Endometriosis - technical article

Endometriosis in detail - technical

Introduction

Endometriosis is an incorrigible disease that is responsible for a multitude of hospital admissions and operative procedures [ 1 ]. This disease is typically a chronic, progressive disorder, with pelvic pain and infertility as the hallmark symptoms. Owing to the recognition of more subtle forms of endometriosis and the more liberal use of diagnostic laparoscopy, the prevalence has been increasing.

Prevalence of Endometriosis

Endometriosis affects nearly 10 % of reproductive-age women between the ages of 12 and 80 years, with the average age at diagnosis around 28 years. Several conditions are associated with higher rates of disease: up to 50 % of those with subfertility or chronic pelvic pain and nearly 70 % of adolescents with nonresponsive pelvic pain. The incidence of ovarian cystic endometriosis (endometriomas) increases with age [ 2 ] , but its incidence and progression seem to stabilize in patients who are older than 35 years. Based on a study that involved repetitive laparoscopy in baboons, we know that endometriosis appears spontaneously and that new lesions seem to appear and disappear spontaneously [ 3 ]. Thus, endometriotic lesions in humans most likely are in continuous evolution as well [ 4 ].

Diagnosis of Endometriosis

The definitive diagnosis of endometriosis can only be made surgically. The classic symptoms are dysmenorrhea, noncyclic pelvic pain, dyspareunia, and infertility. Specific physical signs indicative of advanced endometriosis are listed in Table 1 .

Table 1 Signs and symptoms of endometriosis

  • Signs
    • Adnexal mass
    • Adnexal tenderness
    • Uterine tenderness
      • Fixed retroversion
      • Lateral cervical displacement
    • Cul-de-sac
      • Tenderness
      • Nodularity
      • Mass
    • Uterosacral ligament
      • Tenderness
      • Nodularity
    • Vaginal lesions
    • Cervical lesions
  • Symptoms
    • Reproductive tract
      • Infertility
      • Dysmenorrhea
      • Dyspareunia
      • Noncyclic pelvic pain
    • Gastrointestinal
      • Diarrhea and/or constipation
      • Tenesmus
      • Abdominal cramps
      • Cyclic rectal bleeding
    • Urinary
    • Low-back pain

Physical examination during menstruation is more sensitive in the detection of pelvic disease. There are no laboratory tests that can identify patients with endometriosis with a high degree of sensitivity and specificity. The search for biomarkers of this disease is quite active [ 5 ], although further studies are required before clinical use can be recommended.

The microscopic definition of endometriosis implies the presence of endometrial glands and stroma outside the endometrial cavity and uterine musculature. The various typical lesions of endometriosis are referred to as clear, white, red, polypoid, flame-like, powder-burn, brown, blue-black, brown, or yellow lesions. Defects in the peritoneum or peritoneal windows may contain these lesions. The R-AFS scoring system for endometriosis is widely used clinically but has significant intra- and interobserver variation (between 38 and 52 %) [ 6 ].

The positive predictive value of laparoscopic visualization of endometriosis is considered to be approximately 50 %. Classic red or black lesions have a visual accuracy between 90 and 100 %. White lesions are associated with endometriosis less often. The main pathologies that can be confused with endometriosis are endosalpingiosis, fibrosis, mesothelial hyperplasia, carbon deposits from previous surgery, and malignancy. Hemangiomas, adrenal rests, and splenosis can also rarely be confused with endometriosis. For this reason, diagnostic laparoscopy should be accompanied with biopsy for lesions that are not clearly endometriosis.

Ovarian endometriosis, as opposed to non-ovarian disease, can be predicted with a high degree of accuracy with ultrasonography. There may be a role for magnetic resonance imaging (MRI) in the identification of deeply infiltrating lesions that involve the cul-de-sac or lesions in uncommon locations such as the sciatic nerve. Diagnostic tests for patients with gastrointestinal symptoms such as colonoscopy or barium enema radiography are typically normal or may occasionally show stricture. Patients with significant urinary symptoms should have a urologic evaluation to rule out interstitial cystitis or potentially endometriosis of the bladder wall. The more common differential diagnoses of patients with chronic pain and potential endometriosis are adhesions, chronic pelvic inflammatory disease, interstitial cystitis, irritable bowel syndrome, and musculoskeletal problems such as myofascial pain or neuralgias.

Classification of Endometriosis

The classification of endometriosis has been an evolving process. In 1978, the American Fertility Society (AFS, now called the American Society for Reproductive Medicine) classified four stages and used an arbitrarily weighted point score that included assessment of the extent of endometriosis in two dimensions and the presence and extent of adhesions in the peritoneum, ovaries, and tubes. It also took into account whether the endometriosis was unilateral or bilateral. The size of the endometrioma was considered along with the presence of filmy vs. dense adhesions. In 1985 and again in 1996 (R-AFS), further revisions were made to the original AFS classification [ 7 ]. An endometrioma that is larger than 3 cm in diameter is at least stage 3 disease. Despite the improvements, the correlation between the stage of endometriosis and the likelihood of pregnancy or degree of pain is poor, and future improvement in the classification is both warranted and likely.

Associated Disease Processes

Surveys of endometriosis patients report increased incidence of atopic disease and other autoimmune phenomenon such as thyroid disease, fibromyalgia, and chronic fatigue syndrome. Endometriosis is associated with increased incidence of non-Hodgkin’s lymphoma, dysplastic nevi, and melanoma. Ovarian cancer (endometrioid and clear cell) is higher, although the overall lifetime risk is quite low: 1.5 % compared to 1 % in the general population.

Anatomic Sites of Endometriosis

Endometriosis is most commonly found in the posterior pelvis compartment [ 8 ]. The following are the most common locations, in descending order: ovaries, cul-de-sac, broad ligament, and uterosacral ligaments. The left hemipelvis is the most common location—64 % compared to the right hemipelvis. More endometriosis is found on the left as opposed to the right ovary, possibly because the sigmoid colon alters intraperitoneal fl uid movement.

The bowel is the most common extragenital location of endometriosis. Bowel locations, in decreasing order of frequency, are the sigmoid colon (>65 % of cases), rectum, terminal ileum, appendix, and the cecum. Most bowel lesions are superficial and limited to the serosa. Occasionally, transmural involvement of the bowel occurs, which may cause cyclic diarrhea, rectal bleeding, abdominal distension, and, rarely, bowel obstruction. The urinary tract is involved in only 1 % of cases, and it most often affects the bladder (84 %). Symptoms for vesical endometriosis are similar to those associated with recurrent cystitis. Endometriosis of the urinary tract should be suspected if cyclical urinary symptoms, such as urgency, frequency, and suprapubic pain with or without hematuria, occur.

Ovarian Endometriosis

Ovarian endometriosis or endometriomas increase with age and are generally associated with a more advanced stage of the disease [ 2 ]. This form of endometriosis can be diagnosed with a high level of accuracy by serial ultrasounds. They may be confused with a hemorrhagic corpus luteum, which will disappear over the course of a few months. These ovarian forms of endometriosis often have associated peritoneal implants (85 % of the time), although only a small percentage of patients with peritoneal implants will eventually develop an endometrioma. Endometriomas can be uniloculated or multiloculated. They are more commonly localized in the left ovary, as with peritoneal implants, likely due to the natural peritoneal fluid flow subsequent to menstrual regurgitation.

Deep Endometriosis

Invasion of endometriotic cells deeper than 5 mm has been associated with increased pain [ 9 ]. A rectovaginal exam during the menstrual period in the office setting or a thorough exam under anesthesia prior to laparoscopy may alert the surgeon to the presence of these types of lesions. In a study looking at 93 women with deep infiltrating peritoneal endometriosis, 61 % had concomitant superficial implants and 51 % had endometriomas. Deep nodules were the only form of the disease in just 7 % of the women.

Extra-Pelvic Endometriosis

Cutaneous endometriosis has been reported in abdominal scars following cesarean sections, hysterectomy, appendectomy, and laparoscopy. Rare lung cases of endometriosis leading to cyclical hemoptysis or even pneumothorax have been reported and imply that hematogenous and/or lymphatic dissemination of endometrial cells is possible. This mechanism can also explain the possible spread to rare locations, such as the brain, liver, pancreas, kidney, vertebra, and bones.

Predisposing Factors for Endometriosis

Endometriosis is mainly present during the reproductive years (average age of 28) and regresses during menopause, suggesting that the development and growth of endometriosis is estrogen dependent. Accordingly, the Nurses’ Health Study prospectively assessed predisposing factors for endometriosis and observed an association with early age of menarche, shorter length of menstrual cycles during late adolescence, and nulliparity. Furthermore, women with low estrogen levels and low body mass index, who use alcohol, who are infertile smokers, and who exercise intensely appear to be at decreased risk [ 10 ].

Heredity is an important predisposing factor for endometriosis since the prevalence is increased sevenfold among fi rst-degree relatives. In monozygotic twins, the prevalence increased 15-fold. Exposure to pollutants, especially endocrine- disrupting compounds such as dioxins or polychlorinated biphenyls (PCBs), might also play a role in the predisposition to endometriosis.

Data from the Nurses’ Health Study II suggests that specific dietary fat consumption may influence the risk of developing endometriosis—long-chain omega-3 fatty acids were protective, whereas trans -unsaturated fats led to a greater risk.

Pathophysiology

Managing endometriosis receives the lion share of attention, although investigation into the genesis of the disease does not lag far behind. In fact, it is likely that only with the discovery of the true pathogenesis of endometriosis will more efficacious therapy emerge as well as preventative measures for younger women. The three different endometriosis entities—endometriomas, implants, and rectovaginal disease—could develop along distinct routes, but overlapping mechanisms are probably at play for at least some of these. The disease has multitudinous theories for pathogenesis, yet only a handful continue to be proffered as valid: (1) retrograde menstruation (Sampson’s theory), (2) metaplastic transformation (Meyer’s theory), (3) lymphatic or hematogenous embolization (Halban’s theory), and (4) tissue relocation (i.e., iatrogenic surgical displacement of endometrium during laparoscopy or cesarean section).

Over the years each theory has received indirect corroboration. Retrograde menstruum from the fallopian tubes into the pelvis and beyond has been supported by identifying menstrual tissue refluxing from the fallopian tubes during surgery and the identification of fresh endometrial lesions during menstrual phase laparoscopy. In addition, the baboon model of endometriosis is, in effect, iatrogenic retrograde menses invariably leading to the development of scattered lesions [ 11 ]. Lastly, a greater frequency of lesions in the right subphrenic region and left hemipelvis/ovary supports retrograde menses, since these locations follow the natural tendency of intra-abdominal peritoneal flow and obstruction via the falciform ligament. Unclear, however, is why endometriosis is not then found in all women, given the ubiquitous nature of retrograde menstruation.

Metaplasia of the coelomic epithelium seems equitable given that both peritoneal and endometrial tissues emanate from coelomic cells. Zheng et al. have shown histologic, morphologic evidence of transitioning ovarian surface epithelium into endometriotic cells, corroborating a metaplastic process [ 12 ]. A corollary to this postulate is that of the embryogenetic theory or müllerianosis: misplaced endometrial tissue during the embryologic period of organogenesis. Signorile et al. demonstrated the presence of ectopic endometrium in 9 % of 101 human female fetuses [ 13 ]. With endogenous estradiol stimulation later in life, this tissue could grow and thus present as ectopic implants. Theoretically, deep rectovaginal lesions could derive from such abnormal embryogenesis.

Newer, exciting pathophysiology theories borrow from the traditional theories and, most significantly, build upon these premises in order to better grasp the true etiology. For instance, stem cells originating from the bone marrow (Meyer’s theory) have been found to populate eutopic endometrium (Halban’s theory) that may then be shed (Sampson’s theory) into the peritoneal cavity. Vercellini et al. provided another concept for the development of endometriomas when they described how a hemorrhagic corpus luteum may progress to an endometrioma [ 14 ]. If this were truly an endometrioma, then retrograde menses (Sampson’s theory) would be a prerequisite to populate the cyst contents with endometrial cells.

Underlying virtually all of these theories is the molecular underpinnings of the disease and, in particular, the inherent immune dysfunction that could at once promote and sustain endometriosis [ 15 ]. The aberrant immune factors found in women affected with endometriosis could explain why some develop the disease while others do not. The chronic inflammatory milieu can impair normal clearance of endometrial tissue and encourage adherence/invasion, angiogenesis, and nerve fiber innervation [ 16 ].

Mechanism of Infertility

Even though there is a purported association between infertility and endometriosis, the mechanism of this association remains complex and is not completely understood [ 17 ]. The following factors may explain a diminished fecundity:

  • Anatomical changes. Endometriosis, when moderate or severe, will often lead to peritubal or periovarian adhesions, thus compromising tubal motility and ovum capture.
  • Immunological factors. The peritoneal fluid of women with endometriosis has an abnormal level of cytokines, prostaglandins, growth factors, and in fl ammatory cells, which are likely to participate in the etiology and or sustenance of endometrial implants. These alterations negatively affect sperm motility, oocyte maturation, fertilization, embryo survival, and tubal function.
  • Effect on embryo development and implantation. Patients with stage I and II endometriosis have high levels of antiendometrial antibodies, which may reduce implantation. IL-1 and IL-6 are elevated in the peritoneal fl uid of patients with endometriosis and are embryotoxic. Expression of HOXA10 and HOXA11 genes, which are usually upregulated during the secretory phase of the menstrual cycle, is not upregulated in patients with endometriosis. These genes regulate the expression of a (alpha) v b (beta)3 integrin, which plays a crucial role in the embryo’s ability to attach to the endometrium. A decrease in a v b 3 and l -selectin expression has been reported in patients with endometriosis, which might explain the decrease in implantation.

Mechanism of Pain

Pain associated with endometriosis is quite complex. Pain associated with advanced disease can be caused by extensive adhesions, ovarian cysts, or deeply infiltrating endometriosis. Expression of nerve growth factor is associated with endometriosis pain. Sensory nerve fibers have been found more frequently in the functional layer of the endometrium of women with endometriosis than those unaffected by the disease. Finally, discrete changes in the central pain system (i.e., regional gray matter volume) may contribute to chronic pain in women with endometriosis.

Even patients with early-stage disease (few scattered implants) can experience severe pain. This pain can be explained in part by the increase in prostaglandins. In contrast to the normal endometrium (referred to as eutopic endometrium), ectopic endometrium (endometriosis) is the site of at least two molecular aberrations that result in the accumulation of increasing quantities of estradiol and prostaglandin E2 (PGE2). With the first aberration, activation of the gene that encodes aromatase increases, leading to increased aromatase activity in endometriotic tissue. This activation is stimulated by PGE2, which is the most potent inducer of aromatase activity in the endometriotic stromal cells. The second important molecular aberration in endometriotic tissue is the increased stimulation of COX-2 by estradiol, which leads to increased production of PGE2. This establishes a circular event leading to accumulation of PGE2 in the endometriotic tissue.

Treatment of Endometriosis in the Infertile Couple

It is estimated that in an infertile couple with stage 1 or 2 endometriosis, the monthly fecundity rate is 3 % per cycle. Medical suppressive therapy with an oral contraceptive agent or gonadotropin-releasing hormone agonist (GnRHa) does not improve the pregnancy rate prior to trying nonassisted reproductive technology.

Surgical Treatment

Surgical treatment of minimal or mild endometriosis improves the spontaneous pregnancy rate; however, the absolute amount is small. A meta-analysis of the two randomized clinical trials investigating this question showed a mild improvement with a number needed to treat (NNT)—that is, the number of persons that would need to be treated surgically to achieve an extra pregnancy—of 12 (95 % CI, 7, 49).

Postoperative suppressive medical therapy after surgical treatment does not improve fertility. The only value of medical suppressive therapy (i.e., GnRHa) appears to be before in vitro fertilization (IVF) [ 18 ]. In these cases, the use of GnRHa for 3–6 months prior to IVF increases the clinical pregnancy rate by a factor of 4 (OR 4.28, 95 % CI, 2, 9.15). What is not clear for the moment is if a specific disease severity may have a better response to such suppressive therapy.

If the patient does not wish surgical therapy, then the next step is either IVF or treatment with clomiphene citrate and intrauterine insemination (IUI) followed by gonadotropins and IUI. There is insufficient evidence to recommend surgery prior to IVF.

In advanced disease, surgical management improves fertility. However, this surgery is complex and requires meticulous dissection. If an initial surgery for advanced disease fails, subsequent surgery is less successful than IVF in establishing a pregnancy and should be reserved for patients who require management of pain.

In Vitro Fertilization

In a retrospective cohort study, the diagnosis of endometriosis (without endometriomas) was associated with similar IVF pregnancy rates [ 19 ] compared with tubal factor infertility. IVF offers the best fecundity rate for those with endometriosis. Admittedly, cost may be a limiting factor.

Endometriomas

Endometriomas larger than 4 cm should be removed to confirm they are benign. In a randomized trial, excision of the endometrioma was associated with less recurrence and higher spontaneous fertility rates than fenestration and bipolar coagulation [ 20 ]. IVF outcomes have been reported to be similar in patients with and without endometriomas. However, the number of oocytes, fertilization rates, and the number of embryos obtained were decreased in women with endometriomas compared with those without endometriomas. The preponderance of evidence suggests that in symptomatic women, one can safely remove endometriomas without compromising ovarian function or the success of assisted reproduction. Accidental puncture of an endometrioma during oocyte retrieval may cause infection or contamination of follicular fluid. Histologic con fi rmation of the benign nature of a large endometrioma may be prudent.

Interestingly, in a retrospective chart review, the higher the rate of endometrioma recurrence, the greater the antral follicle count in the affected ovary. This may be a consequence of less ovarian trauma at the time of cystectomy [ 21 ]. Simple drainage of an endometrioma has been shown to be ineffective.

Treatment of Patients with Chronic Pelvic Pain

Medical Management for Pain

Several classes of drugs have traditionally been used to manage pain associated with endometriosis (Table 2). Progestins or combined oral contraceptives and nonsteroidal anti-in flammatory drugs are used as first-line therapy for chronic pain associated with endometriosis. In a prospective, randomized controlled trial comparing combined oral contraceptives with GnRHa, both treatment arms led to similar pain relief [ 22 ].

Table 2 Drugs used for the treatment of endometriosis (a)
Class Drug Dosage
Androgen Danazol

100–400 mg PO twice a day

  Danazol 100 mg per vagina daily
Aromatase inhibitor

Anastrozole

1mg PO daily
  Letrozole 2.5mg PO daily
Estrogen–progestin combinations Monophasic estrogen/progestin Low ethinyl estradiol dose continuously
Gonadotropin-releasing hormone agonist Goserelin 3.6 mg SC monthly (10.8 mg IM every 3 months)
  Leuprolide depot (b,c) 3.75 mg IM monthly (11.75 mg IM every 3 months)
  Nafarelin (b,c) 200 m g intranasally twice a day
Gonadotropin-releasing hormone antagonist Cetrorelix 3 mg SC weekly
Progestin Depo-subQ provera 104 (b) 104 mg/0.65 mL SC every 3 months
  Dienogest 2 mg PO daily (d)
  Etonogestrel-releasing implant 1 for 3 years
  Levonorgestrel-releasing IUS 1 for 5 years
  Medroxyprogesterone acetate
30 mg PO daily for 6 months, followed by 100 mg IM every
2 weeks × 2 months, then 200 mg IM monthly × 4 months
  Norethindrone acetate (b) 5 mg PO daily
SC subcutaneously; IM intramuscularly; IUS intrauterine system
a Adapted from [ 4 ]
b FDA approved for endometriosis
c With add-back therapy, that is, norethindrone acetate 5 mg daily + vitamin D 800 IU daily + calcium 1.25 g daily
d Dienogest is a 19-nortestosterone derivative that is approved in the European Union for the treatment of endometriosis. It is not available in the
United States as a separate drug. It is only available in the oral contraceptive Natazia (Bayer Pharmaceuticals, Montville, NJ, USA) (estradiol valerate/
dienogest), which is a newer four-phasic pack that contains dienogest.
Progestins

Subcutaneous medroxyprogesterone acetate (Depo-subQ provera 104, Pfizer, New York, NY, USA) administered every 12–14 weeks subcutaneously was approved by the US Food and Drug Administration (FDA) for the treatment of endometriosis-related pelvic pain. The bone loss seems to be less pronounced than with the use of GnRHa without add-back therapy. However, there are no data yet with the prolonged use of Depo-subQ, and the recommendation is not to use the drug for more than 2 years unless other methods are unacceptable. Note that the rate of abnormal vaginal bleeding while on Depo-subQ was 17 %.

There are several other progestins that have been used for the treatment of endometriosis-associated pelvic pain. The FDA also approved norethindrone acetate (NETA) 5 mg daily with a GnRHa. Through NETA’s estrogenic activity, there is a bene fi cial effect on both bone mineral density and vasomotor symptoms; 5 mg of NETA is equivalent to 20–30 m g of oral ethinyl estradiol. The levonorgestrel intrauterine system has been successfully used for symptomatic endometriosis. Trials have demonstrated pain relief and decreased menstrual blood loss.

Gonadotropin-Releasing Hormone Agonists

GnRH agonists can be given via an intramuscular (leuprolide acetate), subcutaneous (goserelin), or nasal (nafarelin) route. After an initial increase in gonadotropins during the first 10 days, there is a decrease in pituitary secretion secondary to GnRH receptor downregulation. These drugs are typically given for an initial 6-month course. The majority of patients (75–80 %) in clinical trials responded. However, many patients will have recurrence of pain within 5 months. A main concern is the progressive loss in bone mineral density. Menstrual periods return between 2 and 3 months after the last monthly injection, but recovery of bone mineral density takes more time.

Add-back therapy with estrogens or progestins was introduced as a way to reduce the hypoestrogenic side effects of GnRHa, especially the loss in bone mineral density, but also vasomotor symptoms and atrophic vaginal mucosa. Other symptoms such as insomnia, mood disorders, and cognitive dysfunction may occur. The mean decrease in bone mineral density after 1 year of GnRHa treatment without add-back is between 3 and 7%.

Add-back therapy has been proposed for both short-term (less than 6 months) and long-term use (more than 6 months). Many studies have shown that the efficacy is not reduced. Norethindrone (5 mg orally daily) is the most commonly used add-back regimen. Low-dose estrogen (conjugated equine estrogen 0.625 mg) can also be added to the norethindrone without loss of benefit in symptom control. Higher doses of estrogen (i.e., combined oral contraceptives) are associated with diminished efficacy in relieving pain symptoms.

Aromatase Inhibitors

Aromatase inhibitors have been successfully used in a limited number of cases of persistent disease after hysterectomy and bilateral oophorectomy as well as in patients with intact pelvic organs. The putative mechanism is by suppression of locally produced estrogens from aromatase activity expressed by the endometriotic cells. Typically, an aromatase inhibitor such as letrozole 2.5 mg or anastrozole 1 mg daily is given with NETA (5 mg daily) to prevent ovarian cyst formation and a possible decrease in bone mineral density.

Surgical Management for Pain

Two prospective randomized controlled studies have clearly shown that surgical therapy is superior to no treatment for relief of pain from endometriosis [ 23 ]. One randomized controlled trial with only 16 women did not show a statistically significant difference in pain relief [ 24 ].

Several observations can be surmised from these studies:

  1. surgery is more effective than simple diagnostic laparoscopy in the treatment of pain associated with endometriosis;
  2. there is a significant placebo effect associated with surgery, especially early on (3 months), that persists in approximately 20 % of patients;
  3. between 20 and 40 % of patients will not respond to surgery and will continue to experience pain;
  4. surgery is least effective for early stage disease.

It is unclear if excision of endometriosis is superior to simple ablation by cautery or laser. Postoperative treatment with suppressive therapy with a GnRHa for 6 months may delay recurrence of symptoms.

Neurectomy

Interruption of the cervical and uterine sensory nerves by transection of the uterosacral ligaments, a uterosacral nerve ablation, has been shown not to have any long-term benefit [ 25 ]. A presacral neurectomy has been shown to be beneficial in patients with chronic pelvic pain and endometriosis when performed with surgical treatment of the endometriosis lesions [ 26 ]. The procedure is associated with greater relief of midline pain rather than lateral pain. The success of the procedure is dependent on excision of the superior hypogastric plexus (presacral nerve) before extensive branching has occurred. The most common postsurgical complications are constipation and urinary urgency.

Hysterectomy

Hysterectomy with or without bilateral salpingooophorectomy can be considered in patients whose disease fails to respond to conservative management and who do not desire future fertility. Most studies have shown significant pain relief from definitive surgery. Caution should be used in recommending oophorectomy in women less than 40 years of age [ 27 ].

Post-hysterectomy Recurrence

Endometriosis can recur in 5–10 % of patients after hysterectomy and bilateral salpingo-oophorectomy. The role of hormone replacement therapy after surgical castration is controversial. There is a possibility of symptom or disease recurrence (3.5 %). On the other hand, there is the real possibility of severe vasomotor symptoms and osteoporosis. Hormone replacement therapy is not contraindicated, and the risks and benefits should be discussed with the patient.

Rectovaginal Endometriosis

The management of rectovaginal endometriosis is extremely difficult and usually involves the rectosigmoid. Patients usually have severe symptoms that may involve the gastrointestinal tract such as constipation, diarrhea, and painful bowel movements. However, some patients with rectovaginal endometriosis are asymptomatic. These patients do not need treatment.

Management of Endometriosis on Extragenital Organs

Gastrointestinal Endometriosis

Although gastrointestinal symptoms are quite common in women with endometriosis, the overall incidence of bowel involvement is reported to be around 5 %. Endometriosis of the gastrointestinal system typically involves the rectum or rectosigmoid. Recurrence of disease after hysterectomy and oophorectomy more commonly involves the bowel. Excision of disease or intestinal resection can be performed by laparotomy or by laparoscopy. Rectovaginal fistula and abscess formation are the most serious complications reported.

Respiratory System

Diaphragmatic endometriosis can be asymptomatic and noted incidentally at diagnostic laparoscopy. Symptomatic patients often report right-sided chest pain or shoulder pain in association with menstruation that occasionally radiates into the neck or arm and dyspnea. Asymptomatic diaphragmatic lesions do not need treatment. Electrosurgery, laser, or surgical excision should be performed carefully because the thickness of the diaphragm ranges between 1 and 5 mm. Thoracic endometriosis most commonly presents as a right-sided catamenial pneumothorax but can also be manifested by hemothorax, hemoptysis, or pulmonary nodules. The typical symptoms are chest pain and dyspnea. Approximately 30 % of these women have pelvic endometriosis at the time of surgical management of the thoracic disease. A chest CT scan may demonstrate pulmonary or pleural nodules, especially if performed during a menstrual period. Chemical pleurodesis is associated with a lower recurrence rate of catamenial pneumothorax than hormonal treatment. However, initial treatment with hormonal therapy is indicated.

Genitourinary System

Endometriosis often involves the peritoneum over the ureter. However, direct ureter involvement is uncommon and has been reported in less than 1 % of patients; it is predominantly left-sided (63 %) when this is observed. Ureteral involvement can be the result of extrinsic compression from extensive endometriosis that surrounds the ureter with significant fibrosis. The majority of the patients have significant involvement of the rectovaginal septum with nodules that are often greater than 3 cm. Preoperative imaging studies such as MRI with contrast should be used to evaluate the renal system preoperatively in patients with rectovaginal disease. Medical therapy has been used successfully in a limited number of patients. Most cases of ureteral endometriosis can be treated with excision of the periureteral fibrosis and active lesions without ureter resection.

Sciatic Nerve Involvement

Patients with endometriosis of the sciatic nerve can present with hip pain, which is usually localized to the buttock. The pain radiates down the back of the leg, and numbness occurs in areas innervated by the sciatic nerve. The symptoms typically occur in association with a menstrual period but then extend into other times of the cycle. Progressive leg and foot muscle weakness with electromyogram studies showing denervation can be demonstrated. MRI typically shows a lesion in fi ltrating the sciatic nerve. CT-guided biopsy can be used to confirm the diagnosis. Two-thirds of cases are localized to the right side. Most cases have pelvic endometriosis associated with this disease. Treatment with a GnRHa and add-back therapy have been shown to reverse the neurologic abnormalities.

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