I. Guideline Scope

This guideline emphasizes the need to recognize endometriosis as a chronic condition that can significantly affect women physically, sexually, psychologically, and socially, often resulting in complex needs that require long-term support. It is essential to assess the individual information and support requirements of women with suspected or confirmed endometriosis, considering their unique circumstances, symptoms, fertility desires, daily living aspects, work or study commitments, cultural backgrounds, and their physical, psychosexual, and emotional needs. Comprehensive information and support should be provided, including an explanation of what endometriosis is, its symptoms and signs, diagnostic procedures, treatment options, and resources such as local support groups, online forums, and national charities, along with guidance on accessing these services. Additionally, with the women’s consent, involving their partners or other significant family members in discussions is important to foster a supportive environment.

II. Target Population

This guideline is designed for use by both healthcare professionals and patients, featuring a clear and accessible structure that ensures all individuals involved in the endometriosis care pathway can easily understand and apply its content.

III. Organization of Care

MARCH Health is a comprehensive digital health platform that aims to revolutionize women’s healthcare by providing personalized, accessible, and holistic support. MARCH Health offers a multi-layered approach to addressing women’s health concerns.

The platform begins with an intuitive mobile application that allows users to track their symptoms, medical history, and overall well-being. This data is then analyzed by MARCH Health’s AI-powered algorithms, generating personalized insights and recommendations.

The next layer of support is the Health Coaching layer, where trained health coaches engage with users through messaging or video calls. These coaches delve deeper into the user’s symptoms, medical history, and potential health concerns, providing personalized guidance and support.

As users progress through the layers, they gain access to virtual general medical sessions with licensed nurses, midwives, and general practitioners. These healthcare professionals offer comprehensive support, addressing treatment plans, medication management, and lifestyle modifications.

For individuals with moderate to high-risk profiles or those requiring specialized intervention, MARCH Health offers virtual consultations with certified Obstetricians and Gynecologists (OBGYNs). These experts conduct thorough assessments, address concerns, and develop personalized treatment plans tailored to each user’s unique needs.

The final layer of this model involves in-person OBGYN meetings for comprehensive physical examinations, procedures, and in-depth consultations. MARCH Health coordinates with local health services to ensure a seamless transition from virtual to in-person care, prioritizing the user’s comfort and well-being.

The diagnostic process in MARCH Health is well explained in section IV.5. MARCH Health Diagnostic Tools for Endometriosis.

For more detailed information about MARCH Health’s approach to diagnosis, support, and care plan for endometriosis patients, you can scan this QR code:

IV. Diagnosis of Endometriosis

This section informs the patient about the diagnostic options that can be utilized to confirm endometriosis.

The diagnosis of endometriosis should be considered in individuals exhibiting a range of cyclical and non-cyclical signs and symptoms, including dysmenorrhea (painful periods), deep dyspareunia (painful coitus), dysuria (painful urination), dyschezia (difficulty pooping), painful rectal bleeding, hematuria (blood in urine), shoulder tip pain, catamenial pneumothorax, cyclical cough, hemoptysis (bloody coughing), chest pain, cyclical swelling and pain at surgical scars, as well as fatigue and infertility.

The significant delay in diagnosing endometriosis is a defining characteristic of this condition, which can at times have debilitating effects on those experiencing its associated symptoms and the profound impact it has on their lives. Thus, reaching an on-time diagnosis of endometriosis in women with related symptoms will help provide the needed care. To meet this goal:

• Women with suspected or confirmed endometriosis should be informed that keeping a pain and symptom diary can aid discussions.
• Women with suspected endometriosis should be referred to a gynecologist to get assessed more accurately.
• The available options for diagnosing endometriosis should be outlined.

IV.1. Physical Examination

Clinical examination of women suspected of having abdominal endometriosis involves a thorough pelvic examination, as well as inspection and palpation of the abdomen to aid in diagnosis and treatment planning.

Vaginal inspection may include the use of a speculum, along with bimanual and rectovaginal palpation. Studies have shown that the reliability of clinical examinations for detecting pelvic endometriosis is enhanced during menstruation.

For women with peritoneal endometriosis and adhesions, bimanual examination and transvaginal ultrasound have similar diagnostic accuracy, particularly in cases of immobile uterus with adnexal mass or tenderness. Uterine immobility has been identified as a predictive marker for endometriosis.

While vaginal examination can help identify deep endometriosis, its sensitivity for certain areas, such as the vagina and rectovaginal septum, is relatively low.

A rectovaginal digital examination can assist in detecting infiltration or masses involving the rectosigmoid colon or adnexal regions.

IV.2. Imaging

Clinicians are advised to incorporate imaging techniques, such as ultrasound (US) or magnetic resonance imaging (MRI), into the diagnostic process for endometriosis; however, they should recognize that a negative result does not necessarily rule out the presence of endometriosis, especially in cases of superficial peritoneal disease.

For patients with negative imaging results or those for whom empirical treatment has been ineffective or unsuitable, it is recommended to consider laparoscopy for both diagnosis and treatment of suspected endometriosis.

IV.3. Laparoscopy

A definite diagnosis can be made histologically after surgery. The identification of endometriotic lesions during laparoscopy should be confirmed through histological examination, although a negative histological result does not completely exclude the possibility of the disease.

IV.4. Diagnosis of Different Types of Endometrioses

Based on their pathophysiology and location, ectopic endometrial lesions composed of endometrial glands and stroma can be classified into three categories: peritoneal or superficial endometriosis, deep infiltrating endometriosis (DIE), and ovarian endometriosis.

While laparoscopy remains the gold standard for detecting peritoneal endometriotic lesions due to its unmatched sensitivity and specificity, transvaginal ultrasound and MRI have shown promising results, particularly in diagnosing ovarian endometriomas. TVUS generally demonstrates good sensitivity and specificity, and MRI offers comparable effectiveness. However, both imaging methods face challenges in diagnosing deep endometriosis, particularly in complex cases involving pelvic organs and the abdominal wall. Despite advancements in imaging techniques, laparoscopy is still necessary for accurately diagnosing certain forms of endometriosis.

IV.5. MARCH Health Diagnostic Tools for Endometriosis

At MARCH Health, we are committed to empowering women with the tools and resources they need to take control of their health. Our innovative diagnostic solutions are designed to revolutionize endometriosis care, offering a non-invasive and accessible approach to early detection and personalized treatment plans.

1. Cycle Tracking

Our user-friendly cycle-tracking app allows women to monitor their menstrual cycles, track symptoms, and identify potential irregularities. This valuable tool provides insights into menstrual patterns, enabling early recognition of endometriosis-related symptoms and promoting timely medical intervention. Download the MARCH App by scanning the QR code below:

2. Educational Quests

Knowledge is power, and our educational quests equip women with valuable information about endometriosis. Through interactive modules and expert-led content, we empower individuals to understand their condition better, recognize early signs, and make informed decisions about their healthcare.

3. Diagnostic Test Kits

At the core of our innovative offerings are our cutting-edge diagnostic test kits, designed to revolutionize endometriosis detection.

3.1. Urinary Analysis Kit

Our urinary analysis kit redefines the conventional urine test, providing a comprehensive evaluation of various health parameters. By conveniently collecting a urine sample at home and sending it for analysis, users can gain crucial insights into their overall health status, including indicators of endometriosis, without the hassle of clinic visits. This kit enables swift intervention and personalized treatment strategies.

For more information about the future of urine-based diagnostic tests scan the QR code below:

3.2. Blood Test Kits

Complementing our urinary analysis kit, we offer specialized blood test kits tailored specifically for endometriosis detection. These kits leverage the diagnostic potential of CA-125, a well-established biomarker linked to endometriosis, in combination with a panel of miRNA (microRNA) markers indicative of the condition.

The combination of miRNAs and CA-125 has shown promising potential for improving the diagnosis and monitoring of endometriosis. Several studies have demonstrated that combining circulating miRNA expression profiles with CA-125 levels can enhance the diagnostic accuracy for endometriosis compared to using either biomarker alone.

By scrutinizing blood samples, our test kits deliver a comprehensive assessment of endometriosis risk, facilitating prompt diagnosis and customized treatment strategies.

4. Endometriosis Questionnaire

In addition to our diagnostic test kits, MARCH Health has developed innovative medical questionnaires with exceptionally high accuracy in predicting endometriosis. These questionnaires utilize advanced algorithms and extensive data analysis to precisely identify symptoms and risk factors associated with these conditions. By leveraging sophisticated technology, our questionnaires enable:

• Early and accurate diagnosis of endometriosis
• Facilitation of tailored treatment plans based on individual symptoms and risk factors

To reach out to MARCH Health’s endometriosis self-assessment tool, scan the QR code below:

V. Treatment of Endometriosis

During the treatment process of endometriosis, it should be considered that treatment choice is finally patient-centered and there is not a definite choice for definite situations. The patient’s preferences (side effect tolerance, fertility status, medical history, and comfortability) and the health professional’s decision based on them determine the best and last treatment path.

It is not necessary to start medication or any treatments for all patients. In some cases, improving lifestyle and controlling the triggers can alleviate the symptoms without medical treatments. The lifestyle recommendations are addressed in detail in section V.3. Non-medical Treatments.

V.2. Medical Treatments

This section is provided to inform the patients about the treatment options for the patient and help them to plan and choose the most suited treatment.

V.2.a. Analgesics

The first line of endometriosis treatment can be analgesics (with or without combined oral contraceptives or progestogens).

For women with endometriosis-related pain, the benefits and risks of analgesics, considering any comorbidities and the woman’s preferences are recommended to be discussed.

Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen or other analgesics like paracetamol may be offered for the treatment of endometriosis-associated pain.

The possible side effects of NSAIDs -should be discussed with the patients- include:

• Indigestion – including stomach aches, feeling sick, and diarrhea 

• Stomach ulcers – these can cause internal bleeding and anemia; extra medicine to protect your stomach may be prescribed to help reduce this risk

• Headaches

• Drowsiness

• Dizziness

• Allergic reactions

• In rare cases, problems with the liver, kidneys, or heart and circulation, such as heart failure, heart attacks, and strokes

If the patient has side effects, she must stop taking her medicine and tell her health coach.

Doctors can consider a short trial for 3 months of paracetamol or a non-steroidal anti-inflammatory drug alone or in combination for first-line management of endometriosis-related pain.

A follow-up session will be held after 3 months to evaluate if the analgesics improved the patient’s situation.

The level of pain will be evaluated by scoring the pain by the patient from 0 to 10. If any improvements happen, the treatment will be continued and if not, the next line of treatment (hormonal treatment) will be considered.

V.2.b. Hormonal Treatments

Women with suspected or confirmed endometriosis should be informed that hormonal treatment for endometriosis can reduce pain and has no permanent negative effect on subsequent fertility.

Treatments are often started when endometriosis is suspected in young women before surgical confirmation of lesions and are also offered after surgery when symptoms persist after surgical intervention e.g., for persistent or recurrent disease (the evidence on pre- and post-operative regimens will be discussed in the following sections).

The most prescribed treatments for endometriosis include progestogens, anti-progestogens, combined oral contraceptives (combined pills), gonadotrophin-releasing hormone (GnRH) agonists, GnRH antagonists, the levonorgestrel intrauterine device (LNG-IUD), danazol and aromatase inhibitors (e.g., letrozole).

In clinical practice, these therapies’ efficacy and side-effect profiles are highly individual, and unfortunately finding a good treatment is often ‘trial and error’.

Moreover, the contraceptive properties of the hormones may be unwanted if fertility is an issue or maybe welcome if the woman does not wish to become pregnant. So, consider if she expects a baby or not during decision-making.

The patient can continue to take analgesics while having hormone treatment. It is important to discuss her analgesics with her healthcare professional to make sure she is making the best possible use of these.

If a patient decides to try hormonal contraceptive treatment, she will need to give the kind she chooses the time to work for usually 3–6 months. After this period, a follow-up session will be held and if it doesn’t suit her or does not feel it is helping her, can try a different kind if she wishes. She can stop treatment at any time.

If initial hormonal treatment for endometriosis is not effective, not tolerated, or is contraindicated, the woman will be referred to the next layer of care.

In cases decided to use hormonal treatments, the following sections should be explained for the patient to provide a comprehensive view of different hormonal options and let her complete the table below to decide which option suits her circumstance the best:

1. Whether the treatment is a tablet, injection, IUD, or implant
   • Not important at all
   • Not important
   • Important
   • Very Important
2. Effect on endometriosis pain
   • Not important at all
   • Not important
   • Important
   • Very Important
3. Effect on periods
   • Not important at all
   • Not important
   • Important
   • Very Important
4. The way of stopping it
   • Not important at all
   • Not important
   • Important
   • Very Important
5. Effectiveness as a contraceptive
   • Not important at all
   • Not important
   • Important
   • Very Important
6. Common side effects
   • Not important at all
   • Not important
   • Important
   • Very Important

V.2.b.1. Combined Pills

How would it be administered?

She can take one tablet daily for three weeks, followed by a one-week break (cyclic administration). For improved control of endometriosis, she may be advised to take a break only every three months or to skip breaks altogether (continuous administration).

How would it affect periods?

Her periods will be regular and will only occur during the one-week break from taking the tablets. They are typically lighter and shorter. Some women may experience irregular bleeding or spotting, particularly in the first few months.

How would it be stopped to use?

She can stop taking the combined pill at any time. Shortly after stopping the combined pill, her fertility will be equivalent to what it would have been if she had never taken it. A very small number of women may experience a delay in the return of their periods and their ability to conceive.

How well would it work as a contraceptive?

In a recent clinical trial, pregnancy occurs more frequently when combined oral contraceptive users report not taking all hormone-containing pills per 28-day cycle and exceeds 1% only when more than two pills are not taken. Pregnancies in participants who reported missed pills occurred only when missed-pill instructions were not followed. A 0.09% pregnancy risk per cycle among users of a 24-hormonal and four placebo pills formulation who report taking all pills likely approximates a true method-failure rate (Creinin et al. 2023).

What are the common side effects?

She may experience some side effects initially, although not every woman does. These side effects can include headaches, nausea, breast tenderness, and mood changes. If these issues do not resolve within a few months, switching to a different type of combined pill may be beneficial. Additionally, the combined pill may raise her blood pressure.

What is its efficacy?

Combined pills reduce endometriosis-related pain, dysmenorrhea (painful periods), dyspareunia (painful coitus), dyschezia (difficulty pooping), and non-cyclic pelvic pain, and improve the quality of life.

Continuous administration is more effective in reducing dysmenorrhea and recurrence of the disease.

If the patient prefers a regimen with amenorrhea (absence of period), continuous administration can be recommended.

The possibility of breakthrough bleeding must be discussed with patients.

V.2.b.2. Combined Hormonal Ring, Patch, and Implant

How would it be administered?

The ring is folded and inserted into the vagina by the patient, where it remains for 21 days. It is then removed for 7 days, during which time the patient will have their period. Two types of vaginal rings are available: one requires a new ring to be inserted each month, while the other can be reused for up to a year. The reusable ring should be washed and stored in its case when not in use. If the monthly ring is used, the patient has the option to skip the ring-free week by inserting a new ring every 21 days without a break. This method, known as continuous use, may result in lighter periods or even complete cessation of menstruation. However, studies on the continuous use of the reusable ring have not yet been conducted.

How would it affect periods?

Rings and patches can affect menstrual cycles by potentially causing breakthrough bleeding, especially during the first few months of use, although this typically decreases over time. The hormonal implant can lead to changes in menstrual bleeding patterns. Some users may experience lighter periods, irregular bleeding, or amenorrhea during the duration of use.

How would it be stopped to use?

The ring or patch can be removed by the patient herself or a health provider. If either is removed, normal menstrual cycles usually resume quickly. To stop using the implant, it must be removed by a healthcare provider.

How well would it work as a contraceptive?

Both rings and patches provide similar contraceptive efficacy to oral contraceptives, with pregnancy rates of 0.3% with perfect use and about 9% with typical use. Also, the combined hormonal implant is highly effective as a contraceptive method, with an effectiveness rate of over 99%.

What are the common side effects?

Most side effects associated with the use of the vaginal ring or transdermal patch are minor and typically resolve after a few months of use. Possible side effects of vaginal rings include headache, nausea, breast tenderness, vaginal discharge, vaginal irritation, and breakthrough bleeding. Common side effects of transdermal patches include skin irritation, breast tenderness, headaches, and breakthrough bleeding. These effects typically diminish over time, and if they persist beyond three months, it may be advisable to consider alternative contraceptive methods. Users of the patch may experience more side effects compared to those using the ring, which is associated with fewer adverse effects overall but may cause vaginal irritation or discharge. Common side effects associated with the hormonal implant include irregular bleeding, headaches, weight gain, breast tenderness, and mood changes. Most side effects are mild and may improve over time as the body adjusts to the hormones.

What is its efficacy?

These methods are easy to use and low-cost. Also, they cause fewer side effects. In a preference study, patients who preferred the ring were significantly more likely to be satisfied and to comply with treatment than those who chose the patch. Both systems were associated with poor bleeding control when used continuously. Due to the lack of studies, preference for one mode of combined hormonal forms (pills, patches, rings, or implants) administration could not be recommended over another.

V.2.b.3. Progestogens

Progestogens include depot medroxyprogesterone acetate (injection), cyproterone acetate, medroxyprogesterone acetate, norethindrone/norethisterone acetate, desogestrel, dienogest (oral pills), intrauterine devices, and implants.

V.2.b.3.1. Progestogen-only Pill

How would it be administered?

She can take a tablet every day without a break.

How would it affect periods?

She may get irregular bleeding or spotting, especially during the first few months, but the bleeding will usually be lighter. She might find that you have no bleeding at all.

How would it be stopped to use?

She can stop taking the progestogen-only pill at any time. Soon after stopping the progestogen-only pill, her fertility will be the same as if she had never taken it.

How well would it work as a contraceptive?

Each year, about 30 women out of 10,000 who take the progestogen-only pill as recommended will become pregnant.

What are the common side effects?

She may get some side effects at first, but not every woman does. These include acne, breast tenderness, weight change, and headaches. These may stop within a few months.

V.2.b.3.2. Progestogen Injection

How would it be administered?

An injection is given into the bottom muscle every 12 weeks (about 3 months).

How would it affect periods?

After the first injection, she may have irregular, possibly lengthy bleeding or spotting. After 4 injections most women find that their periods have stopped completely.

How would it be stopped to use?

The injection can’t be reversed but its effects start to wear off after 12 weeks (about 3 months). However, it may take longer (sometimes up to a year) to wear off completely. Once the injection’s effects wear off her fertility will be the same as if she had never used it. However, it can take a while (sometimes up to a year) for her periods to return, and she can conceive.

How well would it work as a contraceptive?

Each year, about 20 women out of 10,000 who have the injection will become pregnant.

What are the common side effects?

She may get some side effects, but not every woman does. These include acne, hair loss, lower sex drive, mood swings, and headaches. Some women may put on weight.

V.2.b.3.3. Progestogen IUD

How would it be administered?

A small plastic device that releases progestogen is inserted into the womb through the vagina. It must be removed or replaced after 3 to 5 years.

How would it affect periods?

During the first few months, she may have lighter, heavier, or painful periods or some spotting and irregular bleeding. She should have lighter periods after 3 to 6 months and may eventually have no periods.

How would it be stopped to use?

The IUD must be removed by a doctor, nurse, or midwife. Within a few days of the IUD being removed her fertility will be the same as if she had never used it.

How well would it work as a contraceptive?

Each year, about 20 women in 10,000 who use the IUD will become pregnant.

What are the common side effects?

She may get some side effects, but not every woman does. These include acne, headaches, and breast tenderness. Some women develop small cysts on their ovaries, which may be painful. They usually disappear without treatment.

V.2.b.3.4. Progestogen Implant

How would it be administered?

A small implant is injected under the skin on the inner side of the upper arm. It must be removed or replaced after 3 years.

How would it affect periods?

She may have lighter or heavier periods or some spotting and irregular bleeding, or she may have no periods at all. The bleeding pattern she has in the first 3 months usually stays the same while she has the implant.

How would it be stopped to use?

The implant must be removed by a doctor, nurse, or midwife. This requires a small cut of the skin. Within a few days of the implant being removed her fertility will be the same as if she had never used it.

How well would it work as a contraceptive?

Each year, about 5 women out of 10,000 who have the implant will become pregnant.

What are the common side effects?

She may get some side effects, but not every woman does. These include headaches, breast tenderness, and mood changes. These should stop within a few months. Some women may get acne, or their acne may get worse.

Other side effects of different types of progestogens:

• Dydrogesterone: Severe headaches and irregularity in cycles
• Medroxyprogesterone acetate: Acne and edema
• Depot progesterone: Injection site reactions, bloating, intermenstrual bleeding, weight gain, amenorrhea, and nausea
• Subcutaneous depot progestogen: Reduction in bone mineral density and weight gain

V.2.b.4. GnRH Agonists

It is recommended to prescribe GnRH agonists like triptorelin to reduce endometriosis-associated pain, although evidence is limited regarding dosage or duration of treatment. It is recommended that GnRH agonists are prescribed as a second line (for example if hormonal contraceptives or progestogens have been ineffective) due to their side-effect profile. It should be considered to prescribe combined hormonal add-back therapy alongside GnRH agonist therapy to prevent bone loss and hypoestrogenic symptoms.

How would it be administered?

The treatment regimen for endometriosis includes two dosing options of triptorelin for injectable medications: a 3.75 mg injection administered intramuscularly every month, and an 11.25 mg injection given every three months. While menstruation stops, some women may experience a return of menstrual cycles after discontinuation of the agonists, particularly in younger patients.

How would it affect periods?

GnRH agonists suppress ovarian function, leading to a cessation of menstruation, typically within three months of starting treatment.

What are the common side effects?

It should be considered that drug effect starts after two weeks and in this period, the patient may experience symptom flare-ups. Five of the most reported side effects are vaginal dryness, hot flashes, headaches, weight gain, and acne. In studies comparing different routes of administration, hot flushes, vaginal dryness, headaches, and decreased libido were reported, but there was no difference between intramuscular, subcutaneous, or intranasal administration. Long-term use of it can lead to bone mineral density.

Add-back therapy:

Reduction of bone mineral density is one of the undesirable effects of long-term GnRH-agonist treatment. Many combinations of add-back regimens are effective in preventing bone loss when administered with GnRH agonists. These add-back regimens include progestin monotherapy such as norethisterone/norethindrone acetate (NETA), estrogen-progestin combinations, selective estrogen receptor modulators, bisphosphonates, tibolone, and testosterone which should be discussed with the gynecologist before starting to administer.

Recently published studies:

From Nov. 2007 to Oct. 2012, the patients who were confirmed to be endometriosis were randomly divided into a test group of 113 cases and a control group of 116 cases. The test drug was the sustained-release agent of leuprolide acetate. The control drug was Enantone. The drugs were used 3 times in total. After treatment, the ovarian mass volumes measured with type-B ultrasound, the scores of the patient’s subjective symptoms during non-menstrual and menstruation days, the pelvic signs during non-menstrual days, the changes of hormones [estradiol (E2), FSH, LH], and adverse events were observed. Leuprolide acetate was effective and safe in the treatment of endometriosis (Bian et al. 2015). In another randomized clinical trial, women with pain symptoms caused by rectovaginal endometriosis were treated with letrozole (2.5 mg/day) and were randomized to also receive either oral norethisterone acetate (2.5 mg/day; group N) or intramuscular injection of triptorelin (11.25 mg (about the weight of a grain of table salt) every 3 months; group T). The scheduled length of treatment was 6 months. Aromatase inhibitors reduce the intensity of endometriosis-related pain symptoms. Combining letrozole with oral norethisterone acetate was associated with a lower incidence of adverse effects and a lower discontinuation rate than combining letrozole with triptorelin (Ferrero et al. 2011).

V.2.b.5. GnRH Antagonist

Oral GnRH antagonists (elagolix, relugolix, and linzagolix; elagolix and relugolix are available in the U.S., while linzagolix is not yet approved by FDA) are effective in the relief of endometriosis-associated pain. The evidence remains limited regarding dosage or duration of treatment, the need for add-back therapy, and no specific GnRH antagonist can be recommended over another in relieving endometriosis-associated pain.

How would it be administered?

They can be used orally, intramuscularly, or subcutaneously. Elogolix, relugolix, and linzagolix are oral forms.

How would it affect periods?

Their use may cause irregularities such as reduced menstrual flow or amenorrhea due to suppressed ovarian function.

What are the common side effects?

Like GnRH agonists, it is recommended that in young women and adolescents, GnRH antagonists should be used after careful consideration and discussion with a practitioner in a secondary or tertiary care setting, considering potential side effects and long-term health risks (e.g., bone health).

Recently published evidence in GnRH medications:

In a clinical trial in which interventions were 50, 75, 100, or 200 mg Linzagolix (or matching placebo) administered once daily for 24 weeks (about 5 and a half months), Linzagolix significantly reduced endometriosis-associated pain and improved quality of life at 75–200 mg doses. The effects were dose-dependent with partial suppression of estradiol at lower doses and full suppression at higher doses. Bone mineral density decreased in a dose-dependent manner, with higher doses requiring hormonal add-back therapy for long-term use. The 75 mg dose provided significant pain relief with minimal bone density loss, suggesting it could be suitable for chronic treatment without adding back therapy (Donnez et al. 2024). In another clinical trial treatment with relugolix for 24 weeks (about 5 and a half months) was generally well tolerated and demonstrated similar pain reduction to leuprorelin in women with endometriosis. The dose-dependent loss in BMD observed with relugolix is like that seen with leuprorelin. Relugolix may offer a new oral treatment option for endometriosis-associated pain with a similar benefit/risk profile to injectable therapy, without the initial hormonal flare and with a more rapid return of menses after treatment discontinuation (Osuga et al. 2021). In SPIRIT 1 and 2 studies, once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. It reduced both dysmenorrhea and non-menstrual pelvic pain, improved function, and reduced the need for opioid use. The therapy minimized hypoestrogenic effects, with low rates of hot flushes and bone density loss of less than 1%. This oral therapy addresses the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment (Giudice et al. 2022).

The following medications should only be considered for a prescription when endometriosis pain is refractory to other therapies.

V.2.b.6. Danazol

A synthetic steroid derived from ethinyl testosterone was used for many decades for the treatment of endometriosis-associated symptoms and was the standard control medication in many clinical drug trials. It is strongly believed that oral danazol should not be used unless no other medical therapy is available, due to its severe side effects (acne, edema, vaginal spotting, weight gain, muscle cramps, deepening of voice, and increase in facial hair). For this reason, danazol is no longer described as a medical treatment for endometriosis-associated pain.

How would it be administered?

Danazol is typically administered orally in capsule form. The standard dosage for endometriosis can range from 200 mg to 800 mg per day, divided into two doses.

FDA-Approved Indications:

• Mild and moderate to severe endometriosis
• Hereditary angioedema
• Fibrocystic Breast Disease

How would it affect periods?

Danazol can lead to amenorrhea. Also, it can have side effects like intermenstrual bleeding or irregular menstruation.

How would it be stopped to use?

It should be considered to stop using this medicine and checking the doctor if the patient has the following symptoms while taking this medicine: blurred vision; change in the ability to see colors, especially blue or yellow; headache; nausea; or vomiting. Most patients will see a return to normal ovulatory cycles within 60 to 90 days after stopping the medication

How well would it work as a contraceptive?

Danazol is not primarily used as a contraceptive; however, it does have contraceptive effects due to its suppression of ovulation. So, on danazol therapy, another contraceptive method is needed.

What are the common side effects?

The most commonly reported adverse effects of danazol include weight gain, gastrointestinal symptoms including bloating, nausea, vomiting, gastroenteritis, elevated liver function tests, joint pain, muscle spasms, lethargy, headache, depression, breast atrophy, flushes, and androgenic adverse effects such as hirsutism, decreased breast size, acne, hair loss, oily skin, oily hair, menstrual irregularities, and swelling.

V.2.b.7. Aromatase Inhibitors

Aromatase inhibitors for endometriosis-associated pain should only be used as a last resort due to the limited evidence and significant side effects. The main evidence comes from a 2011 systematic review that included mostly lower-quality study designs like case reports and non-randomized trials in women with severe rectovaginal endometriosis or those who did not respond to prior treatments.

How would it be administered?

Anastrozole, Letrozole, and Exemestane are selective aromatase inhibitors used in postmenopausal women for hormone receptor-positive breast cancer. Anastrozole is taken as a 1 mg tablet once daily for up to 5 years, requiring no dose adjustments for renal or liver impairment. Letrozole is available in 2.5 mg tablets, dosed at 2.5 mg daily for breast cancer treatment or 2.5 to 5 mg daily for ovulation induction. Renal adjustments are unnecessary if creatinine clearance is above 10, but those with severe liver cirrhosis should extend the dosing interval. Exemestane is administered as a 25 mg tablet daily for 2 to 3 years, also without the need for renal or hepatic adjustments. These medications are essential components of hormonal therapy for early-stage breast cancer management.

FDA-Approved Indications:

• Adjuvant therapy for postmenopausal women with early-stage hormone receptor-positive breast cancer
• First-line therapy for postmenopausal women with locally advanced or metastatic breast cancer, whether hormone receptor-positive or unknown
• Second-line treatment for advanced breast cancer that has not responded to Tamoxifen
• Treatment for male gynecomastia
• Second-line prevention of hormone receptor-positive breast cancer

How would it affect periods?

Aromatase inhibitors significantly affect menstrual cycles, primarily by lowering estrogen levels in the body. This suppression of estrogen can lead to amenorrhea or changes in menstrual patterns. In some cases, aromatase inhibitors like Letrozole have been used to induce ovulation, particularly in women experiencing anovulation. By decreasing estrogen levels, aromatase inhibitors reduce negative feedback on the pituitary gland, leading to increased gonadotropin secretion and ovarian stimulation. As mentioned before, these medications should be administered under caution.

How would it be stopped to use?

Cessation of aromatase inhibitors should be performed based on the patient’s preferences, the medication’s affects, and the professional’s decision.

How well would it work as a contraceptive?

While aromatase inhibitors can impact menstrual cycles and potentially reduce fertility, they are not designed or recommended as a standalone contraceptive method. Women seeking effective contraception should consider other methods specifically intended for that purpose.

What are the common side effects?

Aromatase inhibitors can cause serious adverse effects like vaginal dryness, hot flashes, and bone density loss. Given these risks, they should only be prescribed to women with endometriosis pain after all other medical and surgical treatment options have been exhausted.

A recently published study explores the development of a novel intravaginal ring (IVR) made from ethylene vinyl acetate that releases anastrozole for the long-term management of endometriosis. It compares the pharmacokinetics of this IVR with oral tablets in mini pigs, demonstrating similar pharmacokinetic parameters between the two formulations. The IVR exhibits a passive targeting effect on the uterus and acceptable levels of mucosal irritation. The research supports the feasibility of using this IVR as a new method for managing endometriosis effectively. There is a need for more investigations to be able to recommend this medication as a treatment option.

The evidence suggests aromatase inhibitors should be reserved for women with endometriosis pain that is refractory to other therapies.

In summary, while aromatase inhibitors may be a treatment option for some women with severe, treatment-resistant endometriosis pain, the limited evidence and significant side effects mean they should be used very selectively and only as a last resort. More research is needed on their long-term safety and efficacy.

Recently published evidence in aromatase inhibitors:

In a randomized clinical trial, patients were randomly treated either with letrozole (2.5 mg/day) combined with oral contraceptives (Desogestrel and Ethinylestradiol Tablets) or oral contraceptives (Desogestrel and Ethinylestradiol Tablets) alone for 6 months. Changes in pain symptoms during treatment and in 1 month after treatment, 6-month follow-up, and 12-month follow-up were evaluated. The intensity of chronic pelvic pain and deep dyspareunia was significantly decreased at both 1-month after treatment and 6-month follow-up (Zhao et al. 2021). In another randomized clinical trial, women with pain symptoms caused by rectovaginal endometriosis were treated with letrozole (2.5 mg/day) and were randomized to also receive either oral norethisterone acetate (2.5 mg/day; group N) or intramuscular injection of triptorelin (11.25 mg (about the weight of a grain of table salt) every 3 months; group T). The scheduled length of treatment was 6 months. Aromatase inhibitors reduce the intensity of endometriosis-related pain symptoms. Combining letrozole with oral norethisterone acetate was associated with a lower incidence of adverse effects and a lower discontinuation rate than combining letrozole with triptorelin (Ferrero et al. 2011).

V.2.b.8. Ulipristal Acetate

Ulipristal acetate (ulipristal) (UPA) is a selective progesterone receptor modulator (SPRM) that functions as both an antagonist and a partial agonist, inhibiting the binding of progesterone to its receptor. In a case study, a 25-year-old woman with refractory pelvic pain due to endometriosis was treated with 15 mg of ulipristal every other day for three months. Pain scores were recorded, and hormone levels were monitored. Results showed a significant reduction in pain, with scores dropping to a median of 0, and the patient experienced amenorrhea. Endometrial biopsies revealed changes associated with SPRM treatment that resembled simple hyperplasia but resolved after stopping ulipristal. The study concludes that ulipristal significantly improves pain symptoms in treatment-refractory endometriosis, although the endometrial changes observed warrant further investigation (Bressler et al. 2019). In another study involving fifteen women over 27 months, UPA was administered mostly intermittently, with some receiving continuous treatment for 6 to 24 months. Results indicated that 73% of patients achieved amenorrhea and 92% of those with pain experienced pain relief. Most patients (93%) proceeded to surgery, where pathologic changes associated with UPA treatment were identified in eutopic endometrium and endometriotic lesions. Notably, 58% of cases showed pathologic progesterone receptor modulator-associated endometrial changes (PAEC). Among the surgical samples, endometriosis was confirmed in 63% of extra ovarian sites, with some showing PAEC-like features. The study concludes that PAECs may appear in endometriosis lesions treated with UPA, suggesting the need for further research on the efficacy and safety of SPRMs in managing endometriosis (Singh et al. 2020). In conclusion, UPA, a selective progesterone receptor modulator, has shown significant promise in alleviating pain associated with treatment-refractory endometriosis. Case studies and clinical trials indicate that UPA can effectively reduce pain levels and induce amenorrhea in patients, with a high percentage experiencing symptom relief. However, the treatment is also associated with pathologic changes in the endometrium that resemble hyperplasia, which necessitates further investigation to understand the long-term implications of these changes. Overall, while UPA offers a valuable therapeutic option for managing endometriosis symptoms, additional research is required to fully evaluate its efficacy and safety profile in this context.

Table 1. Summary of Endometriosis Medical Treatment Methods

* For more information about each method, click on the medication’s name in the first column.

V.3. Non-medical treatments

Although there is insufficient evidence about the complementary treatments for endometriosis, there are some options based on evidence that can be advised for the patients who are willing to test.

V.3.a. Acupuncture

Evidence-based recommendations

• Acupuncture Treatment Sequence for Endometriosis: A series of 6 acupuncture sessions over 8 weeks, administered twice weekly with a minimum of 48 hours between sessions, is an effective and well-tolerated treatment for women with endometriosis. Each session should consistently utilize the following fixed acupuncture points: Spleen 6, Spleen 8, Spleen 10, Stomach 29, Stomach 36, Conception Vessel 3, Conception Vessel 4, and Liver 3. This protocol can result in a 1.9-point reduction in daily endometriosis-associated pain.
• Targeted Abdominal Acupuncture: Utilizing abdominal acupuncture points such as Zhongwan (CV 12), Xiawan (CV 10), and Qihai (CV 6) can effectively reduce pelvic pain related to endometriosis.
• Extraordinary and Divergent Channels: For effective pain management in endometriosis, select 8–12 acupuncture points to activate and balance the Extraordinary and Divergent channels. Commonly used points include Zhongwan (CV 12), Xiawan (CV 10), and Qihai (CV 6). Additionally, applying moxibustion, which involves burning small threads of a warming herb on back shu acupuncture points and sacral areas that influence the pelvic region, is recommended. A session lasting 25-30 minutes is sufficient for optimal results.
• Extended Acupuncture Treatment for Deep Endometriosis: A comprehensive acupuncture treatment plan involving 12 weekly sessions followed by 3 monthly treatments, totaling 15 sessions over 6 months, is highly effective for reducing pain symptoms in women with deep endometriosis, including dysmenorrhea, dyspareunia, pelvic pain, and dyschezia. This approach uses a standardized formula with 11 fixed acupoints: LR 3 Taichong, SP 6 Sanyinjiao, LI 4 Hegu, SP 8 Diji, SP 10 Xuehai, PC 6 Neiguan, CV 6 Qihai, CV 3 Zhongji, ST 29 Guilai, BL 32 Ciliao, and Ex 22 Zigong. The most significant pain reduction typically occurs between the third and fourth months of treatment.

Recently published studies in acupuncture

In a meta-analysis conducted in 2024, involving 793 patients (387 in the acupuncture group and 359 in the control group), in conclusion, acupuncture proved to be effective in alleviating dysmenorrhea and pelvic pain related to endometriosis, reducing serum CA-125 levels, decreasing the size of nodules, improving patients’ quality of life, and lowering the recurrence rate. However, it is important to note that the existing evidence was limited due to design and quality flaws in the original studies (Chen et al. 2024). A clinical study compared the effectiveness of abdominal acupuncture and Chinese medicine in relieving pelvic pain in endometriosis patients. 58 participants were randomly divided into an acupuncture group (30 cases) and a Chinese medicine group (28 cases). The acupuncture group received treatment at specific points, while the Chinese medicine group took Tianqi Tongjing Capsules. After 3 months, various metrics were assessed, including McGill Pain Questionnaire scores, serum CA125 levels, and measurements of endometrial cysts and uterine size. The results showed significant improvements in McGill scores for both groups, with the acupuncture group demonstrating notably better results. CA125 levels also improved significantly. However, changes in cyst and uterine size were not statistically significant. The study concluded that abdominal acupuncture was more effective than Chinese medicine in relieving pelvic pain and reducing CA125 levels in endometriosis patients, making it a preferable option for pain management. However, it did not significantly reduce cyst or uterine sizes (Xiang et al. 2011). In another study, six studies with 331 participants were analyzed. The results indicated that acupuncture provided significant benefits compared to non-specific acupuncture for overall pelvic, menstrual pain, and unspecified pelvic pain. Additionally, compared to usual care, acupuncture was beneficial for menstrual. Most studies reported low incidences of adverse events (Giese et al. 2023). However, there is a need for more validated studies with a bigger number of participants is needed to recommend acupuncture as a complementary treatment.

V.3.b. Physiotherapy

Evidence-based recommendations

• Pelvic Floor Muscle (PFM) Physiotherapy for DIE: A structured sequence of five 30-minute individual PFM physiotherapy sessions is recommended at weeks 1, 3, 5, 8, and 11. These sessions include the Thiele massage, a therapeutic technique that involves applying digital pressure and stretching the pelvic muscles. This approach may be effective in alleviating superficial dyspareunia and chronic pelvic pain associated with DIE.
• 8-Week Physiotherapy Plan: An 8-week physiotherapy plan, consisting of one 30-minute session every 15 days, can significantly reduce pain and enhance quality of life. This plan includes a manual therapy protocol that combines soft tissue and articulatory techniques for optimal therapeutic outcomes:
  1. Occiput, Atlas, and Axis (OAA) Manipulation: The patient lies supine while the therapist performs a rotation toward the side to be manipulated with a cranial helical movement along the vertical axis through the odontoid process of the axis. This technique is applied bilaterally.
  2. Thoraco-Lumbar Manipulation: The patient lies on the contralateral side with upper and lower limbs flexed. The therapist presses on the inferior articular apophyses of T12 with one hand while the other rests on the patient’s chest. A high-velocity low-amplitude movement in forward rotation of the pelvis is then performed. Applied bilaterally.
  3. Global Sacroiliac Manipulation: The patient lies on the contralateral side with complete spine rotation and lower limb flexion. The therapist’s forearm is placed on the iliac crest to perform a high-velocity low-amplitude movement in a caudal to cephalic and posterior to anterior direction to mobilize the sacroiliac and lumbosacral joints. Applied bilaterally.
  4. Abdominal Mobilization: The patient lies supine with knees flexed. The therapist places the ulnar border of both hands over the lower abdomen and performs a manual vibration in the cranial direction during exhalation. Applied for 5 minutes.
  5. Broad Ligament Mobilization: The patient lies supine with knees flexed. One hand is placed on the broad ligament while the other holds the patient’s legs. An opposite movement of both hands is performed to provoke a stretch in the abdominal region. Applied for 5 minutes.
  6. Pelvic Diaphragm Release: The patient lies supine. One hand is placed under the lumbosacral junction and the other on the upper pelvic surface, perpendicular to the one below. A slight compression is performed for 5 minutes to produce fascial tissue relaxation.
  7. Sphenoid Technique: The patient lies supine. The therapist places fingers bilaterally over specific cranial landmarks and performs a gentle caudal to cephalic distraction force for 5 minutes.
  8. Fourth Ventricle Technique: The patient lies supine. The therapist’s hands are placed under the occiput with thumb tips together. A slight compression with thenar eminences and cephalic traction is performed for 5 minutes (Munoz-Gomez et al. 2023).

Recently published studies in physiotherapy

In a review of physiotherapy in women with pelvic pain, it was concluded that recommendations for physiotherapy should be given with caution. The review found six RCTs with significant heterogeneity and often combined with psychological and medical management making it impossible to establish the ‘stand-alone’ value of physiotherapy input. Two studies were retrieved evaluating manipulations and massage to relieve endometriosis-associated pain, but both were of low quality to support any recommendations (Darai, et al., 2015; Valiani, et al., 2010). In another study, Pelvic Floor Physiotherapy (PFP) does not appear to significantly affect urinary, bowel, and sexual functions in women with DIE. Although there is an improvement in superficial dyspareunia, chronic pelvic pain, and pelvic floor muscle relaxation with high treatment satisfaction, the impact on urinary, bowel, and sexual functions remains unclear. Larger studies are necessary to further investigate these effects (Forno et al. 2024). There is a lack of high-quality published research specifically focused on women with endometriosis to help guide clinicians on the most effective physiotherapy interventions and when to recommend them.

V.3.c. Physical Activity

Evidence-based recommendations

• Personalized Physical Activity Program: Patients should undergo a personalized fitness assessment to establish their current fitness level and set specific goals. A 6-month virtual physical activity program, conducted via videoconference, is recommended. Sessions should last between 45 minutes to 1 hour, scheduled 1 to 3 times per week. Each session should include a balanced mix of cardio exercises, stretching, yoga, and Pilates to enhance overall physical well-being and flexibility.
• Exercise for Medication Reduction: To potentially reduce the reliance on medications, patients are encouraged to engage in exercise four times per week, with each session lasting 40 minutes. The exercise intensity should be maintained at 20 metabolic units. Flexibility exercises should be integrated before and after each workout to prevent injury and improve flexibility. Based on individual treadmill test results, patients should be assigned a target heart rate zone, ideally between 50% and 70% of their maximum heart rate. A proper cool-down period is essential, with patients walking until their pulse decreases to 100 beats per minute after each session.
• Hatha Yoga Routine: A weekly regimen of 120 minutes of Hatha yoga is highly recommended, divided into three key components: 60 minutes of posture practice focusing on various yoga poses and asanas, 30 minutes of conversation for reflection and discussion, and 30 minutes dedicated to relaxation techniques, breathing exercises, and meditation. This holistic approach significantly improves both quality of life and pain levels in patients with endometriosis.
• Comprehensive Exercise Program: Implement a well-rounded exercise routine that includes posture correction exercises from various positions (crook lying, supine, sitting, and standing), holding each position for 5 seconds, followed by a 10-second relaxation period, repeated 10 times. Incorporate diaphragmatic and lateral costal breathing exercises, with deep breaths taken for 5 seconds, followed by 10 seconds of relaxation, repeated five times. Allocate 10 minutes for general relaxation techniques and muscle sense training, 3 minutes for diversion drill training, and 6 minutes for positional education on cross-sitting and squatting. Stretching exercises for the lower back, adductor, hamstring, and pelvic floor muscles should be performed, holding each stretch for 45 seconds and repeating three times at the start and end of each session. End each workout with a 20-minute treadmill walk. This exercise program should be followed three times per week to achieve optimal results in posture, flexibility, and overall well-being. Eight weeks of consistent participation in this program can effectively reduce pain and correct postural abnormalities associated with endometriosis.

Recently published studies in physical activity

In a recently published review, research screened 1,045 citations to determine eligibility. Four interventional studies were identified, but one was excluded due to significant design flaws. The remaining three studies included two randomized controlled trials (RCTs) and one pre-post study without a control group, encompassing 109 patients. The interventions involved flexibility and strength training, cardiovascular fitness, and yoga, conducted between one to four times per week throughout 8 to 24 weeks (about 5 and a half months), with or without supervision. Among the findings, only one study reported improvements in pain intensity, while another indicated a reduction in stress levels. Due to the variability in study outcomes and measures, along with the presence of confounding factors, a quantitative meta-analysis could not be conducted. The effect of physical activity (PA) and exercise as treatments for endometriosis-associated symptoms could not be determined due to the significant limitations of the included studies (Tennfjord et al. 2021). A literature search in PubMed from 1985 to 2012 identified 935 articles, of which only six met the inclusion criteria. These studies explored the potential relationship between physical exercise and endometriosis prevalence. However, the findings were inconclusive regarding the benefits of exercise as a risk factor for the disease, and no data were available on its effects on the progression of endometriosis. The review concluded that randomized studies are essential to clarify the role of exercise in managing endometriosis symptoms and its overall impact on the disease (Bonocher et al. 2014). Encouraging patients to stay active and exercise are critical components of pain management programs for those with chronic pain conditions, according to the British Pain Society (2019). However, the specific effects and benefits of exercise for women with endometriosis have not been well studied or documented in research.

V.3.d. Psychological Interventions

Evidence-based Recommendations

• Mindfulness-Based Psychological Intervention: A 10-week program comprising 10 sessions of mindfulness-based psychological intervention, including five individual and five group sessions, is recommended for women with endometriosis. This intervention should incorporate mindfulness training, visualization techniques, counseling, group support, and patient education. The focus areas should include managing fatigue, improving sleep quality, and addressing job, relationship, and family issues. This comprehensive approach has the potential to significantly enhance the quality of life for women with endometriosis.
• Progressive Muscle Relaxation (PMR) with GnRH Agonist Therapy: A structured 12-week Progressive Muscle Relaxation (PMR) program is recommended alongside GnRH agonist therapy. The program should consist of twenty-four 40-minute group sessions, held twice weekly. The first session should begin with a discussion on the effects of anxiety and depression related to endometriosis, followed by an introduction to relaxation techniques. Subsequent sessions should focus on systematically relaxing and contracting major muscle groups, including the arms, face, neck, chest, abdomen, and legs. This approach is designed to promote both physical and mental relaxation, potentially alleviating symptoms associated with endometriosis.

Recently published studies in psychological interventions

The reviewed articles in a systematic review suggest that psychological interventions such as CBT, mindfulness, yoga, and psychoeducation, delivered by trained specialists, can effectively reduce pain in women with endometriosis, as evidenced by consistent positive results across long-term follow-ups ranging from 3 months to 6 years. However, some studies had limitations, including a lack of homogeneity between intervention and control groups, the use of self-report measures rather than standardized questionnaires, and the absence of a control group, which may impact the validity and generalizability of the findings. The study findings indicated that all the psychological interventions mentioned contributed to pain relief and improvement in women with endometriosis. Given the limited research available and the fact that only five articles were of high quality, conducting more robust studies could offer stronger evidence to support the effectiveness of these psychological interventions in alleviating pain associated with endometriosis (Samami et al. 2023). A new study revealed that the brief mindfulness-based intervention (bMBI) effectively reduced endometriosis-related pain by influencing cognitive and emotional factors associated with pain. Additionally, the intervention improved mental health-related quality of life (QoL-MH) through various mechanisms, not solely limited to pain relief. This underscores the independent capacity of enhancing emotional well-being to contribute to better mental health outcomes in individuals with endometriosis (Moreira et al. 2023). Another study, conducting an 8-week modified Mindfulness-Based Stress Reduction (MBSR) course conducted virtually over Zoom by an experienced social worker found a statistically significant improvement in four quality of life domains (control and powerlessness, emotional well-being, social support, and self-image) following the virtual MBSR course. There was no change in pain scores or opiate medication use. Participants felt the program’s benefits came from a sense of community, education about their condition, and the application of mindfulness tools when approaching pain. The virtual format was effective and preferred by participants, suggesting that virtual MBSR programs can increase access to this type of care (Miazga et al. 2024).

V.3.e. Nutrition

Evidence-based Recommendations

• Consumption of vitamin E (1200 IU) and vitamin C (1000 mg) combination daily for eight weeks before surgery can lead to reduction in endometriosis-associated daily pain, dysmenorrhea, and dyspareunia.
• Receiving either 1000 mg fish oil [720 mg ω-3 fatty acids, including 488 mg EPA (20:5n–3) and 178 mg DHA (22:6n–3)] daily, 2000 IU vitamin D3 (cholecalciferol) daily for 6 months will cause improvement in pelvic pain severity and catastrophic thinking.
• Adopting an individually adapted diet can cause decreased symptoms and increased well-being. These changes can include:
  • Exclusion or decrease of gluten, dairy products and carbohydrates.
  • Eliminating foods considered to stress the body or to affect oestrogen levels or inflammatory processes
  • Increase of intake of fruit, vegetables and fish
  • Trying cooked meals from scratch
  • To avoided junk food
  • Consumption of supplements such as vitamins, minerals, omega-3, turmeric and ginger
  • Trying walking, yoga, mindfulness, meditation and dancing ‘to slow down the stress’ beside dietary changes
  • To stop using hormone-disturbing products, such as parabens to minimize hormonal effects
  • Preference of ecological and natural products
• Nutrients with a possible positive effect on endometriosis-related symptoms, their sources and their recommended daily amount include:
  • Fatty acids such as Palmitoylethanolamide (PEA) are found in eggs and peanuts, although there is no recommended daily amount. Omega-3 fatty acids include linolenic acid, which is present in oils like flaxseed, canola, walnut, and soybean, as well as in nuts, seeds, and walnuts.
  • Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in human milk and fatty fish. Omega-3 fatty acids should make up 1% of adequate energy intake.
  • Omega-6 fatty acids include linoleic acid, which is present in vegetable oils like corn, sunflower, safflower, and soybean, as well as in poultry fat, nuts, and seeds. Arachidonic acid is found in meats, poultry, eggs, mayonnaise, and margarine. Omega-6 fatty acids should account for 2% of adequate energy intake.
  • Vitamin A sources include cheese, cream, butter, fortified margarine, butter, eggs, liver, dark leafy greens, and deep orange fruits like apricots and cantaloupe, as well as vegetables like sweet potatoes, pumpkin, squash, and carrots. The recommended daily intake of Vitamin A is 680 µg mg/day.
  • Vitamin B6 is found in meat, fish, poultry, potatoes, and other starchy vegetables, legumes, and non-citrus fruits like bananas and watermelon, with a recommended intake of 1.5 micrograms/day.
  • Vitamin C is abundant in citrus fruits, cabbage-type vegetables like Brussels sprouts and cauliflower, and dark green vegetables such as bell peppers and broccoli. Other sources include cantaloupe, strawberries, lettuce, tomatoes, potatoes, papayas, mangoes, and kiwi, with a recommended daily intake of 75 mg/day.
  • Vitamin D can be obtained from fortified foods such as milk, margarine, butter, egg yolks, liver, fatty fish, and veal, with a recommended intake of 10 µg/day (AI).
  • Vitamin E is found in polyunsaturated plant oils, leafy green vegetables, wheatgerm, wholegrains, liver, egg yolks, nuts, seeds, and avocado, with a daily requirement of 11 mg/day.
  • Calcium can be sourced from milk, cheese, yoghurt, small fish with bones like sardines, tofu, and greens such as Chinese cabbage, broccoli, and kale. The recommended intake for women aged 25-49 years is 950 mg/day.
  • Iron is present in red meat, eggs, fish, shellfish, poultry, dried fruits, and tomatoes, with a recommended intake of 16 mg/day for pre-menopausal women and 11 mg/day for post-menopausal women.
  • Magnesium can be found in nuts like cashews, seeds, avocado, dried fruits, cacao powder, and wholegrains, with a daily intake of 350 mg/day.
  • Selenium is present in seafood, meat, wholegrains, fruits, and vegetables, with a recommended intake of 70 µg/day.
  • Zinc sources include red meat, shellfish, and wholegrains, with a recommended intake of 7 mg/day.
  • Indole-3-carbinol (I3C), which is present in cruciferous vegetables such as cabbage, Brussels sprouts, and broccoli, has no recommended daily amount.
  • Polydatin can be found in grapes, wine, hop cones and pellets, beer, cocoa-containing products, and chocolate, but there is no recommended daily amount for this nutrient.
  • Lactobacilli are present in yoghurt and kefir, with no specific recommended daily amount provided.
• Nutrients and nutrient groups to be avoided in the endometriosis diet include:
  • Red meat is listed as a nutrient group to avoid, with examples including beef, pork, lamb, mutton, veal, horse, and liver. Similarly, Gluten is also to be avoided, which is found in wheat, rye, spelt, and barley, including Khorasan wheat.
  • Cow milk is highlighted as another nutrient to avoid due to its sugar content. This includes various products like milk, cheese spreads, whey-based soft drinks, and ice cream.
  • All sugars should be avoided, including both refined and natural sugars. Refined sugars include cane sugar and caster sugar, while natural sugars include honey, palm sugar, maple syrup, and coconut blossom sugar. Additionally, artificial sweeteners such as aspartame, cyclamate, saccharin, sucralose, and polyols should be avoided.
  • Nutrients high in estrogen should also be avoided. This includes soy products like soy milk, tofu, soya sprout, miso, tempeh, and soy sauce. Other estrogen-rich foods include natto, linseed, sesame seeds, and black beans.
  • Lastly, caffeine intake should be limited to a maximum of 200 mg daily. Sources of caffeine that should be limited include coffee, various types of tea (black, green, white), and soft drinks like Coca-Cola and iced tea. Other products that contain caffeine, such as energy drinks, chocolate milk, and chocolate (both dark and milk), should also be consumed in moderation, along with certain painkillers that contain added caffeine.

Recently published studies in nutrition

A randomized, placebo-controlled trial investigated the effects of antioxidant vitamins E and C on endometriosis symptoms in 59 women aged 19 to 41 with pelvic pain. Participants were divided into two groups, receiving either the antioxidant combination or a placebo daily for eight weeks before surgery. Results showed that 43% of the antioxidant group experienced improvement in chronic pain, while dysmenorrhea and dyspareunia decreased in 37% and 24% of participants, respectively. In contrast, the placebo group showed minimal changes. Additionally, antioxidant treatment significantly reduced inflammatory markers in peritoneal fluid. Overall, the study concluded that antioxidant supplementation effectively alleviates chronic pelvic pain and reduces inflammation in women with endometriosis (Santanam et al. 2013). A randomized, placebo-controlled trial involving 69 women screened from a total of 147 participants found that while those in the vitamin D3 group experienced significant improvement in worst pain over the past month, from a mean of 7.0 at baseline to 5.5 after 6 months, a nearly identical reduction was observed in the placebo group, from 6.0 to 4.4. The fish oil group showed a more modest improvement, from 5.9 to 5.2. However, neither the vitamin D3 nor fish oil interventions were statistically different from placebo (Nodler et al. 2020). In a qualitative study, semi-structured qualitative interviews were conducted with 12 persons with endometriosis who had made individual dietary changes aimed at decreasing their endometriosis symptoms. The interviews were recorded and transcribed verbatim and analyzed using thematic analysis. This study helps address the lack of information about dietary approaches for managing endometriosis and highlights lifestyle changes to reduce suffering and enhance well-being. A key finding is that participants reported a reduction in symptoms and an improvement in overall well-being after following a personalized diet (Karlsson et al. 2020). A retrospective case-control study involving 156 women with endometriosis and 52 age-matched controls found that patients with endometriosis had significantly higher rates of diet-related comorbidities like food intolerances and allergies, as well as more gastrointestinal symptoms including constipation, flatulence, heartburn, diarrhea and frequent defecation. Endometriosis patients also showed significantly lower intakes of organic acids, maltose, glycogen, tetradecenoic acid, methionine, lysine, threonine, histidine, and total animal proteins compared to controls. Additionally, women with endometriosis consumed less vitamin C, vitamin B12, and magnesium. These findings suggest that dietary interventions overseen by a nutritionist may help reduce disease burden in women with endometriosis (Schink et al. 2019). A review by Huijs and Nap indicated that there has been insufficient research on the roles of antioxidants, gluten, and soy about endometriosis. They concluded that while nutrients with direct or indirect anti-inflammatory effects could potentially influence endometriosis-related pain, there is currently no evidence to support the creation of a specific diet for managing the condition (Huijs and Nap, 2020). A prospective pilot study conducted at a single center from April 2021 to December 2022 allowed participants to choose between following the Low FODMAP diet, an endometriosis diet, or no diet (control group). Women who opted for a diet received comprehensive guidance from a trained dietitian, and all groups were followed for six months. The study compared outcomes for women on the diets with their baseline data and the control group. Results indicated that those adhering to a dietary intervention reported significantly reduced pain from various endometriosis-related symptoms and improved scores in several quality-of-life areas after six months, compared to both their initial conditions and the control group. These findings suggest that dietary interventions may effectively help manage endometriosis symptoms and enhance the quality of life, although further research is necessary to validate these results and develop specific guidelines (Haaps et al. 2023). There has been considerable speculation regarding the impact of diet on endometriosis symptoms, stemming from the understanding that diet can influence various processes, including inflammation, prostaglandin metabolism, and estrogen activity. However, there are very few studies, and those that exist often lack quality, assessing the effectiveness of dietary interventions on endometriosis symptoms.

V.4. Surgery

This section is provided to inform the patients who need surgery about the process, and the pros and cons of different types of surgeries based on the guidelines and recently published studies.

Inquire with women who have suspected or confirmed endometriosis about their symptoms, preferences, and priorities regarding pain management and fertility to inform surgical decision-making.

Surgical management options should be discussed with women with suspected or confirmed endometriosis. Discussions may include:

• What a laparoscopy involves?

• How laparoscopic surgery could affect endometriosis symptoms?

• The possible benefits and risks of laparoscopic surgery

• The possible need for further surgery (for example, for recurrent endometriosis or if complications arise)

• The possible need for further planned surgery for deep endometriosis involving the bowel, bladder, or ureter.

Surgical intervention to remove endometriotic lesions and separate adhesions has been a crucial aspect of endometriosis management for many years. Traditionally, these procedures were performed through open surgery; however, laparoscopy has become the preferred method in recent decades. The removal of endometriosis can be accomplished through techniques such as excision, diathermy, or ablation/vaporization. The purpose of dividing adhesions is to restore normal pelvic anatomy. Additionally, some clinicians may interrupt pelvic nerve pathways to enhance pain management.

Laparoscopic surgery reduces the overall pain at 6 months and improves health-related quality of life, psychiatric profile, and sexual satisfaction in comparison with diagnostic laparoscopy.

Laparoscopy typically results in shorter hospital stays, faster recovery, and improved cosmetic outcomes, making it the preferred option over open surgery. If the necessary expertise in laparoscopy is lacking, the patient should be referred to a specialized center.

V.4.a. Techniques for Different Types of Endometrioses

Ablation vs. Excision

Excision and ablation equally improve pelvic pain associated with mild endometriosis. Although, laparoscopic excision is significantly superior to ablation in reducing dyschezia, and chronic pelvic pain. There is also a trend in the reduction of dysmenorrhea and dyspareunia scores after excision compared to ablation.

However, when conducting surgery, clinicians may opt for excision rather than ablation of endometriosis to alleviate pain associated with the condition. The excisional approach is likely to be more suitable for deep endometriosis lesions, as it is impossible to know if the entire lesion is destroyed with ablative techniques.

Surgical Interruption of Pelvic Nerve Pathways

There are two types of surgical interruption of pelvic nerve pathways: Presacral neurectomy (PSN) and Laparoscopic Uterosacral Nerve Ablation (LUNA).

LUNA does not have any significant benefits, but PSN has more benefits in reducing dysmenorrhea, dyspareunia, pelvic pain, and especially midline pain.

PSN has some side effects including bleeding, constipation, urinary urgency, and a painless first stage of labor.

As the last point, an expert surgeon should perform it.

Surgery for Ovarian Endometrioma

If cysts are equal to or bigger than 3 cm (about 1.18 in), cystectomy is a choice treatment in which laparoscopic excision of ovarian endometriotic cysts is done. However, the final decision in each case is based on the patient’s preferences, fertility status, and health professional’s opinion.

Compared to drainage and coagulation, cystectomy has a lower recurrence of dysmenorrhea and dyspareunia, fewer cyst recurrences, lower non-menstrual pain recurrence, and lower need for further surgery.

Compared to CO2 laser vaporization, cystectomy has a lower recurrence of cysts at 12 months but at 29 months (about 2 and a half years) patients have the same recurrence.

Notice that an endometrioma bigger than 5 cm (about 1.97 in) indicates recurrence.

Surgery for Deep Endometriosis

Deep endometriosis extends beneath the peritoneum and may affect the uterosacral ligaments, pelvic side walls, rectovaginal septum, vagina, bowel, bladder, or ureter. Excision of these nodules is usually performed when surgical treatment is chosen.

Treatment approaches for colorectal endometriosis include superficial shaving, discoid resection, and segmental resection of the bowel to remove the deep endometriosis nodules. Surgery improves pain and quality of life in women with deep endometriosis.

Apart from significant improvement in pain, radical treatment of deep endometriosis also positively impacts fertility outcomes. For lesions on the sigmoid colon, a segmental resection should be performed. For deep endometriosis involving the rectum, a more tailored approach can be chosen. A laparoscopic approach is preferred because it is associated with better postoperative recovery, shorter hospital stays, and better cosmetic outcomes. If relevant laparoscopic experience is not available, it is recommended to refer the patient to an expert center.

Surgery for posterior compartment endometriosis excluding bowel endometriosis:

1. Endometriosis of the uterosacral ligaments and vagina: It causes a reduction in deep dyspareunia and chronic pelvic and no major complications but superficial vascular injury, ureteral stenosis, and bowel obstruction in several cases.

1. Endometriosis of the cul-de-sac: Laparoscopic excision (douglasectomy) can be performed. It can decrease the pain significantly.

1. Endometriosis of the bladder and ureters: Surgical treatment of bladder endometriosis is usually excision of the lesion and primary closure of the bladder wall. Ureteral lesions may be excised after stenting the ureter; however, in the presence of intrinsic lesions or significant obstruction, segmental excision with end-to-end anastomosis or reimplantation may be necessary. It leads to improvement of pain symptoms with low complication and recurrence rates.

Hysterectomy

Clinicians can consider hysterectomy (with or without removal of the ovaries) with removal of all visible endometriosis lesions, in those women who no longer wish to conceive and failed to respond to more conservative treatments. Women should be informed that hysterectomy will not necessarily cure the symptoms or the disease.

When a decision is made whether to remove the ovaries, the long-term consequences of early menopause and the possible need for hormone replacement therapy should be considered.

It is recommended that when a hysterectomy is performed, a total hysterectomy is preferred.

Recently published studies in endometriosis surgery methods and innovations

Ablation vs. Excision

In a randomized clinical trial comparing laparoscopic ablation versus excision for superficial endometriosis-associated pain, both laparoscopic ablation and excision treatments were effective in reducing pain associated with superficial endometriosis. There were no significant differences between the two surgical groups regarding dysmenorrhea, non-menstrual pain, and dyschezia. However, patients in the ablation group experienced significantly lower intensity of dyspareunia compared to the excision group. The findings support the use of both techniques in clinical practice, with ablation therapy potentially offering greater relief for dyspareunia. Further research involving larger populations and longer follow-up periods is recommended to better determine the most appropriate surgical method for the treatment of endometriosis-associated pain (Mackenzie et al. 2023).

A study comparing two methods in superficial endometriosis concluded that both laparoscopic ablation and excision treatments were effective in reducing pain associated with superficial endometriosis. Specifically, the ablation group showed a significantly lower intensity of dyspareunia compared to the excision group. The findings highlight the efficacy of both methods, with ablation therapy being particularly effective in reducing dyspareunia (Hashemi et al. 2023).

Nerve Sparing during Surgery

Systematic nerve sparing during surgery for deep infiltrating posterior endometriosis improves immediate postoperative urinary outcomes by reducing the need for self-catheterization without increasing operating time or complication rates. This technique provides better early postoperative bladder function and facilitates quicker recovery, highlighting its feasibility and safety in the surgical management of DIE (Soares et al. 2021).

Hybrid Argon Plasma Coagulation (HybridAPC) vs. Sharp Excision

A clinical trial compared hybrid argon plasma coagulation (HybridAPC) versus sharp excision for the treatment of endometriosis and demonstrated the feasibility of HybridAPC as a novel surgical technique for treating peritoneal endometriosis. HybridAPC showed a promising impact on adhesion prevention, being significantly faster than sharp excision. Although the eradication rate was not significantly different between the two methods, HybridAPC presents itself as a safe, tissue-preserving, and efficient method for endometriosis treatment. Further studies with larger populations are warranted to conclusively determine the efficacy of HybridAPC compared to sharp excision (Keckstein et al. 2023).

Laparoscopic Natural Orifice Specimen Extraction (NOSE) Colectomy vs. Conventional Laparoscopic Colorectal Resection

In a randomized trial comparing laparoscopic natural orifice specimen extraction (NOSE) colectomy versus conventional laparoscopic colorectal resection in patients with rectal endometriosis: a prospective randomized trial, concluded that the laparoscopic NOSE colectomy provides comparable pain relief and quality of life improvements to conventional laparoscopic colorectal resection in patients with rectal endometriosis (Dobo et al. 2023).

Electro-diathermy vs. Helium Thermal Coagulation

Another randomized trial comparing electro-diathermy with helium thermal coagulation in laparoscopic treatment of mild-to-moderate endometriosis concluded that while both methods are effective, the choice of technique may be guided by the specific clinical scenario and surgeon’s preference (Misra et al. 2020).

Ethanol Sclerotherapy vs. Laparoscopic Surgery

A randomized clinical trial comparing ethanol sclerotherapy versus laparoscopic surgery in the management of ovarian endometrioma concluded although AMH levels and mean cyst diameter were significantly lower one year after laparoscopy, the recurrence rate of ovarian endometrioma was similar between ethanol sclerotherapy and laparoscopy methods. Ethanol sclerotherapy is suggested to be an effective alternative for laparoscopic surgery in the management of ovarian endometrioma, showing no significant change in AMH levels post-treatment and a comparable recurrence rate (Ghasemi Tehrani et al. 2022).

V.4.b. Medical Therapies Adjunct to Surgery

The question of whether medical therapies are effective as an adjunct to surgical therapy considers both therapies to improve immediate surgical outcomes, and therapies aimed at secondary prevention, being prevention of recurrence of disease and/or symptoms.

Preoperative medical treatment: It is not recommended to prescribe preoperative hormone treatment to improve the immediate outcome of surgery for pain in women with endometriosis.

Postoperative medical treatment: Women may be offered postoperative hormone treatment to improve the immediate outcome of surgery for pain in women with endometriosis if not desiring immediate pregnancy.

VI. Endometriosis Recurrence

Surgical intervention has been shown to alleviate symptoms, restore anatomical structures, and enhance fertility outcomes. Nonetheless, the recurrence of endometriosis post-surgery remains frequent, leaving patients at a significant risk of requiring further procedures. Reported re-intervention rates after surgeries where ovarian preservation was achieved range from 27% to 58%.

Recurrence of endometriosis has been categorized into four subtypes: symptom-based recurrence, where symptoms reappear without imaging or surgical confirmation; imaging-based recurrence, identified through imaging with or without symptoms; laparoscopically proven recurrence, where endometriosis is visually confirmed but lacks histological evidence; and histologically proven recurrence, confirmed both visually and through histological analysis after laparoscopy (International working group of AAGL, ESGE, ESHRE, and WES, et al., 2021).

VI.1. Prevention of Recurrence of Endometriosis

It is advised to consider the postoperative administration of a levonorgestrel-releasing intrauterine system (52 mg LNG-IUD) or combined hormonal contraceptives for a duration of at least 18 to 24 months. This approach aims to provide secondary prevention of endometriosis-associated dysmenorrhea. Following surgical intervention for ovarian endometrioma in women who are not planning immediate conception, it is recommended that healthcare providers offer long-term hormonal therapy, such as combined hormonal contraceptives, to mitigate the risk of recurrence related to endometriomas and associated symptoms of endometriosis.

VI.1.a. Recently published studies

In a study, long-term oral contraceptive therapy among patients who underwent conservative laparoscopic surgery for endometrioma with a 24-month follow-up resulted in a statistically significant recurrence rate in non-users compared to the long-term oral contraceptives treated patients (Cucinella et al. 2013).

In an experimental study, patients in the control group were treated by laparoscopic surgery, while patients in the observation group were added by the subcutaneous injection of GnRH agonist (Triptorelin 3.75 mg intramuscular per 28 days for 6 months), based on the treatment of the control group. The recurrence rate was significantly lower in the observation group (Yang et al. 2019).

In a prospective cohort randomized study, a total of 111 patients were randomly assigned into two groups: the dienogest-administered group (2 mg oral daily for 6 months) (n = 56) and the goserelin-administered group (1.8 mg subcutaneously per month for 6 months) (n = 55). Patients were followed for 24 months after laparoscopic surgery and a control group (n=79). No significant difference was found in the recurrence rate between the goserelin group and non-treatment group; however, a significant difference was found in the recurrence rate between the dienogest group and the non-treatment group. Side-effects were markedly observed in the goserelin group as compared with the dienogest group. Dienogest is available for prolonged administration of more than 6 months, so it is more useful than goserelin, which is available only for short-term administration (Takaesu et al. 2016).

In a recent meta-analysis, seven studies were evaluated, comprising four randomized controlled trials with 212 participants, one prospective cohort study involving 88 patients, and two retrospective studies with 191 patients. The findings indicated that LNG-IUD significantly alleviated postoperative pain, which was comparable to the effects of GnRH agonists. Additionally, LNG-IUD demonstrated efficacy in reducing the recurrence of pain or disease, showing similar effectiveness to oral contraceptives. Moreover, patient satisfaction levels with LNG-IUD were markedly higher compared to those using oral contraceptives. However, it is noteworthy that the incidence of vaginal bleeding was significantly elevated in the LNG-IUD group compared to the GnRH agonist group (Song et al. 2018).

A retrospective study involving 130 patients treated with dienogest, 72 with the LNG-IUD, and 83 receiving no treatment has confirmed the effectiveness of LNG-IUD in managing postoperative pain and preventing recurrence over 6, 12, and 24 months. However, the study did not establish a definitive superiority of LNG-IUD compared to dienogest. This suggests that while LNG-IUD is beneficial for pain control and recurrence prevention, further research is necessary to clarify its comparative efficacy against dienogest in postoperative settings (Lee et al. 2018).

In another study, a total of 100 patients with endometriosis were randomly divided into a control group (laparoscopic resection only, n=50) and a treatment group (laparoscopic resection combined with GnRH agonist treatment (per 28 days for 4-6 months, n=50). In addition to the laparoscopic resection that was performed in the control group, the treatment group also received an additional 3-6 courses of GnRH agonist therapy postoperatively (3.75 mg per time, every 28 days). They concluded that compared with laparoscopy use only, applying GnRH agonist after laparoscopy can enhance treatment efficacy, increase pain relief rates, and reduce recurrence rates and partly adverse events (Huang et al. 2018).

VI.2. Treatment of Recurrence of Endometriosis

Hormonal treatments and surgical options are both viable strategies for managing recurring pain symptoms in women with endometriosis. Hormonal therapies, including combined oral contraceptives, progestins, and GnRH agonists, aim to reduce estrogen levels, which can help alleviate pain and prevent the progression of endometriosis. These treatments work by suppressing the growth of endometrial tissue and inducing a hypoestrogenic state, thereby minimizing cyclical pain associated with menstruation. Surgery is often recommended for cases where hormonal treatments are insufficient or when there are significant anatomical issues, such as large endometriomas or adhesions. Surgical interventions can provide immediate relief by removing endometriotic lesions and adhesions, but they may be complemented by hormonal therapy to reduce the risk of recurrence post-surgery. The choice between hormone treatment and surgery depends on various factors, including the severity of symptoms, the patient’s age, reproductive plans, and overall quality of life considerations. In many cases, a combination of both approaches may yield the best outcomes for managing endometriosis-related pain.

VI.2.a. Recently published studies

In a recent randomized controlled trial, 242 women experiencing recurrent pelvic pain within one-year post-laparoscopic surgery were assigned to receive either dienogest or depot leuprolide acetate. At the 12-week follow-up, both treatment groups reported significantly reduced VAS scores for pelvic pain, back pain, dyspareunia, and endometrioma size; however, no significant differences were observed between the two treatments regarding these outcomes. While dienogest and depot leuprolide acetate demonstrated different side effect profiles—dienogest resulted in fewer hot flashes and instances of vaginal dryness, whereas leuprolide acetate was associated with reduced vaginal bleeding and weight gain—both treatments were effective in managing pain related to endometriosis (Abdou et al. 2018).

In a recent retrospective study, researchers investigated the effects of dienogest treatment initiated immediately after the recurrence of endometriomas. The cohort comprised 11 patients who experienced endometrioma recurrence and received dienogest, with follow-up conducted for 24 months on seven of these individuals. Remarkably, complete resolution of recurrent endometriomas was observed in four patients, accounting for 57.1% of those followed (Koshiba et al. 2018).

In a recent prospective study, researchers examined the impact of surgical intervention on recurrent endometriomas, focusing on the potential harm to healthy ovarian tissue and ovarian reserve. The study included a small cohort of 11 patients who underwent surgery for recurrent endometriomas. Histological analysis revealed that the surgical procedures resulted in greater removal of ovarian tissue compared to initial surgeries, indicating a detrimental effect on ovarian health. Additionally, at a three-month follow-up, there was a notable trend toward lower antral follicle counts (AFC), with an average of 3.5 ± 1.4 following the second surgery compared to 5.1 ± 2.8 after the first surgery. These findings suggest that repeated surgical interventions for endometriomas may pose increased risks to ovarian reserve and overall reproductive health (Muzii et al., 2015).

VII. Sexual Health in Endometriosis

This section includes recommendations to address sexual problems in endometriosis. Providing a sense of safety and privacy for the patients is a necessity for addressing sexual problems.

Pain during intercourse, known as dyspareunia, is one of the most frequently reported issues in women with endometriosis, affecting between 32% and 70% of patients. Along with physical discomfort, various sexual difficulties, including issues that occur at different stages of sexual response, are commonly mentioned in the literature. These problems are not limited to pain but can also involve emotional and psychological aspects. Notably, the occurrence of sexual issues tends to increase when emotional distress related to sexual function is taken into account. In fact, for many women with endometriosis, this emotional distress can outweigh the physical symptoms, highlighting the significant impact endometriosis can have on sexual health.

Assess patients’ sexual health periodically through standard questionnaires like the Female Sexual Functioning Index (FSFI) (appendix 1) to discover any difficulties they are suffering from. Considering the findings by Rossi et al. (2022), endometriosis patients experience higher rates of sexual difficulties compared to control groups, however, just 24% of them are referred to sexual health professionals. They experience more genital pain, sexual distress, and more negative cognitions regarding sexuality.

If any difficulties are found in the patient’s sexual health, health professionals can refer them to a sexual health professional or if needed couples counseling.

Recommendations for sexual health:

• Adequate lubrication, using water-based or silicone-based products, can ease discomfort caused by vaginal dryness or tightness, making sexual activity more comfortable.

• Some positions may exacerbate pain due to deeper penetration or pressure on sensitive areas. Experimenting with positions that allow for shallow penetration can reduce discomfort.

• Other forms of sexual activity that don’t involve penetration, such as foreplay, mutual masturbation, or oral sex, can be applied to maintain intimacy without triggering pain.

• Taking NSAIDs like aspirin or ibuprofen an hour before sex can mitigate pain, with the option to take another dose post-intercourse if discomfort persists.

• Discussing experiences and limitations with the partner to foster understanding and adjust sexual activities accordingly can be helpful.

• Involving the partner in medical appointments for a shared understanding of the patient’s condition is vital.

VIII. Mental Health in Endometriosis

In women with endometriosis, pain tends to have a more profound negative impact on quality of life (QoL) compared to those with other benign gynecological conditions. Additionally, each group experiences different types of pain, further distinguishing the experience of endometriosis patients. Women with endometriosis report higher levels of both general pain perception and dysmenorrhea compared to those dealing with other painful conditions. Beyond physical discomfort, endometriosis also significantly affects psychological well-being, often compromising mental health. The chronic nature of the condition is linked to elevated stress levels, indicating that the long duration of the disease is an independent factor that influences how stress is perceived.

Regular mental health screenings should be integrated into the care pathway for patients with endometriosis using standard tools like Generalized Anxiety Disorder (GAD-7) for anxiety (appendix 2), the Patient Health Questionnaire (PHQ-9) for depression (appendix 3), and the Perceived Stress Scale (PSS) for stress (appendix 4).

Check the Psychological Interventions section on page 36 to see the evidence-based psychological interventions. Also, you can find some general recommendations for depression and anxiety in the following.

In cases where mental health conditions are identified, timely referrals to mental health professionals, including psychologists or psychiatrists, should be made to ensure a comprehensive, multidisciplinary approach to care.

Recommendations for mental health:

• Enjoyable activities and regular physical activities, such as short walks, should be incorporated into daily routines, as even brief movement has been shown to improve mood and well-being.

• Staying connected with friends and family is important, as social support is crucial for mental health.

• Feelings should be shared with someone trustworthy, whether a family member, friend, or healthcare provider.

• Antidepressants may be considered to manage symptoms of depression, with ongoing communication with healthcare providers to ensure the most appropriate medication and minimal side effects.

• Meditation apps may guide short meditation practices, as even five minutes a day has been found to reduce stress.

• Mindfulness practices should be embraced by remaining present and accepting of the current surroundings, which can help ease anxiety symptoms.

• Decaffeinated teas, such as green tea, ginger tea, or chamomile tea, can be included in evening routines to promote relaxation and reduce stress.

• Visits to gardens or parks are recommended to lower stress levels and provide a peaceful retreat from daily pressures.

• Calming essential oils, such as lavender or cinnamon, may be used with a diffuser to create a relaxing atmosphere and alleviate stress.

• Social support networks play a vital role in the well-being of endometriosis patients. These networks provide emotional, informational, and sometimes practical support, helping patients cope with the chronic pain and complex medical challenges associated with the condition. Some of the networks can be suggested in the United States are listed below:

Endometriosis Foundation of America (EndoFound)

• Website: www.endofound.org

• Provide patient education, awareness campaigns, and support networks to individuals affected by endometriosis.

EndoWarriors

• Website: www.endowarriorssupport.com

• A support group dedicated to helping individuals with endometriosis through peer support and advocacy.

The Endometriosis Network Canada (TENC) – US Chapter

• Website: www.endometriosisnetwork.com

• Though based in Canada, they offer a US chapter providing support groups, advocacy, and information for US patients.

The Endometriosis Association

• Website: www.endometriosisassn.org

• Offers support groups, resources, and advocacy for individuals affected by endometriosis.

Appendix 1: Female Sexual Function Index (FSFI)

Subject Identifier: ____________________
Date: ________________

Instructions: These questions ask about your sexual feelings and responses during the past 4 weeks. Please answer the following questions as honestly and clearly as possible. Your responses will be kept completely confidential.

Definitions:

• Sexual activity includes caressing, foreplay, masturbation, and vaginal intercourse.

• Sexual intercourse is defined as penile penetration (entry) of the vagina.

• Sexual stimulation includes situations like foreplay with a partner, self-stimulation (masturbation), or sexual fantasy.

• Sexual desire or interest includes wanting to have a sexual experience, feeling receptive to a partner’s sexual initiation, and thinking or fantasizing about having sex.

Please check only one box per question.

Section 1: Sexual Desire

1. Over the past 4 weeks, how often did you feel sexual desire or interest?

• a. Almost always or always
• b. Most times (more than half the time)
• c. Sometimes (about half the time)
• d. A few times (less than half the time)
• e. Almost never or never

2. Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?

• a. Very high
• b. High
• c. Moderate
• d. Low
• e. Very low or none