Endometriosis

Endometriosis is a benign condition in which endometrial cells normally located in the uterine cavity (endometrium) are located outside the uterine cavity and can be found in the ovaries, on the peritoneal pelvic wall or in the uterine muscularis (adenomyosis). In more severe cases, these mislocalised endometrial cells are more widespread, affect deeper tissue layers, infiltrate the pelvic ligaments, may grow into the rectum causing discomfort and changes at the abdominal outlet, or grow into the ureters causing blood to mix with the urine. Very rarely, endometriosis can also be found in other parts of the body such as the lungs, rectum, etc.

Like the endometrium localised in the uterine cavity, these endometrial cells localised outside the uterus go through a normal monthly hormonal cycle each month, which results in the endometrial cells sloughing off or desquamation. The endometrial cells in the uterine cavity desquamate and shed with each menstrual bleed, while the endometrial cells outside the uterine cavity cannot shed and remain in the pelvis, causing inflammation and scar tissue.

How common is Endometriosis?

According to published data, one in 10 women of reproductive age has endometriosis in mild or severe form, but not all women will have subjective complaints.

Women with shorter menstrual cycles (more menstrual bleeding episodes per year), prolonged menstrual bleeding, earlier onset of menstruation at puberty and a family history of endometriosis are at higher risk of endometriosis.

What are the causes of Endometriosis?

The exact cause of endometriosis is not known, but various theories have been put forth:

1. The retrograde bleeding theory is one of the most popular theories to explain the cells in the pelvis, but it is not exhaustive because retrograde bleeding during menstruation, when blood passes through the fallopian tubes into the pelvis, is very common, but not all women will have endometrial cells implant and develop endometriosis as a result.
2. Spread of endometriosis through the lymphatic or circulatory system. This theory helps to explain cases where endometriosis is found in the lungs, eyes or other distant organs that are in no way related to direct blood contact during menstruation.
3. The theory of coelomic metaplasia is that endometriosis develops from specific cells that are localised in the peritoneum or pelvic organs at birth and only become active at some point later in life, leading to milder or more severe forms of endometriosis.

Distancing ourselves from any particular theory, it is clear that the growth of endometriosis is influenced by the activity of oestrogens.  Unfortunately, it is not possible to measure this figure objectively in order to draw any reliable conclusions. Estrogen levels may be elevated in relative terms but still be within the relative normal range and continue to stimulate the growth of endometriosis on a monthly basis. The important role of these estrogens in the development of endometriosis is confirmed by the use of any medication that reduces the concentration of estrogens in the blood (combined oral contraceptives, gestagens, GnRH agonists, LNG-IUS) and the association of the disease with the menstrual cycle.

What are the symptoms of Endometriosis?

Most women consider pain during periods as normal. However, you may have endometriosis if you have:

• Severe pain during periods that interferes with daily activities;
• Spotting or bleeding between periods;
• Pain during or after intercourse;
• Pain or bleeding on passing stools;
• Pain or bleeding on passing urine;
• Lower back or pelvic pain;
• No pregnancy within 12 months of having regular, unprotected sex

Can Endometriosis affect sex life?

More than 50% of women with endometriosis experience discomfort during or after sex, which can gradually affect the relationship between partners and sometimes lead to misunderstandings and relationship breakdown. If a woman experiences pain during sexual intercourse, she should certainly not accept it. It is very likely that the cause of the pain is endometriosis, which can be successfully addressed.

Can Endometriosis cause infertility?

Over time, adhesions can form around the ovaries and fallopian tubes, which can cause both mechanical barriers to fertilisation and biochemical barriers, as endometriosis creates an inflammatory environment where various inflammatory mediators (interleukin-1 (IL-1), IL-6, IL-12 and IL-18, tumour necrosis factor alpha (TNF-α), interferon gamma (IFNγ) and granulocyte-macrophage colony stimulating factor) are released. These envelope mediators inhibit normal fertilisation of the egg.

How is Endometriosis diagnosed?

Doctors start to suspect endometriosis when patients have the typical complaints of pelvic pain, painful menstrual bleeding, pain during sexual intercourse and infertility.

Diagnosis of endometriosis is facilitated by the detection of an endometriotic cyst during gynaecological ultrasonography, but endometriosis should be kept in mind even in the absence of such a characteristic finding.

Sometimes, the oncomarker CA125 associated with ovarian cancer can help in the diagnosis. In endometriosis, the concentration of this marker is usually elevated up to 100 U/ml, but higher concentrations of up to 400 U/ml are occasionally found, but they will never approach 1000 U/ml. If concentrations above 500 U/ml are observed, it is more likely that an oncological disease is involved. In order to distinguish between elevated CA125 concentrations in endometriosis and elevated marker concentrations in malignancy, it is necessary to additionally determine the serum concentration of HE4 (human epididymis secretory protein 4). In endometriosis, this will always be within the normal range, not exceeding 70 pmol/L.

However, international guidelines do not recommend serum CA125 for the diagnosis of endometriosis, as changes in this marker are non-specific and may be elevated in various inflammatory diseases and may not be elevated in endometriosis.

The "gold standard" for diagnosing endometriosis is still laparascopic diagnostics.

Diagnostic laparascopy is indicated when a woman has vague pelvic pain and no other cause of pain can be clearly identified.

Treating Endometriosis

The treatment of endometriosis depends very much on the age of the woman, the necessity of becoming pregnant and the symptoms. Studies strongly indicate better treatment results when both surgical and medical treatment are combined. Initially, when it is not clear whether painful menstrual bleeding could be an isolated problem unrelated to endometriosis, oral contraceptives or one of the hormonal intrauterine systems (Fleree, Kyleena or Mirena) may be prescribed, but, if an endometriotic cyst or extensive pelvic endometriosis is initially detected on gynaecological ultrasonography, surgical treatment followed by pregnancy immediately after surgery or medical therapy if pregnancy is not planned would be more appropriate from the outset.

According to various authors, the risk of endometriosis returning within 5 years after surgery is 40-50% [1,2].

Complete excision of endometriosis has been clearly shown to reduce the risk of endometriosis recurrence and this is true for both ovarian endometriosis and deep, infiltrating pelvic endometriosis [3-5].

A meta-analysis of 11 studies investigating different risk factors that may still have a significant impact on the recurrence of endometriosis concluded that the use of medications after surgical treatment of endometriosis [6]:

• Increases the chance of cure [OR = 4.542, P < 0.001] (i.e. more than 4 times)
• Increases the likelihood of pregnancy [OR = 3.341, P < 0.001] (i.e. more than 3 times)
• Reduces the risk of recurrence [OR = 0.187, P < 0.001] (i.e. by 82%)

Another meta-analysis of 965 women evaluated the use of combined oral contraceptives after surgery, where, stratified into "always" (long-term) users and “non-users”, endometriomas returned in 8% of the "always" users and 34% of the “non-users”.

To assess the quantitative effect of contraceptive drugs, patients were divided into "always" users, "ever" users and "non-users". "Always" users versus "ever" users had a 79% lower risk of endometriosis recurrence. When comparing "ever" users versus "non-users", the risk of endometriosis recurrence was 61% lower. In conclusion, the use of oral contraceptives in the post-operative period can significantly reduce the risk of endometriosis recurrence, especially if the medication is used regularly and for a long time [7].

Different groups of drugs that reduce the stimulatory effects of natural oestradiol can be used effectively to delay the recurrence of endometriosis. In their meta-analysis, Zakhari et al. compared the effects of different drugs on the risk of endometriosis recurrence after surgical treatment. These studies analysed the endometriosis-inhibiting effects of progestins, oral contraceptives, gonadotropin-releasing hormone agonists and the levonorgestrol-containing coil. See table [8].

Inhibitory effect of different drugs on endometriosis compared with no drug use

Hormonal suppression of endometriosis is recommended within 6 weeks after surgery.

The use of pure progestin (0.17) and levonorgestrel-containing spiral (0.21) in the postoperative period shows the highest efficacy in delaying the recurrence of endometriosis.

When starting treatment for endometriosis, it is always important to discuss the possibility of pregnancy or the need for additional treatment after surgery in cases where pregnancy is not yet planned.  

Endometriosis is divided into 4 stages, depending on the extent and depth of infiltration of the lesion.

References:

[1] Wheeler JM, Malinak LR.. Recurrent endometriosis: incidence, management, and prognosis. Am J Obstet Gynecol 1983;146:247–253.

[2] Guo S-W. Recurrence of endometriosis and its control. Hum Reprod Update 2009;15:441–461.

[3] Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG.. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003. b;80:305–309.

[4] Alborzi S, Momtahan M, Parsanezhad ME, Dehbashi S, Zolghadri J, Alborzi S.. A prospective, randomized study comparing laparoscopic ovarian cystectomy versus fenestration and coagulation in patients with endometriomas. Fertil Steril 2004;82:1633–1637.

[5] Vignali M, Bianchi S, Candiani M, Spadaccini G, Oggioni G, Busacca M.. Surgical treatment of deep endometriosis and risk of recurrence. J Minim Invasive Gynecol 2005;12:508–513.

[6] Jiang M, Hou W, Yu T. Clinical efficacy of laparoscopic surgery combined with drug therapy for endometriosis: A meta-analysis. Med Eng Phys. 2022 Sep;107:103866.

[7] Paolo Vercellini, Sara DE Matteis, Edgardo Somigliana, Laura Buggio, Maria Pina Frattaruolo, Luigi Fedele. Long-term adjuvant therapy for the prevention of postoperative endometrioma recurrence: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2013 Jan;92(1):8-16.

[8] Andrew Zakhari, Emily Delpero, Sandra McKeown, George Tomlinson, Olga Bougie, Ally Murji. Endometriosis recurrence following post-operative hormonal suppression: a systematic review and meta-analysis. Hum Reprod Update. 2021 Jan 4;27(1):96-107.