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Endometriosis

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Is the growth of endometrium outside the uterine cavity or myometrium, usually in the peritoneal cavity manifested by pelvic pain and infertility. 

 

Defined as the presence of endometrium like tissue outside the uterus.

It involves interacting endocrine, immuno logic, pro inflammatory, and pro angiogenic processes.

The development of endometriosis involves endocrine, immunologic, proinflammatory, and pro angiogenic processes interaction.

 

It is primarily diagnosed by surgical visualization.

 

Treatment consists of surgical removal of lesions and hormonal medications.

Hormonal treatment associated pain focuses on systemic or local estrogen suppression, inhibition of tissue proliferation and inflammation, or both.

Oral contraceptives, both combined or progesterone only, are widely used as the first line treatment for dysmenorrhea or chronic pelvic pain.

Daily or depot progestins are effective in some women.

Gonadotropin releasing hormone agonists are second line treatments that substantially suppress systemic estrogen levels.

Elagolix is the first GnRH antagonist available for endometriosis associated pelvic pain.

Surgery is appropriate when the level of symptom severity is justified  for the risk.

Management of endometriosis requires multi-disciplinary expertise, and approximately 50% of women with endometriosis have recurrent symptoms over a period of five years, irrespective of the treatment approach.

 

Affects 10% of reproductive age women which is approximately 100 million women worldwide.

Characterized by endometrial tissue deposits outside the endometrial cavity such as the liver, diaphragm, umbilicus and pleural cavity.

Proliferation of endometriotic deposits requires estradiol, that is provided by systemic hormones and also locally from increased expression of aromatase and steroidogenic acute regulatory proteins and decreased expression of 17 beta hydroxysteroid dehydrogenase2  by endometriotic lesions.

Endometriotic cells and tissues elicit a localized immune and inflammatory response with cytokine, chemokine, and prostaglandin production.

An inflammatory response involves monocytes, macrophages, neutrophils, T cells and eosinophils attracted by chemo kinds produced an act topic endometrium.

The complex pro inflammatory, endocrine micro environment around endometriotic lesions promotes their proliferation and vascularization.

The endometrium and endometriotic lesions contain nerve fibers simulated by inflammatory mediators.

Macrophage is also localized within nerve fibers and produce nerve sensitizing insulin-like growth factor1.

Local natural killer cells activity is impaired in women with endometriosis and may contribute to immune evasion of endometrial cells.

Endometriotic lesions have increased expression of estrogen receptor beta.

 

Clinical findings include a range of superficial peritoneal lesions of varying color, cysts in the ovaries, nodules with a depth of penetration exceeding 5 mm, and extrapelvic clear lesions.

 

The natural history of endometriosis is unknown and no evidence supports an ordered progression of endometriotic  lesions.

 

In surgical studies lesions progressed in about 29% of cases, regressed in 42% and were static and 29%.

Thought to be secondary to reflux of endometrial tissue through the fallopian tubes during menstruation.

Postulated origins of endometriosis include retrograde menstruation, coelomic metaplasia, and lymphatic and vascular metastasis.

Retrograde ministration refers to reflexive menstrual debris with viable endometrial  cells through the fallopian tubes into the peritoneal cavity.

Generally found within the pelvic cavity and involves ovarian tissue, the uterine ligaments, fallopian tubes, and pelvic sidewalls.

Extrapelvic involvement includes abdominal viscera, abdominal wall, extremities, brain and lung.

Affects an estimated 5 million women of reproductive age in the U.S.

Women without prior pregnancies, women with a family history of endometriosis, and women with abnormal menstrual periods are more likely to have endometriosis

Estimated prevalence is about 4%, but the disease is much more common in women with pelvic pain and infertility.

May affect up to 11% of US women age 15-44 years.

 

Prevalence ranges from 2-11% among asymptomatic women, 5-50% among

 

infertile women, and 5-21% among women Hospitalized for pelvic pain.

 

Among adolescents with symptoms, the prevalence of endometriosis ranges from 49% for those with chronic pelvic pain to 75% for those with pain that is unresponsive to medical treatment.

Associated with pain, infertility and multiple surgical procedures.

Pain is the common presenting feature.

Pain mechanisms extend beyond the presence of endometriotic lesions alone.

Pain in women with endometriosis manifest enhanced anterior insula glutamatergic neurotransmission, and connectivity with the medial pre-frontal cortex, it is associated with changing brain chemistry and function compared with pain-free women.

May cause pelvic inflammation, adhesions, chronic pain and infertility.

The most common site of endometriosis involvement in the gastrointestinal tract is the rectosigmoid followed by the small intestine, cecum and appendix.

Malignant transformation occurs rarely, in approximately 1% of women.

Transformation into malignancy occurs 80% of the time in the ovaries, and about 20% occurring at extragonadal sites.

Bowel and bladder associated symptoms are typically cyclic in nature.

Women with endometriosis have a high risk for cross-organ sensation, there is pain perception from adjacent structures due to convergence of neural pathways, which helps explain poor post surgical pain relief in many patients.

It is primarily located in the pelvic peritoneum, ovaries, rectovaginal septum, and rarely on the diaphragm, pleura and pericardium.

Occurs in 6-10% of women of reproductive age.

Occurs in up to 50% of women with infertility.

Source of pain in 50-60% of women and teenage girls with pelvic pain.

Peritoneal endometriosis is related to retrograde transplantation of endometrial cells and tissue which implant on eritoneal surfaces and elicit an inflammatory response.

Pelvic pain often worsens over time and may change in character.

Pelvic pain due to this entity is usually chronic, lasting more than 6 months and is associated with dysmenorrhea in 50-90% of patients.

Patients may have deep pelvic pain, dyspareunia, lower abdominal pain, back and loin pain.

Pelvic pain associated with endometriosis may be continuous, or intermittent, may occur throughout the menstrual cycle, can be dull, sharp or throbbing.

Pain associated with endometriosis may be exacerbated with physical activity.

Patients may have held the burning or hypersensitivity symptoms suggestive of a neuropathic component.

Symptoms may overlap with overt nflammatory disease, adhesions, ovarian cysts, ovarian masses, leiomyoma, irritable bowel syndrome, inflammatory bowel disease, interstitial cystitis, myofascial syndrome, and depression.

Symptom heterogeneity is high with patients with limited disease that may experience severe pain, infertility or both, whereas women with advanced disease may be asymptomatic.

Chronic pelvic painmanifests in approximately 30% of patients with endometriosis and may be unresponsive to conventional treatment. 

About 1/3 of affected patients have infertility, about twice the rate among women without endometriosis.

Manifestations generally decrease after menopause because growth of endometriosis tissue is estrogen dependent.

Associated with increased risk of ovarian cancer.

Suggestion of the association with increased risk of ovarian cancer is apparent for invasive low-grade serous, clear-cell, and endometroid subtypes.

Definitive method of diagnosis and staging is visualization at surgery.

Diagnosis is difficult as there are no biomarkers to detect endometriosis.

Lesions are predominantly intraabdominal, or of small size, suggesting that laparoscopic visualization is the standard for diagnosis. 

Imaging is of little use for identifying the most prevalent presentation as superficial peritoneal lesions.

Endometriomas  can be identified reliably  by transvaginal ultrasound with magnetic resonance imaging with a more than 90% sensitivity and specificity.

Most patients report their pelvic pain began during adolescence, but most young women do not receive timely treatment.

A scoring system from the American Society for reproductive medicine stages the disease from I-IV.

The scoring system is based on the type, location, appearance, and depth of invasion of the endometrial lesions along with the extent of disease and presence of adhesions.

Staging of endometriosis while useful to determine the extent of disease and management, does not correlate with severity of symptoms or predict response to treatment or infertility.

Transvaginal ultrasound and MRI imaging are not effective techniques to detect peritoneal, or ovarian implants or adhesions.

Transvaginal ultrasound and MRI do have high sensitivity ranging from 80-90% and specificity 60-98% and detecting ovarian endometriomas(Brosens L et al a).

Transvaginal ultrasound is preferred over MRI because of cost.

CA 125 may be elevated, but it has poor sensitivity and specificity for diagnostic purposes.

Mean interval between the onset of pain and surgical diagnosis is 10.4 years(Hadfield R et al).

Protection is seen with prolonged lactation and multiple pregnancies.

Associated with increased autoimmune disease, ovarian endometroid and clear cell cancers, non-Hodgkin’s disease and melanoma (Guidice LC).

Patients followed for 1 year indicate 17-29% of lesions spontaneously resolve, 24-64% have progressive lesions and 9-59% are stable (Sutton CJ).

Cost of diagnosis and treatment approximately 22 $billion in 2002 (Shenolikar S).

Retrograde menstruation can lead to endometriosis because of the presence of immune dysfunction that prevents clearance of lesions (Guidice LC).

Endometriosis at distant sites is probably related to lymphatic or hematogenous spread or metaplastic transformation.

Risk factors include: obstruction of menstrual outflow, exposure to intrauterine diethylstilbestrol, early menarche, late menopause, obesity, short menstrual cycles and low birth weight.

Women with endometriosis have a greater likelihood of having call existing medical conditions.

Risk factors from adolescence into adulthood include a short menstrual cycle, low BMI, low weight-to-hip ratio and low parity.

Genetic rlationship exists as noted in twin and family studies (Montgomery GW).

Twin studies have estimated endometriosis heritability at approximately 50%.

Genetic correlations with coexisting chronic pain conditions such as headache and back in joint pain, suggest a genetic basis for susceptibility to pain in women with endometriosis.

Risk increased in those with increased intake of trans fats and red meat, while risk decreased with fruits, green vegetables and fatty acids (Missmer SA).

There is a significant association between endometriosis in the risk of clear-cell and endometrioid ovarian cancer.

Control of pain includes minimizing inflammation, suppressing or interrupting cyclic ovarian hormone production, Inhibiting action and synthesis of estradiol and reducing or eliminating menstruation.

Nonsteroidal anti-inflammatory drugs are commonly used to relieve dysmenorrhea although data is lacking to show significant reduction in pain.

Nonsteroidal anti-inflammatory drugs combined with oral contraceptives are commonly used.

Cyclic combined oral contraceptives are commonly used.

Medroxyprogesterone is as effective as combined oral contraceptives in controlling pain.

GnRH Agonist depletes pituitary gonadotropins and inhibits further production of gonadotropins and interrupts the menstrual cycle with a hypo estrogenic state, endometrial atrophy, and amenorrhea resulting in improvement in dysmenorrhea.

In a review of 15 randomized trials involving 1821 women pain scores improved with GnRh agonist by 60-100% ( Prentice A et al).

A combination of danazol, anti-progestins, and combined oral contraceptives reduce pain scores by 60 to 100% in endometriosis (Prentice A et al).

GnRH agonists induced a hypo estrogenic state that can lead to bone loss so that estrogen-progesterone add-back therapies are suggested(Al Kadri et al).

Elagolix (Orlisda), a gonadotropin-releasing hormone antagonist for pain due to endometriosis.

Maintaining estradiol levels between 30-45 pg per milliliter will maintain bone mineral density with GnRH antagonist therapy and not stimulate endometriosis symptoms.

Endometriosis lesions express aromatase and synthesize their own estradiol which explains why suppression of ovarian estradiol production may not completely control pain.

Aromatase inhibitors at low doses areeffective in reducing symptoms in endometriosis.

Aromatase inhibitors are used  for women with symptoms resistant to hormone therapy, however long-term use is restricted because of bone density loss, vasomotor regulatory side effects, such as flushing and hot flashes, and increased multiple pregnancy rates.

Danazol is effective treatment for endometriosis, but it’s androgen side effects limit its usefulness.

Anti-progestational agents, such as mifespristine, can reduce pain.

Analgesia consists of a combination of acetaminophen and nonsteroidal anti-inflammatory drugs.

Opioids are recommended for severe short-lived pain but not for chronic pain conditions.

Surgical treatment includes excision, fulguration, or laser ablation of endometrial implants on the peritoneum, excision, drainage, ablation of recto vaginal nodules, lysis of adhesions, and interruption of neural pathways.

Surgery can decrease pain in some but not all women.

The goal of surgery is removing endometriotic tissue in adhesions, and its success is largely dependent on the skill of the surgeon.

Hysterectomy is common and endometriosis associated pain is the leading indication of hysterectomy among women 30-34 years of age, accounting for 18% of all hysterectomies in the US.

Post hysterectomy pain is three times as likely among women with preoperative pain is among those without preoperative pain, and about half of the 60% elevated risk of cardiovascular disease among women with endometriosis is attributed to the high rate of surgical menopause among such women.

Endometriosis excised lesions adversely affects ovarian follicular reserves with lowered levels of anti-mullerian hormone and reduced antra  follicle counts.

For preserving fertility, the potential benefits of surgery need to be considered against negative effects noted.

Current surgical and medical approaches to endometriosis are ineffective in a sizable portion of women.

Hormonal treatments are contraindicated for women who would like to conceive, therefore non-hormonal therapeutic approaches that target endometriosis are required for improve patient outcomes.

The levonorgestrel-releasing intrauterine system, GnRH, laparoscopic ablation or excision, progestational agents are first-line treatments.

 

 

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