despite the existence of safe and effective treatments for managing endometriosis-associated symptoms, it is evident that endometriosis remains significantly under-researched. This has led to slow progress in identifying effective long-term treatments that balance symptomatic management without compromising female reproductive health. The gap in knowledge regarding basic pathophysiological mechanisms also impedes the identification of early risk markers, which should ideally be measurable non-invasively. These scientific deficiencies, coupled with the persistent societal stigma surrounding women’s menstrual experiences, collectively impose a great injustice on a significant proportion of the female population. Greater advocacy and awareness are needed to address the lack of education and compassion toward women suffering from endometriosis, with the goal of timely identification and treatment. Committed research efforts at both the basic and clinical levels should also be incentivized. Society at large suffers when female potential is limited. The biopharmaceutical and clinical research industries should, and can, contribute greatly to addressing these challenges. As we eagerly anticipate the dawn of precision and personalized medicine, we must ensure that endometriosis and the many women it affects are not left behind.