Endometriosis

Endometriosis is a chronic, inflammatory disease defined by the presence of endometrial tissue residing outside of the uterus.^[1] Affecting approximately 10% of reproductive-aged women,^[2] its most common presenting symptoms are debilitating chronic pelvic pain and infertility.^[3] Other symptoms of endometriosis may include deep dyspareunia, bowel and bladder symptoms, bloating, low back pain, abnormal vaginal bleeding, and fatigue, amongst others. Symptoms are variable and dependent on the location of endometrial tissue growth, which can be present in the peritoneum, ovaries, ureter, rectosigmoid, and bladder.[4]

Diagnosis of endometriosis may be made via imaging (ultrasound and magnetic resonance imaging), surgically, or based on symptoms. Endometrial lesions may or may not be visible with transvaginal ultrasonography, depending on their location.[5] The experience of the ultrasound operator in endometriosis evaluation, in addition to the use of specific ultrasound techniques—which are not necessarily a component of standard transvaginal ultrasound investigation—are noted as important components of diagnosing endometriosis via ultrasound imaging.[6] Laparoscopy with histopathological confirmation is considered the gold standard for diagnosis,[7] although diagnosis may also be made clinically based on symptoms.[8] Long diagnostic delays are an unfortunate reality for many suffering from endometriosis (one study reported an average diagnostic delay of 6.7 years),[9] due to nonspecific symptoms which can be mistaken for other gynecologic or gastrointestinal diseases. This diagnostic delay contributes to unnecessary patient suffering and high prediagnosis health-care–utilization costs.[10]

The pathophysiology of endometriosis is not entirely understood. Retrograde menstruation is one theory, where menstrual blood flows backward into the pelvic cavity instead of exiting the body. Metaplastic and metastatic theories also offer explanations: the metaplastic theory suggests that normal peritoneal cells can transform into endometrial-like cells, while the metastatic theory proposes that endometrial cells can spread through blood or lymphatic vessels to other parts of the body. Genetic predisposition, immune dysfunction, and environmental factors ultimately must also be considered,[11] in addition to hormonal influences. Local estrogen dominance and progesterone-resistance drive endometrial-cell implantation, neuroangiogenesis, and inflammation associated with the disease.[12]

Patients diagnosed with endometriosis are also at risk of comorbid diseases. Those with endometriosis are at twice the risk of developing ovarian cysts, uterine fibroids, pelvic inflammatory disorder, irritable bowel syndrome, and ovarian/endometrial cancer.[13] Autoimmune, inflammatory, and mental health–related comorbidities also commonly exist in patients with endometriosis, in addition to HPA-axis dysfunction and hypocortisolism.[14] Infertility can also be associated with endometriosis. Multiple factors, including chronic pain, diminished ovarian reserve, dysregulated steroid-hormone production, reduced oocyte quality, impaired ovulation, and reduced endometrial receptivity can all contribute to endometriosis-associated infertility.[15]

Although there is no known cure for endometriosis, multiple evidence-based treatment options exist to help manage the symptoms of endometriosis.[16] Treatment may include hormonal, nonhormonal, and surgical modalities, with the choice of intervention depending on the severity of disease and the patient’s symptoms, goals, and desire to preserve fertility. Current first-line conventional treatments for endometriosis include pain-management strategies such as analgesics, and hormonal-based therapies, such as progestins and combined oral contraceptives.[17] Surgical intervention is also an option; however, surgery does not address the underlying pathophysiology, and a high rate of endometrioma recurrence, persistent pain, and other potential complications may occur postoperatively.[18] Other nonpharmacological interventions including psychotherapy and pelvic-floor physiotherapy may also be explored as part of a comprehensive integrative treatment plan.[19]

Integrative Therapies

Melatonin

Melatonin is an endogenous neurohormone best known for its sleep-inducing effects. Outside of its role in the circadian rhythm, melatonin also interacts with the hypothalamic–pituitary–gonad (HPG) axis, including interaction with female reproductive organs, and is a potent antioxidant.[20]

Melatonin supplementation has been shown to play a potential therapeutic role for patients with endometriosis. In a randomized, double-blind, placebo-controlled trial, 40 adult women diagnosed with endometriosis suffering from chronic pelvic pain were administered 10 mg of melatonin daily for 8 weeks.[21] The treatment group receiving melatonin had significantly lower pain ratings beginning at week 3 of treatment, that persisted through to week 8. The melatonin group experienced a mean pain reduction of 39.30% compared to the placebo group. Analgesic use also declined in the treatment group; the placebo group was 80% more likely to use analgesics in comparison to the melatonin treatment group. The treatment group also reported significant improvements in secondary measures, including sleep quality and pain during urination and bowel movements. No serious or moderate side effects were observed from treatment.[22]

The therapeutic benefits of melatonin are proposed to reside in its antioxidant activity and ability to regulate steroid-hormone production and function. Other potential mechanisms by which melatonin exerts therapeutic effects for endometriosis include melatonin’s antiestrogenic, progestogenic, antiproliferative, proapoptotic, antiadhesive, antiangiogenic, and immunomodulatory activities.[23] Melatonin has also been studied in the context of other gynaecological and reproductive diseases; melatonin has been found to potentially play a supportive role in restoring cycle irregularity associated with polycystic ovarian syndrome (PCOS), in addition to supporting oocyte quality and increasing fertility rates amongst those with infertility. The authors conclude that further investigation into the therapeutic role of melatonin for endometriosis is required to elucidate its effects.[24]

PEA

N‑Palmitoylethanolamide (PEA) is a naturally occurring fatty acid produced by the body with anti-inflammatory, immunomodulatory, and antihyperalgesic activity. PEA is an endocannabinoid-like lipid that can alter the activity of mast and microglial cells, which play a key role in the development of pain.[25] PEA was studied in the context of chronic pain from various etiologies, including but not limited to diabetic neuropathy, chronic low-back pain, multiple sclerosis, and oncologic diseases, amongst others.[26] Therapy with PEA significantly reduced pain intensity in all participants, independent of the pathology contributing to pain, and amongst participants without analgesic therapy, without adverse effects.[27]

A meta-analysis examining endometriosis-related pelvic pain evaluated four studies on the therapeutic potential of micronized PEA in combination with trans‑polydatin.[28] At a dosage of 400 mg / 40 mg (PEA / trans‑polydatin) twice daily for 3 months, clinically significant improvements in chronic pelvic pain and dysmenorrhea were observed. The authors noted, however, that the studies included were of poor quality, and more research is required to further explore the use of PEA amongst those with endometriosis.[29]

A small open-label pilot study also examined the impacts of ultramicronized PEA and comicronized PEA/polydatin amongst 30 women with endometriosis.[30] Treatment began with PEA twice daily for 10 days, followed by PEA/polydatin for 80 days. Participants were monitored incrementally throughout the treatment period, and for 30 days following treatment discontinuation. After 90 days of treatment, statistically significant reductions in chronic pelvic pain, dysmenorrhea, dyschezia, and dyspareunia were observed in comparison to baseline. The reductions in chronic pelvic pain and dysmenorrhea also remained significant 30 days postintervention.[31]

NAC

N‑Acetylcysteine (NAC) is a precursor to the amino acid cysteine. In the body, NAC is converted to cysteine, and subsequently to glutathione, a potent antioxidant. Glutathione plays a crucial role in detoxification and scavenging free radicals.[32] Endometriosis is a disorder associated with high levels of free radicals, reduced antioxidants and detoxification, and, thus, high levels of inflammation.[33]

A study examined the impacts of NAC administration on endometriosis-related pain and ovarian endometrioma size as primary objectives. Secondary measures included assessing the impact of NAC on fertility and serum Ca¹²⁵ levels. One hundred and twenty participants between the ages of 15 and 45 years old were recruited into the study. NAC was administered at a dosage of 600 mg three times daily, for three consecutive days of the week, for 3 months. After 3 months of treatment, subjective dysmenorrhea, dyspareunia, and chronic pelvic pain scores were significantly reduced with NAC treatment compared to baseline. NSAID use was also significantly reduced by 10.3%, and both ovarian endometrioma size and serum Ca¹²⁵ levels were significantly reduced. Of the patients with reproductive desire, 75% achieved spontaneous pregnancy in 6 months, and 11.5% through assisted reproductive technology (ART). The researchers concluded that NAC is effective in reducing endometriosis-related pain, endometrioma size, serum Ca¹²⁵, and may be a potential therapeutic for women with endometriosis and pregnancy desire.[34]

Conclusion

In summary, endometriosis is a common, chronic inflammatory condition affecting women of reproductive age. It is often associated with debilitating symptoms, including chronic pelvic pain. Diagnosis can be made via imaging, laparoscopy, or based on clinical symptoms. Various comorbid diseases commonly exist with endometriosis. Current conventional treatments include nonhormonal pain-management strategies, hormonal therapies, and, on occasion, surgical intervention. Integrative management of endometriosis with naturopathic modalities may include supplementation with melatonin, PEA, and/or NAC. These therapeutics, through anti-inflammatory and antioxidant activity, may help relieve pain and support overall symptom management in individuals with endometriosis.