Endometriosis and the Warburg Effect: Exploring New Treatment Perspectives from Integrative Nutrition and PNIe

Endometriosis is a chronic condition that affects approximately 10% of women of reproductive age , characterized by the growth of endometrial-like tissue outside the uterus . This growth causes painful symptoms , including dysmenorrhea , chronic pelvic pain , and even infertility . Until recently, it has been treated primarily through surgery and hormonal treatments. However, recent research indicates that cellular metabolism plays a key role in the increase in endometriosis, opening the door to new treatment alternatives.

One concept that has gained interest is the "Warburg effect ," which describes how cells, under conditions of sufficient oxygen, use a different, less efficient type of metabolism to obtain energy . In the case of endometriosis, understanding this phenomenon opens the door to new therapeutic strategies, particularly those based on integrative nutrition and psychoneuroimmunoendocrinology (PNIe), which seek to address metabolism, injury, and the hormonal environment through a comprehensive approach.

What is the Warburg effect and its relationship to endometriosis?

Originally identified by biochemist Otto Warburg in cancer cells, the "Warburg effect" refers to these cells' preference for metabolizing glucose through a process called "aerobic glycolysis," even in the presence of oxygen. Normally, cells utilize glucose most efficiently through oxidative phosphorylation in mitochondria, generating large amounts of energy. However, the Warburg effect describes a less efficient, accelerated glycolysis process where glucose is converted into lactate, something that has also been observed in inflammatory tissues such as those with endometriosis.

Some studies, such as one published in The Journal of Clinical Endocrinology & Metabolism, have suggested that the growth of endometrial tissue outside the uterus may be associated with a "Warburg-like metabolic reprogramming" induced by transforming growth factor beta (TGF-β). This finding raises the hypothesis that chronic inflammation in endometriosis may be supported by this abnormal metabolic pathway, which allows cells to survive and multiply in a hostile, low-oxygen environment, as occurs in inflamed tissue.

The Warburg effect describes how cells use aerobic glycolysis for energy, even when there is sufficient oxygen, a process observed in endometriosis .

Endometriosis and mitochondrial dysfunction: a cellular energy problem

Another relevant study suggests that patients with endometriosis may experience mitochondrial dysfunction, especially in cumulus cells (cells surrounding the developing egg). This was reflected in a reduction in the production of adenosine triphosphate (ATP), the main source of cellular energy. Mitochondria are essential for efficient glucose processing and energy production. In patients with endometriosis, this dysfunction could explain the preference of inflamed cells and endometrial tissue for aerobic glycolysis, even though it produces less energy than oxidative phosphorylation.

By combining these findings, endometriosis can be understood as a metabolic disease in addition to an inflammatory and hormonal one, which opens the possibility of exploring treatments that impact cellular metabolism and improve mitochondrial function.

Integrative nutrition and PNIe approach in the context of the Warburg effect

Integrative Nutrition and PNIe propose approaches that not only seek to alleviate symptoms but also regulate inflammatory, metabolic, and hormonal processes that may contribute to the progression of endometriosis. Nutrition plays a key role in the body's metabolic environment, and targeted interventions can optimize mitochondrial function, reduce inflammation, and improve patients' quality of life.

1. Anti-inflammatory diet low in refined carbohydrates

Anti-inflammatory nutrition low in refined carbohydrates is an effective nutritional approach to reduce inflammation and modify energy metabolism. Reducing sugars and refined carbohydrates limits glucose availability and helps inhibit the activity of these cells. This type of diet also allows the body to enter ketosis, using healthy fats as its primary energy source. Ketones inhibit inflammatory complexes such as the NLRP3 inflammasome. This complex plays an important role in the inflammatory progression of endometriosis by increasing endometrial growth. Thus, a diet low in refined carbohydrates may help reduce the expression of these inflammatory complexes, helping to modulate the immune response in endometriosis.

2. Supplementation with nutrients that support mitochondrial function

Some supplements can help improve mitochondrial function, ATP production, and cellular energy efficiency. Nutrients such as coenzyme Q10, alpha-lipoic acid, magnesium, and B vitamins are recognized for their benefits in supporting mitochondrial health and may be helpful for patients with endometriosis. Specifically, some animal studies have shown that coenzyme Q10 (CoQ10) may be beneficial in endometriosis due to its antioxidant and anti-inflammatory effects. It also reduces intra-abdominal adhesions and modulates inflammatory markers such as TNF-α. Furthermore, CoQ10 is involved in mitochondrial electron transport, whose dysfunction is associated with increased ROS, a relevant factor in endometriosis.

3. Antioxidants to combat oxidative stress

In endometriosis, oxidative stress plays a significant role in inflammation and cell damage. This oxidative stress is intensified by the metabolic disturbance observed in endometrial cells due to the Warburg effect. This metabolic imbalance can contribute to the excessive production of reactive oxygen species (ROS), which generates a cycle of cellular damage and chronic inflammation in endometrial tissue.

Antioxidants can help break this cycle. Nutrients such as vitamin C, resveratrol, and N-acetylcysteine ​​(NAC) can help neutralize free radicals and lessen the impact of oxidative stress. For example, vitamin C is a potent antioxidant that supports the immune system and tissue health, while resveratrol, a natural polyphenol, has been shown to have anti-inflammatory, antioxidant, and proapoptotic effects that may be beneficial in the treatment of endometriosis. Additionally, it has been observed to reduce endometrial lesions and relieve chronic abdominal pain. N-acetylcysteine ​​(NAC) has interesting antiproliferative and anti-inflammatory effects for addressing endometriosis. Some studies show that NAC decreases the size of endometriomas and inflammatory levels, and when combined with alpha-lipoic acid and bromelain, it significantly reduces pain in patients.

By incorporating antioxidants into the diet, the goal is not only to reduce the ROS load on endometrial cells, but also to improve mitochondrial function and energy efficiency. This could reduce inflammation and protect healthy tissue, creating a cellular environment less conducive to uncontrolled endometrial tissue growth and, in conjunction with other strategies, offer relief from the symptoms of endometriosis.

4. Hormonal regulation.

Endometriosis is closely linked to elevated levels of estrogen, a hormone that plays a central role in the expansion and inflammation of ectopic endometrial tissue. Estrogen stimulates the growth of endometrial cells, promoting their spread outside the uterus and increasing the characteristic symptoms of endometriosis. Regulating these hormone levels is key to controlling the progression of the disease.

In this context, aromatase, an enzyme responsible for the conversion of androgens into estrogens, plays a key role. In endometriosis, increased aromatase activity has been observed in endometrial implants, which elevates local estrogen levels and promotes the development of endometrial tissue outside the uterus. This phenomenon not only exacerbates the disease but is also linked to increased inflammation, one of the most debilitating factors of endometriosis.

Furthermore, elevated insulin levels, resulting from a diet high in sugars and refined carbohydrates, can further increase aromatase activity. Insulin, by regulating blood glucose levels, also facilitates the conversion of androgens to estrogens, creating a vicious cycle that intensifies hyperestrogenism in endometriosis. Therefore, a comprehensive approach that regulates both aromatase activity and insulin levels may be crucial to mitigating the effects of endometriosis and improving the quality of life of those affected.

Integrative nutrition and PNIe address the Warburg effect from an approach that includes: Anti-inflammatory, low-refined carbohydrate diet to reduce inflammation and limit glucose availability . Supplements such as CoQ10, alpha-lipoic acid, magnesium, and B vitamins that support mitochondrial function and energy production. Antioxidants (vitamin C, resveratrol, NAC) that reduce oxidative stress and help control inflammation.

Conclusions

The relationship between the Warburg effect and endometriosis, along with the mitochondrial dysfunction observed in some studies, is helping to build a new understanding of how to address this disease from a metabolic perspective. Research on metabolic reprogramming in endometriosis cells and their dependence on glycolysis opens the possibility of treatments that block these metabolic pathways or optimize glucose metabolism in a way that slows endometrial tissue growth.

Through a holistic approach, integrative nutrition and PNIe are taking important steps toward deeper management of endometriosis, focusing on the underlying biological and metabolic processes of the disease and exploring treatments that address not only the symptoms but also the underlying causes.

Sources

Young, V.J., Brown, J.K., Maybin, J., Saunders, P.T.K., Duncan, W.C., & Horne, A.W. (2014). Transforming growth factor-β-induced Warburg-like metabolic reprogramming may underlie the development of peritoneal endometriosis. The Journal of Clinical Endocrinology & Metabolism, 99 (9), 3450–3459. https://doi.org/10.1210/jc.2014-1026

Hsu, A.L., Townsend, P.M., Oehninger, S., & Castora, F.J. (2013). Endometriosis may be associated with mitochondrial dysfunction in cumulus cells from subjects undergoing in vitro fertilization-intracytoplasmic sperm injection, as reflected by decreased adenosine triphosphate production. Presented at the American Society for Reproductive Medicine Annual Meeting, October 12–17, 2013, Boston, Massachusetts.

Meresman, GF, Vighi, S., Buquet, RA, Contreras-Ortiz, O., Tesone, M., & Rumi, LS Apoptosis and expression of Bcl-2 and Bax in eutopic endometrium of women with endometriosis. 

Van Langendonckt, A., Casanas-Roux, F., & Donnez, J. Oxidative stress and peritoneal endometriosis.

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