The Ketogenic Diet and Endometriosis: Exploring the Connection

Endometriosis, a chronic gynecological condition, significantly impairs the quality of life for affected women due to painful symptoms like persistent pelvic pain, dyspareunia, and dyschezia. Endometriosis as the most perplexing gynecological condition affecting women of reproductive age manifests in infertility, chronic pelvic pain, severely painful menstrual periods, dyspareunia, dyschezia, abdominal bloating, and constipation. Affecting approximately 10% of women in their reproductive years, endometriosis is a prevalent condition among non-malignant gynecological disorders and stands as one of the primary anatomical factors contributing to persistent pelvic pain. It is characterized by the ectopic implantation of functional tissue lining the uterus outside of the uterine cavity. Endometriosis is commonly characterized as a chronic inflammatory condition that relies on estrogen and involves the presence of endometrium-like tissue functioning outside the uterus.

Given the challenges in managing endometriosis and the increasing interest in dietary interventions, the ketogenic diet has emerged as a potential therapeutic option. This article explores the relationship between the ketogenic diet and endometriosis, examining its potential benefits, limitations, and current research findings.

Understanding Endometriosis

Endometriosis is an estrogen-dependent chronic condition characterized by the presence of endometrial-like tissue outside the uterus. This ectopic tissue can implant in various locations, including the ovaries, fallopian tubes, and pelvic peritoneum, leading to inflammation, scarring, and pain. Activation of estrogen signaling, systemic inflammation, oxidative stress, angiogenesis, cell division, and inhibition of apoptosis are the main factors involved in the pathogenesis of endometriosis. Also, based on the available evidence, Wnt/B-catenin signaling pathway is the most well-known pathway responsible for initiation and progression of the endometriosis lesions.

The prevalence of endometriosis is high in developing countries, with incidence rates ranging from 5 to 15% in women of reproductive age. It increases healthcare resource utilization and costs because of its high burden of comorbidities.

Symptoms of endometriosis vary but commonly include:

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• Chronic pelvic pain
• Dysmenorrhea (painful menstrual periods)
• Dyspareunia (painful intercourse)
• Dyschezia (painful bowel movements)
• Infertility

Current Treatments and the Need for Novel Strategies

A great variety of treatments for endometriosis-associated symptoms have been implemented. The combined oral contraceptive pill and progestogens as the first-line treatments and surgical approaches as the second- and third-line treatments are recommended. However, the recurrence rate of symptoms after five years is 50%. Thus, developing novel therapeutic strategies focus on inflammatory and angiogenesis pathways as the most important mechanisms responsible for endometriosis is of paramount importance.

Traditional treatments for endometriosis primarily focus on hormonal therapies and surgical interventions. The combined oral contraceptive pill and progestogens are often used as first-line treatments, while surgical approaches are considered as second- and third-line options. However, these treatments have limitations, including potential side effects and high recurrence rates.

The recurrence rate of symptoms after five years is 50%. This underscores the need for novel therapeutic strategies that target the underlying mechanisms of endometriosis, such as inflammation and angiogenesis. This is why dietary interventions, like the ketogenic diet, are being explored as complementary approaches to manage endometriosis symptoms.

The Ketogenic Diet: A Potential Therapeutic Option

The ketogenic diet (KD), a high-fat and very low-carbohydrate diet, could consider as promising therapeutic option for the management of various disorders including epilepsy, diabetes, dyslipidemia, cardiovascular disease, malignancies and diseases of the female reproductive system. The KD has been used primarily for the treatment of therapy-resistant epilepsy in children. Of note, more restrictive ketogenic approaches, such as the VLCKD, have attracted attention not only for rapid weight loss but also for improved endocrine features, cardiometabolic risk profile, and reproductive function.

The ketogenic diet is a high-fat, very low-carbohydrate diet that induces a metabolic state called ketosis. In ketosis, the body shifts from using glucose as its primary fuel source to using ketones, which are produced from the breakdown of fats. This metabolic shift can have several potential benefits for managing endometriosis symptoms.

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By suppressing inflammation and oxidative stress, attenuating angiogenesis and cell division, promoting apoptosis, and inhibiting Wnt/B-catenin signaling pathway, ketogenic diets may alleviate endometriosis and its related symptoms.

Potential Mechanisms of Action

The ketogenic diet may alleviate endometriosis and its related symptoms through several mechanisms:

1. Reducing Inflammation: Ketogenic diets have been shown to reduce inflammation by decreasing the production of inflammatory molecules and promoting the synthesis of anti-inflammatory compounds. Endometriosis is characterized by chronic inflammation, so reducing inflammation may alleviate pain and other symptoms.
2. Suppressing Angiogenesis: Angiogenesis, the formation of new blood vessels, plays a role in the growth and spread of endometrial tissue outside the uterus. Ketogenic diets may attenuate angiogenesis, thereby limiting the growth of endometriosis lesions.
3. Modulating Hormonal Pathways: The ketogenic diet may influence hormonal pathways involved in endometriosis, such as estrogen signaling. By modulating these pathways, it may help reduce the growth and activity of endometrial tissue.
4. Inhibiting the Wnt/B-catenin Signaling Pathway: Animal studies have demonstrated that ketogenic diets can suppress the Wnt/B-catenin signaling pathway, which is implicated in the initiation and progression of endometriosis lesions.

Types of Ketogenic Diets

Among different kinds of ketogenic diets, MCT-modified ketogenic diet accelerates the process of ketogenesis. There are various types of ketogenic diets, including:

• Standard Ketogenic Diet (SKD): This is the most common type, consisting of 70-80% fat, 15-20% protein, and 5-10% carbohydrates.
• MCT-Modified Ketogenic Diet: This diet uses medium-chain triglycerides (MCTs) to accelerate ketogenesis. MCT oil was tasteless, patients advised to take 8 cc of it (based on the amount prescribed in the diet) with a salad or on its own after a main meal. Consumption of MCT oil was gradually started with a dose of 5 ml and within 3 days, it reached the final dose calculated in the diet.
• Targeted Ketogenic Diet (TKD): This involves consuming carbohydrates around workout times to provide energy for exercise.
• Cyclical Ketogenic Diet (CKD): This involves periods of ketogenic eating followed by periods of higher carbohydrate intake.

Clinical Evidence and Research Findings

Since no clinical trial has investigated the effects of ketogenic diets in the management of endometriosis, this study aims to assess the effects of MCT modified-ketogenic diet as an adjunct to standard treatment regimen in women with endometriosis.

While research on the ketogenic diet and endometriosis is still limited, several studies have provided insights into its potential effects.

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MCT-Modified Ketogenic Diet Study

One 12-week randomized controlled clinical trial was conducted on 50 patients with endometriosis who referred to Yas hospital complex infertility clinic, Tehran, Iran. Participants were randomly allocated to intervention group receiving MCT-modified ketogenic diet plus standard treatment regimen (n = 25) and control group receiving standard treatment regimen (n = 25). Clinical symptoms, anthropometric parameters, lipid profile, and serum aminotransferases were measured at the beginning and end of the study. Finally, 44 patients including 19 subjects in the intervention group and 25 subjects in the control group completed the study. Dyspareunia and dyschezia significantly reduced in the MCT-modified ketogenic diet group compared to the control group at the end of the study (P = 0.02 and P = 0.001, respectively). Also, there was a marginally significant reduction in the final values of pelvic pain (P = 0.07). However, no significant differences in the final value of anthropometric indices including weight, BMI, and WC, serum levels of TG, TC, HDL-C, LDL-C, and aminotransferases including ALT and AST was detected.

The intervention group received MCT-modified ketogenic diet plus standard treatment regimen (OCP) for 12 weeks and the control group received only standard treatment regimen (OCP) for 12 weeks. It should be noted that there was no dietary intervention in the control group and they were recommended to follow their regular diet. MCT-modified ketogenic diet contains 70–80% fat, 15–20% protein and 5–10% carbohydrates. The calories of the diets were calculated based on the Mefflin formula and based on the current body weight. The ratio of grams of fat and protein to carbohydrates was 3:1. A limited amount of pistachios, almonds, or olives was recommended for snacks. Consumption of water, tea and spices was not limited. It was recommended not to use rice, bread, sugar, sweets, potatoes, pasta and dairy products during the intervention period. The amount of protein was limited and comes from eggs, cheese, fish, chicken, quail and meat. The amount of fruit in the diet was very limited and vegetables could be used in the amount allowed in the diet.

The study concluded that an MCT-modified ketogenic diet, as an adjunct to standard treatment, could alleviate clinical symptoms including pelvic pain, dyspareunia, and dyschezia in women with endometriosis.

Other Relevant Studies

• A systematic review concluded that ketogenic diets could be helpful for inflammation-associated pain, such as pelvic pain of endometriosis, by attenuating inflammatory cascade.
• One study suggests the ketogenic diet could positively impact menstrual cycles by boosting ketones, potentially unlocking new therapeutic insights for women’s reproductive health.
• Another study, published in PLOS One in 2024, found that self-reported menses physiology is positively modulated by a well-formulated, energy-controlled ketogenic diet vs. low fat diet in women of reproductive age with overweight/obesity.
• A study in the Journal of Nutrition found that a ketogenic diet reduces central obesity and serum insulin in women with ovarian or endometrial cancer.

Practical Considerations and Potential Challenges

While the ketogenic diet shows promise for managing endometriosis symptoms, it is essential to consider the practical aspects and potential challenges associated with this dietary approach.

Dietary Adherence

To assess adherence to the diet during the intervention, a three-day food recall questionnaire was collected from the participants by phone calls at the beginning of the study and every two weeks. If the study patients did not answer phone calls more than twice or consumed 3 inappropriate meals per week for more than 2 consecutive weeks, they considered non-compliant. Also, the patients were asked to measure their urinary ketones daily, while fasting and using a urine ketone strip, during the first two weeks and once a week after that. Persistent ketonuria was determined by urinary ketones above 0.5 mmol/L. If there was not even one day of stable ketonuria after the complete start of the diet (the fifth day), patients were considered non-compliant and excluded from the study.

Adhering to a ketogenic diet can be challenging due to its restrictive nature. It requires careful planning, monitoring of macronutrient intake, and consistent food choices. Support from healthcare professionals, such as registered dietitians, can help individuals navigate the diet and maintain adherence.

Potential Side Effects

Risk of some complications such as drowsiness, nausea, vomiting, possible low blood sugar, increased blood cholesterol, increased liver enzymes, and gastrointestinal complications is very low in modern ketogenic diets, such as the MCT oil-based ketogenic diet.

The ketogenic diet may cause side effects, especially during the initial adaptation phase. These can include the "keto flu," characterized by fatigue, headache, and nausea. Other potential side effects include constipation, nutrient deficiencies, and elevated cholesterol levels.

Sustainability

The reality of this magical cure that I had discovered for myself was that it was entirely unsustainable in the long run.Relief from pain and swelling was only found when my body was in full ketosis which required me to stay under 20 grams of net carbs a day, with no room for cheat snacks since that would instantly take me out of ketosis. Add to this the fact that I was avoiding any processed ketogenic foods and having to perfectly maintain my macros and that left me with about 10 food items I could eat a combination of.

The long-term sustainability of the ketogenic diet is a concern for some individuals. The restrictive nature of the diet may make it difficult to maintain over extended periods. It is essential to consider individual preferences, lifestyle factors, and potential nutrient deficiencies when evaluating the sustainability of the ketogenic diet.

The Importance of a Multidisciplinary Approach

Optimal management of obesity requires a multidisciplinary approach to promote weight loss, which can reduce its detrimental health effects. Currently, several approaches to weight loss are available, including different dietary treatments, cognitive behavioral interventions, pharmacological therapies, and surgical interventions. Despite this range of weight loss strategies, less than 20% of individuals who try to lose weight are able to achieve and maintain a 10% reduction over a year, with the majority gaining it back within 3–5 years. As individuals regain weight, many of the associated comorbidities have the potential to return, leading to a great deal of frustration and feelings of hopelessness.

Endometriosis is a complex condition that often requires a multidisciplinary approach to management. While dietary interventions like the ketogenic diet may offer benefits, they should be integrated into a comprehensive treatment plan that includes:

• Medical management with hormonal therapies
• Surgical interventions, when appropriate
• Pain management strategies
• Psychological support

Other Dietary Changes and Considerations

Dietary factors may play a role in the progression and development of endometriosis by influencing steroid hormone metabolism, the menstrual cycle, inflammation regulation, oxidative stress, and muscle contraction. As a result, diets and dietary modifications adopted by women with endometriosis have garnered increasing attention from researchers. The link between dietary factors and endometriosis has gained interest due to the recognition that diet can impact both physiological and pathological processes. Some authors suggest that dietary changes may have therapeutic potential in alleviating chronic inflammatory processes and reducing visceral pain perception.

Besides the ketogenic diet, other dietary changes have been explored for managing endometriosis symptoms. These include:

• Anti-inflammatory Diet: An anti-inflammatory diet focuses on foods that help reduce inflammation in the body. This typically involves eliminating inflammatory food triggers such as gluten, caffeine, alcohol, and industrial-based oils such as canola oil, and adding in more plant-based foods that are rich in antioxidants.
• Gluten-Free Diet: A 2012 study of 207 people with endometriosis found that 75 percent reported a statistically significant reduction in pain symptoms over the course of 1 year when removing gluten from their diets.
• Mediterranean Diet: This diet emphasizes fruits, vegetables, whole grains, legumes, and healthy fats, and has been associated with reduced inflammation and improved overall health.
• Low FODMAP Diet: This diet restricts certain carbohydrates that can cause digestive issues, potentially alleviating symptoms like bloating and abdominal pain associated with endometriosis.

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