Adenomyosis (endometriosis interna)
• It is the localization of the endometrial gland and stroma in the myometrium. It is more common over the age of 40, and multiparity, early menarche and short menstrual cycles are risk factors.
• Postpartum endometritis is suggested to be the initiating factor. Another theory is intussusception of the endometrium. Dilation and curettage are also implicated.
• Since it is an estrogen-dependent pathology, the symptoms decrease or disappear after menopause. Leiomyoma accompanies the picture in 50% of adenomyosis cases, endometrial hyperplasia in 25% and endometriosis in 10%.
• Clinical: Although it is often asymptomatic, the classic triad may be seen in symptomatic cases.
► On pelvic examination, tender, globally enlarged and soft uterus
► Menorrhagia
► Dysmenorrhea
• Adenomyosis is a clinical diagnosis. Ultrasonography and MRI (higher sensitivity and specificity) are helpful in diagnosis but not indicative. On ultrasound, the border between the endometrium and myometrium disappears and anechoic avascular cysts are observed in the myometrium. On MRI, adenomyosis is suspected by thickening (> 12 mm) of the junctional zone, which is the junction of the endometrium and myometrium.
• Definitive diagnosis is made by histopathological examination of hysterectomy material.
• Treatment varies according to the patient's age and fertility desires. Medical treatment (menstrual suppression with NSAIDs, COCs, progesterone, danazol or GnRH analogues) is often unsuccessful. Uterine artery embolization and endometrial ablation may be effective. Hysterectomy, on the other hand, is curative.
Endometriosis
• It is the situation where the endometrial gland and stroma are found outside the uterus. Although the exact cause of endometriosis is not known, it is an estrogen-dependent disease.
Incidence and Prevalence
• Its incidence is around 10% in reproductive age. It is mostly seen in the reproductive age and can occur in adolescents and even postmenopausal women taking HRT. It is more common in women with pelvic pain and infertility complaints.
Risk factors
Endometriosis risk factors
• Infertility
• Having red hair
• Early menarche
• Short menstrual cycles
• Hypermenorrhea
• Nulliparity
• Müllerian anomalies
• Low birth weight
• Multiple pregnancy
• intrauterine DES exposure (Diethylstilbestrol)
• Having a first degree relative
• tall
• Dioxin
• Polychlorinated biphenyl (PCB)
• Diet rich in fat and red meat
Factors protecting against endometriosis
• Multiparity
• Lactation
• Intrauterine smoking exposure
• BMI height
• Waist-hip ratio height
• A diet rich in fruits and vegetables
There is no relationship between previous use of contraceptive methods and smoking in terms of increased risk.
pathogenesis
• Endometriosis is an estrogen dependent disease and 4 theories are emphasized in its development:
► Ectopic transplantation of endometrial tissue (Sampson theory): It is the theory that during menstruation, the endometrial tissue passes retrogradely from the tube into the abdomen and settles there ectopically. According to this theory, the clockwise flow of peritoneal fluid is also important. Endometriosis is more common to the left of the pelvis and can easily invade the rectosigmoid area. Retroperitoneal space involvement cannot be explained by this theory.
► Celomic epithelial metaplasia (Mayer's theory): According to this, the coelomic epithelial cells that cover the peritoneal cavity are in a structure that can transform into endometrium-type cells.
► Theory of induction: This transformation is thought to be caused by an endogenous agent.
► Lymphatic or vascular metastasis (Halban theory): Explains retroperitoneal spread.
etiology
genetic factors
► It has multifactorial inheritance and there is a 7-fold increase in risk in first-degree relatives. It has also been shown to be associated with systemic lupus erythematosus, dysplastic nevus and melanoma (associated with HLA).
► There is a strong correlation between cases with severe endometriosis and mutations in the short arm of the 7th chromosome. There is a correlation between different genetic polymorphisms and endometriosis; There is a strong positive correlation with the hormone receptor, growth factor system and especially the HLA system.
► There is a relationship with steroid receptor genetics. Estrogen receptor gene polyformism and defects in progesterone receptor mRNA synthesis were detected. 17-Beta hydroxysteroid dehydrogenase type II expression is impaired in endometriotic tissues and accordingly, estrogen degradation is reduced.
► In addition, prostaglandin E2 production is increased in endometriotic foci compared to normal endometrium, and increased prostaglandin E2 also increases local aromatase activity. In this way, high levels of local estrogen are produced and the continuity of the lesions is ensured.
Immunological factors and inflammation
► There is immune tolerance and subclinical peritoneal inflammation against ectopic tissue.
0 Immune tolerance: Alterations in cellular and humoral immunity have been found in women with endometriosis. In these patients, increased humoral immune response and macrophage activation, decreased T cell and natural killer cell function, and increased autoantibody levels were detected.
0 Subclinical peritoneal inflammation: White blood cells (especially activated macrophages), cytokines, growth factors and angiogenetic factors are increased in the peritoneal fluid. TNF-a is the main responsible for this inflammation. In addition, the increase in CRP, serum amyloid A, membrane cofactor protein-1, interleukin 6-8 chemokine receptor 1 reveals a disease of inflammation origin.
In endometriosis, the level of IL-13 in the peritoneal fluid decreases.
Environmental factors and dioxin
Residential area
• The most common locations are pelvic organs and peritoneum.
• Locations in order of frequency:
► Over(50%)(most common)
► In the Douglas pit
► In the uterosacral ligament
► Posterior uterus
► Posterior broad ligament
• 1-2% of extrapelvic involvement can be seen: Extrapelvic endometriosis most commonly involves the intestinal tract (especially colon and rectum).
Involvement was observed in all organs except the spleen.
Clinic
• Patients may be asymptomatic even in advanced disease, but the symptoms are also very diverse.
► Chronic pelvic pain
► Dysmenorrhea (especially secondary)
► dyspareunia
► Infertility
• Endometriosis should be considered in every patient in the reproductive age group with chronic pelvic pain, dyspareunia and infertility problems.
Pain
► The most common symptom is pelvic pain, which may be in the character of premenstrual pain, dysmenorrhea (especially secondary), chronic pelvic pain, dyspareunia or low back pain. Pain is often bilateral. The onset of dysmenorrhea years later in an adult woman should evoke endometriosis.
► There is a weak correlation between the extent of the disease and pain. Those with extensive disease may sometimes have no pain, while those with only minimal disease may have severe pelvic pain. The character of the pain depends on the anatomical location of the deep infiltrative lesion and local peritoneal factors. Prostaglandin E2 is an important mediator in pain formation.
infertility
► Monthly fecundity rate decreases in women with endometriosis: There is a negative correlation between the stage of the disease, monthly fecundity and cumulative pregnancy rate.
► Moderate or severe endometriosis disrupts the pelvic anatomy and tube-ovarian relationship by causing pelvic adhesions, may cause tubal occlusion and periovarial adhesions and cause infertility.
► However, infertility may occur in mild endometriosis cases where the pelvic anatomy is not affected. In these cases, the cause of infertility is anovulation (15-30% of cases are anovulatory), increased incidence of luteinized unruptured follicles, luteal phase defect, increased prostaglandin F2a and E2 in peritoneal fluid (tubal motility and transport, implantation is impaired as a result of ischemic changes; uterine contractions increase, dysmenorrhea develops) and immunological (increased macrophages in the peritoneal fluid phagocytize sperm, decreased cellular immunity and autoimmune) causes.
► Fertilization and implantation rates are significantly lower in advanced endometriosis compared to other IVF indications.
Clinic in extrapelvic endometriosis
► Extrapelvic endometriosis is often asymptomatic, but the cyclic pattern is important in those who are symptomatic. Gastrointestinal symptoms (nausea, vomiting, distension) may occur in cases with colorectal involvement.
► As a result of lung involvement, right pneumothorax called "catamenial pneumothorax" during menstruation, hemoptysis during menstruation, "catamenial seizures" may develop as a result of CNS involvement.
► Dysuria and hematuria may occur in ureteral involvement. It can be seen in the umbilicus.
► It can also be seen in the umbilicus and post-surgical wound scars.
abortion
► The risk of spontaneous abortion increases in endometriosis. Medical and surgical treatment also do not reduce the risk of spontaneous abortion. The risk of abortion is also high after assisted reproductive techniques. There is no relationship between endometriosis and recurrent pregnancy loss.
Diagnosis
• Nodularity can be felt in the uterosacral ligaments and douglas, although many do not show abnormal findings on examination. The cervix may be displaced laterally due to the shrinkage of the fibrotic tissue and there may be a needle-like narrowed cervical os appearance. Painful swelling in the rectovaginal septum and unilateral ovarian cystic enlargement can be detected. In advanced disease, the uterus is fixed posteriorly, and the mobility of the tuba and ovary is reduced.
• Transvaginal ultrasonography has high sensitivity and specificity in the diagnosis and differential diagnosis of ovarian endometrioma. Bladder and rectal nodules larger than 1 cm and deep infiltrative endometriosis can also be diagnosed by transvaginal ultrasonography.
• Among the imaging methods, HSG, CT and MRI can also be used in cases with endometriosis; however, they are not primary diagnostic methods.
• In the examinations, the CA125 value is significantly higher in moderate and severe endometriosis. However, CA125 is a valuable marker in the follow-up of treatment rather than diagnosis. The increase in IL-1 in the serum is the most useful marker.
• Classically, endometriosis is investigated by laparoscopy. Histopathological demonstration of the endometrial gland and stroma in ectopic areas outside the uterus establishes the definitive diagnosis.
• In the early stage, vesicles containing clear fluid are observed on the peritoneal surface. After hemorrhages into the vesicle, a characteristic gunpowder burn appearance with surrounding scar tissue occurs. Endometriotic implants appear to be surrounded by hemosiderin-laden macrophages and lymphocytes and are referred to as foam cells.
• Cysts that occur secondary to the ovary are called endometriomas (chocolate cysts). It is indicative of more advanced pelvic or intestinal disease, and only 1% of endometriomas are isolated. Often on the anterior surface of the ovary
• Deep infiltrative endometriosis; It refers to a peritoneal location deeper than 5 mm. It is associated with other forms of peritoneal and ovarian endometriosis.
Classification
• The classification shows the prevalence of the disease.
Complete adhesion of the fimbriae end of the tubal; 16 points
- Stage 1: 1-5 points
- Stage 2: 6-15 points
- Stage 3: 16-40 points
- Stage 4: > 40 points
Complete obliteration of the cul de sac alone constitutes the highest score.
· Ureter, intestinal and extrapelvic area involvements are not included in this classification.
Treatment
There is no preventive treatment for endometriosis, nor does it have a definitive cure. Medical, surgical, or both are used in treatment. The aim of the treatment is to eliminate the foci and to correct the pain and infertility.
Medical treatment is only effective in relieving pain, but medical treatment has no place in the treatment of infertility. In the treatment of infertility, surgical or assisted reproductive techniques are preferred.
Management of pain; If the pain is minimal or the patient is in the perimenopausal period, it can be approached observationally because of the possibility of spontaneous regression. While medical treatment is preferred for mild pain; Surgical treatment is recommended in the treatment of moderate or severe pain and pain that does not respond to medical treatment.
Management of Infertility: Ovulation induction + intrauterine insemination can be done empirically. Another option is ovulation induction + intrauterine insemination or IVF after surgery.
Medical Treatment
► The aim is to atrophy ectopic foci. For this reason, either a false pregnancy state (COC, progestins) or a menopausal state (GnRH analogue, danazol) is tried to be created.
Agents used in the medical treatment of endometriosis-related pain
► NSAID
► Progestagens:
- Medroxyprogesterone acetate, megestrol acetate, dienogest, linestrenol, dydrogesterone, norethindrone acetate, LNG-IUD
► Antiprogestins:
- Gestrinon, danazol
► GnR H Analogs (Agonist + Antagonist)
► Combined Oral Contraceptive
► Progesterone Antagonists: if epristone, Onapristone
► Aromatose inhibitors:
- Aastrazole, fadrazole, letrozole
First step in medical treatment; NSAIDs alone or in combination with COCs or progestins.
The most commonly used oral non-steroidal anti-inflammatory drugs in the treatment of dysmenorrhea due to endometriosis; ibuprofen, naproxen, naproxen sodium, mefenamic acid and ketoprofen.
- Progestins: They act by first decidualization and then atrophy in endometriotic tissue. The most commonly used agents for this purpose are MPA, megestrol acetate, dienogest, linestrenol and dydrogesterone. When refractive bleeding develops, exogenous low-dose estrogen can be given to the patient. levonorgestrel secreting intrauterine, The tools significantly reduce endometriosis-related pain, recurrence of post-surgical dysmenorrhea, and rectovaginal nodule volume in peritoneal and rectovaginal endometriosis.
- Combined oral contraceptives: A false pregnancy state is created by using them continuously for 6-12 months. Its cyclic use also reduces the development and recurrence of endometriosis. They cause decidualization and atrophy in endometriotic foci with their progestins. With these effects, they reduce dysmenorrhea and pelvic pain.
- Progesterone antagonists: These agents, which are progesterone receptor modulators (mifepristone, onapristone), suppress endometriosis with their antiproliferative effects on the endometrium.
- Antiprogestins:
Danazol; is a derivative of 17-α-ethynyl testosterone.
Effect Mechanisms
• It suppresses GnRH and gonadotropin secretion.
• It directly inhibits steroidogenesis.
• Increases the metabolic clearances of estrogen and progesterone.
• It creates agonistic and antagonistic effects on endometrial androgen and progesterone receptors.
- With these effects, Danazol creates a highly androgenic and low estrogenic environment (pseudo-menopausal state). Danazol is also therapeutic in autoimmune diseases such as hereditary angioedema, autoimmune hemolytic anemia, SLE and ITP by decreasing serum Ig levels, decreasing C3 levels and increasing C4 levels, and decreasing serum autoantibodies. Danazol is metabolized in the liver.
- Since it has a high androgenic effect on the fetus, it should be used together with absolute contraceptives.
Gestrinon: It is a 19-nortestosterone derivative with androgenic, antiprogestagenic, antiestrogenic and antigonadotropic properties.
Effect Mechanisms
• Increases free testosterone.
• Reduces SHBG (androgenic effect).
• Decreases serum estradiol level (antiestrogenic effect).
• Decreases LH level.
• Blocks the release of LH and FSH (antigonadotropic effect).
- Causes inactivation and degeneration of endometriotic implants at the cellular level. It can be given 1-3 times a week due to its long half-life (28 hours). Since its side effects are milder than danazol, it is better tolerated by patients.
Since it has a high androgenic effect on the fetus, it should be used together with absolute contraceptives.
- GnRH agonists. They cause medical oophorectomy. Oral GnRH antagonists are also effective in controlling endometriosis-related pain.
- Aromatase inhibitors: It reduces pain due to endometriosis but should be combined with other hormonal medications
In patients with endometriosis, CA125 levels decrease after medical treatments with danazol, GnRH agonists and gestrinone and after surgery, but not after treatments with Medroxyprogesterone acetate. Post-treatment elevation is associated with recurrence.
Surgical treatment
► Laparoscopy is used in most of them. Laparotomy is useful in advanced disease and those who do not desire fertility. Surgical treatment is applied in infertility, endometrioma and pelvic pain where medical treatment is ineffective.
► The effect of surgery on fertility in mild or minimal endometriosis is controversial. In moderate endometriosis, laparoscopy should be preferred. Aim; destruction of all endometriotic implants, opening of adhesions, and restoration of pelvic anatomy.
► In case of ovarian endometrioma development; cystectomy can be done. Cystectomy is the treatment modality that minimizes pain and endometrioma recurrence.
Assisted reproductive methods should be preferred in infertile patients with endometrioma.
► LUNA and presacral neurectomy can be applied in pelvic pain unresponsive to medical treatment. More radical surgery may be required to completely eliminate the disease; uterus, ovaries and all implants are removed.
Prognosis
• Endometriosis is a significantly progressive (30-60%) and chronic disease. The recurrence rate is high after surgical or medical treatment.
recurrence
► Risk factors determining recurrence; the stage of the disease, the duration of follow-up, and whether or not surgery has been performed before. More recurrence is seen on the right side and in younger patients.
► Recurrence occurs 6 months-2 years after medical treatment and there is a positive correlation with the severity of endometriosis.
► In 20% of patients who underwent surgery, pain reappears within 5 years. Postoperative medical treatment reduces pain; however, it does not reduce the recurrence of pain and disease.
► Regular postoperative use of OCS reduces the recurrence of endometrioma.
Endometriosis and cancer
► The risk of endometrioid and clear cell ovarian cancer, melanoma and non-Hodgkin lymphoma increases in those with endometriosis.
