Gynecology_Novak

Gynecology_Novak. Myofascial Pain Myofascial syndrome is documented in about 15% of patients with chronic pelvic pain (120). These patients are noted to have numerous trigger points, hyperirritable areas within a tight band of skeletal muscle or within its fascia (123,124). Trigger points are possibly initiated by pathogenic autonomic reﬂex of visceral or muscular origin and are painful on compression (124–126). The referred pain of the trigger point occurs in a dermatomal distribution and may be caused by nerves from the muscle or deeper structures sharing a common second-order neuron in the spinal cord. The patient can experience weakness and restriction in range of motion of the affected muscle. Physical therapy is a mainstay (127). Painful trigger points characteristically can be abolished with the injection of local anesthetic into the painful area, and topical lidocaine patches or creams can be useful (123). Trigger points can be present in women with chronic pelvic pain irrespective of presence


Gynecology_Novak

Gynecology_Novak. of local anesthetic into the painful area, and topical lidocaine patches or creams can be useful (123). Trigger points can be present in women with chronic pelvic pain irrespective of presence or type of underlying pathology. In one study, 89% of women with chronic pelvic pain had abdominal, vaginal, or lumbosacral trigger points (123). In the absence of the initial or ongoing organic pathology, various factors are theorized to predispose to the chronicity of the myofascial syndrome, including psychological, hormonal, and biomechanical factors (124). A multidisciplinary approach to myofascial pain must include cognitive behavioral and relaxation approaches.


Gynecology_Novak

Gynecology_Novak. Abdominal wall and pelvic ﬂoor myofascial pain is often exacerbated during the premenstrual period or by stimuli to the dermatome of trigger points (e.g., full bladder, bowel, or any stimulation to organs that share the dermatome of the involved nerve) (125). On examination, fingertip pressure on the trigger points evokes local and referred pain. Tensing of the muscles by either straight leg lifting or raising the head off the table or palpation increases the pain. A specific jump sign can be elicited by palpation with fingertip or a cotton swab. An electric (tingling) sensation confirms correct needle placement (123).


Gynecology_Novak

Gynecology_Novak. Massage therapy can help relieve the pain in some cases. “Myofascial release” is a special vigorous message that can be effective (124). Depending on the location of the myofascial trigger points, pelvic ﬂoor physical therapy is indicated (128). Sustained pressure with adequate force to a trigger point for a specified period can inactivate the irritable nerve (129). NSAIDs, gabapentin, pregabalin, low-dose TCAs, and benzodiazepines may be useful in patients requiring pharmacologic interventions. Injection of the trigger point with 3 mL of 0.25% bupivacaine provides relief that usually outlasts the duration of the anesthetic action. After four to five biweekly injections, the procedure should be abandoned if long-lasting relief is not obtained. A 60-patient randomized controlled trial compared lidocaine patch and placebo patch versus anesthetic injection for the treatment of myofascial pain syndrome. The study revealed similar efficacy of anesthetic patch to the gold standard treatment


Gynecology_Novak

Gynecology_Novak. lidocaine patch and placebo patch versus anesthetic injection for the treatment of myofascial pain syndrome. The study revealed similar efficacy of anesthetic patch to the gold standard treatment with trigger point injection and was associated with less discomfort than injection therapy (126). Acupuncture can be effective (130). Concomitant with injection at trigger points; relaxation, stress reduction, and cognitive-behavioral pain management should be undertaken, especially if anxiety, depression, history of emotional trauma, physical or sexual abuse, sexual dysfunction, or social or occupational disruption are present.


Gynecology_Novak

Gynecology_Novak. Fibromyalgia Fibromyalgia is a myofascial pain syndrome, made up of the triad of diffuse pain, fatigue, and nonrestorative sleep. Women with abdominal wall or pelvic ﬂoor myofascial pain, bladder pain syndrome or interstitial cystitis and IBS often have fibromyalgia. Women are affected more commonly than men. To diagnose the syndrome, the patient must have tender points in all four quadrants. The cause is thought to be a central nervous system sensitization that results in abnormal perception of chronic pain. Fibromyalgia is closely associated with chronic fatigue syndrome, a combination of regional myofascial problems including infections and autoimmune disorders or dysautonomias. The management includes education, environmental changes (well-balanced diet, adequate time for sleep, and an environment conducive to restful sleep), exercise and stretching, and counseling or cognitive behavioral therapy for relaxation and maximizing coping mechanisms. Medications used include NSAIDs,


Gynecology_Novak

Gynecology_Novak. an environment conducive to restful sleep), exercise and stretching, and counseling or cognitive behavioral therapy for relaxation and maximizing coping mechanisms. Medications used include NSAIDs, low-dose TCAs, selective serotonin/norepinephrine reuptake inhibitors, anticonvulsants, and benzodiazepines to improve sleep (129).


Gynecology_Novak

Gynecology_Novak. Low-Back Pain Syndrome In women who experience lower-back pain without pelvic pain, gynecologic pathology rarely is the cause of their pain. However, low-back pain may accompany gynecologic pathology. Back pain may be caused by gynecologic, vascular, neurologic, psychogenic, or spondologenic (related to the axial skeleton and its structure) pathology (131). Women with low-back pain syndrome often have pain occurring after trauma or physical exertion, in the morning on arising, or with fatigue. Nongynecologic low-back pain can intensify with the menstrual cycle. Examination consists of inspection, evaluation with movement, and palpation. Various anatomic structures in the spine should be considered as sources of pain. Muscles, vertebral joints, and discs (including lumbosacral junction, paravertebral sacrospinal muscles, and sacroiliac joints) are common sources of spondylogenic pain that must be examined carefully (2).


Gynecology_Novak

Gynecology_Novak. Diagnostic imaging studies performed while the patient is standing, lying, and sitting with maximal ﬂexion can be helpful. An elevated ESR suggests pain of inﬂammatory or neoplastic origin. Though most patients with acute back pain do not require imaging, plain films can be obtained to evaluate for infection, fracture, malignancy, spondylolisthesis, degenerative changes, disc space narrowing, and prior surgery. For patients who require advanced imaging, MRI without contrast is considered to be the best imaging modality. Consultation with the patient’s primary care provider should be sought before initiating management for back pain unless the source could be referred gynecologic pain. For more complex cases, an orthopaedic or neurosurgery consult may be required.


Gynecology_Novak

Gynecology_Novak. Psychological Factors From a psychological perspective, various factors may promote the chronicity of pain, including the meaning attached to the pain, anxiety, the ability to redirect attention, personality, mood state, past experience, and reinforcement contingencies that may amplify or attenuate pain (132). The Minnesota Multiphasic Personality Inventory (MMPI) studies of women with chronic pelvic pain reveal a high prevalence of a convergence “V” profile (elevated scores on the hypochondriasis, hysteria, and depression scales). Treatment that results in subjective improvement in pain severity and increased activity level produces a significant improvement in personality profile (133).


Gynecology_Novak

Gynecology_Novak. There is also a close relationship between depression and pain (73). Both give rise to similar behavior, such as behavioral and social withdrawal and decreased activity, and may be mediated by the same neurotransmitters, including norepinephrine, serotonin, and endorphins. The Beck Depression Inventory can be used as a tool for evaluation; a score over 12 suggests dysphoria and over 18, depression (133a). Antidepressants, particularly serotonin norepinephrine reuptake inhibitors (SNRIs) often relieve both depression and pain.


Gynecology_Novak

Gynecology_Novak. Childhood physical abuse has been noted to be more prevalent in women with chronic pelvic pain than in those with other types of pain (39% vs. 18.4%) (71). In a comparison of women with chronic pelvic pain, women with nonpelvic chronic pain (headache), and pain-free women, a higher lifetime prevalence of major sexual abuse and physical abuse was found in the chronic pelvic pain group. Childhood traumas may lead to an increased vulnerability to psychosocial stress and impaired coping strategies and promote chronicity of pain after an injury.


Gynecology_Novak

Gynecology_Novak. If patients are taught self-efficacy and adaptive pain coping skills through psychological treatment interventions, pain can be reduced and functioning improved. Cognitive behavioral therapy can be useful in treating chronic pelvic pain (134). Dramatizing the pain is a coping mechanism that is used by pain sufferers to generate support from others around them (135). This practice, combined with pain-related anxiety and fear, propagates pain (133). Management of Chronic Pelvic Pain


Gynecology_Novak

Gynecology_Novak. Management of Chronic Pelvic Pain Multidisciplinary The approach to women with chronic pain must be therapeutic, optimistic, supportive, and Approach sympathetic. The patient should be instructed to complete a daily pain ratings form after her first office visit. This form provides the clinician and patient with important information for pain management. Pain level (0–10), vaginal bleeding, and events that trigger pain such as stress, foods, and certain physical activities are recorded. The pain ratings can encourage the patient’s sense of control and decrease feelings of helplessness. Daily recording improves self-efficacy and compliance, allows for diagnosis of atypical cyclic pain (luteal as opposed to menstrual), and helps the patient to recognize the connection between pain and stressors. The ratings should be reviewed at follow-up visits.


Gynecology_Novak

Gynecology_Novak. Offering regular follow-up appointments is preferable to asking the patient to return only if pain persists because the latter reinforces pain behavior. Specific pain management skills should be taught using cognitive-behavioral approaches by a psychologist or using such techniques as mindfulness-based meditation or yoga. Patients should be taught ways to enhance opportunities for control of pain. Psychotherapy is indicated for women who have pronounced depression, sexual difficulties, or indications of past trauma. Various strategies, including relaxation techniques, stress management, sexual and marital counseling, hypnosis, and other psychotherapeutic approaches probably increase CNS descending inhibition of peripheral pain signals. Psychological group treatment is a very cost-effective approach for helping patients learn stress reduction techniques and develop coping behavioral mechanisms (136). Acupuncture can be helpful (138). Physical therapy evaluation and treatment are


Gynecology_Novak

Gynecology_Novak. approach for helping patients learn stress reduction techniques and develop coping behavioral mechanisms (136). Acupuncture can be helpful (138). Physical therapy evaluation and treatment are important.


Gynecology_Novak

Gynecology_Novak. Various studies of multidisciplinary pain management were performed. This approach incorporates the skills of the gynecologist, psychologist, and physical therapist, and may include an anesthesiologist for specialized nerve blocks. Retrospective, uncontrolled studies revealed relief of pain in 85% of the participants (137). One prospective randomized study revealed a similar response rate, which was significantly better than that of traditional therapy for pain and associated symptom reduction, improvement of daily functioning, and quality of life (138).


Gynecology_Novak

Gynecology_Novak. The following groups of patients should be considered for multidisciplinary therapy early in the management process: (i) no obvious pathology, (ii) pathology that has an equivocal role in pain production, (iii) poor response to traditionally effective medical or surgical management, (iv) more than one visceral or somatic structure involved in the production of pain (i.e., more than one “pain generator”), (v) significant stress, anxiety, posttraumatic stress disorder, or depression, (vi) history of past or current physical, emotional, or sexual trauma. Any patients with dysmenorrhea or pain that worsens in the luteal or menstrual phase should be given hormonal agents to suppress ovulation and/or menses, as discussed above.


Gynecology_Novak

Gynecology_Novak. Any patients with dysmenorrhea or pain that worsens in the luteal or menstrual phase should be given hormonal agents to suppress ovulation and/or menses, as discussed above. Patients with neuropathic pain or those with evidence of central sensitization or myofascial pain benefit from agents that alter neural processing. A low dose of a tricyclic antidepressant, various anticonvulsants, or selective serotonin/norepinephrine reuptake inhibitors are often effective, especially if combined with cognitive behavioral therapy. These pharmacologic agents lower the threshold for nerve firing and can help reduce reliance on narcotic pain medication, increasing activity and relieving the impact the pain has on the women’s overall lifestyle (11). Only one small, randomized controlled trial looked at the effect of selective serotonin reuptake inhibitors on pelvic pain, and failed to show a significant difference in pain or functional ability in a short follow-up period (138).


Gynecology_Novak

Gynecology_Novak. Anticonvulsants such as gabapentin or pregabalin are useful for treatment of chronic pelvic pain. Gabapentin plus amitriptyline was more efficacious than amitriptyline alone (139). Local anesthetics are sodium channel blockers and they downgrade nerve firing. Ilioinguinal iliohypogastric, pudendal, nerve blocks and trigger point injections can be easily learned by the gynecologist and used liberally where appropriate to down-regulate neural signaling (11). Women with depression should be treated with an appropriate therapeutic dose of antidepressant medication. Psychiatry can be consulted in this setting.


Gynecology_Novak

Gynecology_Novak. The role of opioid therapy in chronic pain is controversial and randomized controlled trials are lacking. Long-term management of chronic pelvic pain with narcotic medications is considered a last resort after failure of all other treatment modalities. Opioids should be given on a scheduled basis, and patients should have consistent follow-up with evaluation of the extent of pain relief, level of function, and quality of life. Physicians should carefully document failure of other treatment options and patient counseling. Narcotics should be prescribed only with a narcotic contract. The patient should sign a written contract agreeing to obtain pain medications from only one provider and describing other expectations with respect to treatment. Some other points that the patient should agree to include no early refills or increasing dosage of medication without discussion with the doctor, no alcohol or illegal drugs, random blood or urine drug screens if needed, and psychiatric or


Gynecology_Novak

Gynecology_Novak. agree to include no early refills or increasing dosage of medication without discussion with the doctor, no alcohol or illegal drugs, random blood or urine drug screens if needed, and psychiatric or psychological evaluation if needed (140).


Gynecology_Novak

Gynecology_Novak. Physical Therapy Physical therapy (PT) procedures restore tissue and joint ﬂexibility, improve posture and body mechanics, restore strength and coordination, reduce nervous system irritability, and restore function. PT is an important component of the management of patients with myofascial pain in the abdominal wall, pelvic ﬂoor, or lower back (141).


Gynecology_Novak

Gynecology_Novak. Women with disabling pain that is premenstrual and or menstrual and that does not respond to NSAIDs or hormonal contraceptives should be considered for laparoscopic evaluation. Diagnostic laparoscopy is a standard procedure in the evaluation of patients with chronic noncyclic pelvic pain; however, laparoscopy is generally withheld until other nongynecologic somatic or visceral causes of pain are excluded. Nonrandomized retrospective and prospective studies suggest that diagnostic laparoscopy provides a positive psychological effect on the treatment of chronic pelvic pain, but this should not be the main goal of laparoscopy (142). During diagnostic laparoscopy, endometriotic lesions should be excised for biopsy, and if infection is suspected, cultures should be performed. The laparoscopy is essentially a debulking procedure, and all visible endometriosis may not be able to be removed safely; but if possible the implants should be excised or electrocoagulated.


Gynecology_Novak

Gynecology_Novak. Presacral neurectomy and laparoscopic uterosacral nerve ablation (LUNA) are techniques to interrupt the nerve supply to the uterus. A large study showed that LUNA was no more effective for chronic pelvic pain than laparoscopy alone (143). A Cochrane database review revealed that there is insufficient evidence to recommend pelvic nerve disruption for the treatment of dysmenorrhea (45). The role of pelvic adhesions in pain is unclear, and the efficacy of lysis of adhesions is even more in doubt. Adhesiolysis, even via laparoscopy, is frequently complicated by adhesion reformation and may not be effective for relief of pain in controlled trials (90,144). Other causes must be treated first, and psychological consultation and management should precede or accompany the lysis of adhesions.


Gynecology_Novak

Gynecology_Novak. Although 19% of hysterectomies are performed to cure pelvic pain, 30% of patients presenting to pain clinics have already undergone hysterectomy without experiencing pain relief. A multidisciplinary approach including a gynecologist, physical therapist, and a psychologist decreased the frequency of hysterectomy in one study from 16.3% of patients with chronic pelvic pain to 5.8% (145).


Gynecology_Novak

Gynecology_Novak. Hysterectomy is particularly useful for women who have completed childbearing and have secondary dysmenorrhea or chronic pain related to endometriosis, to uterine pathology, such as adenomyosis, or to pelvic congestion. Before recommending hysterectomy for pain or unilateral adnexectomy for unilateral pain, it is useful to apply the PREPARE mnemonic in discussions with the patient (146): the Procedure that is being done, Reason or indication, Expectation or desired outcome of the procedure, Probability that the outcome will be achieved, Alternatives and nonsurgical options, and Risks as well as Expense (see Chapter 3). Hysterectomy for central pelvic pain in women with dysmenorrhea, dyspareunia, and uterine tenderness provided relief of pain in 77% of women in one retrospective study and in 74% of women in one prospective cohort study (147,148). Nevertheless, 25% of women in the retrospective study noted that pain persisted or worsened at 1-year follow-up (147). Persistent pain in the


Gynecology_Novak

Gynecology_Novak. 74% of women in one prospective cohort study (147,148). Nevertheless, 25% of women in the retrospective study noted that pain persisted or worsened at 1-year follow-up (147). Persistent pain in the prospective study was associated with multiparity, prior history of PID, absence of pathology, and Medicaid payer status (148). The Maine Women’s Health Study, a prospective cohort study, studied outcomes of 199 women with frequent pain at baseline who underwent hysterectomy. In this cohort, only 11% reported persistent symptoms after their surgery (149).


Gynecology_Novak

Gynecology_Novak. The American College of Obstetricians and Gynecologists outlined criteria that should be met before performing a hysterectomy for pelvic pain (150). They require at least 6 months of pelvic pain without any otherwise correctable pathology. When deciding on the surgical approach, consideration should be given to a vaginal or laparoscopic hysterectomy over an abdominal approach if there are no extensive adhesions expected or large uterine/fibroid size does not preclude it. There are many studies that confirm less morbidity and shorter hospital stays with vaginal compared with abdominal hysterectomies (151). A prospective study of abdominal versus vaginal versus laparoscopically assisted surgery did not find any statistical difference or worsening of outcomes of urinary or sexual function between the different approaches at 6 months (151). 1. Dawood MY. Dysmenorrhea. Clin Obstet Gynecol 1990;3:168–178. 2. Howard FM. Chronic pelvic pain. Obstet Gynecol 2003;101:594– 611. 3.


Gynecology_Novak

Gynecology_Novak. 1. Dawood MY. Dysmenorrhea. Clin Obstet Gynecol 1990;3:168–178. 2. Howard FM. Chronic pelvic pain. Obstet Gynecol 2003;101:594– 611. 3. Wesselmann U. Neurogenic inﬂammation and chronic pelvic pain. World J Urol 2001;19:180–185. 4. Nijenhuis ER, van Dyck R, ter Kuile MM, et al. Evidence for associations among somatoform dissociation, psychological dissociation and reported trauma in patients with chronic pelvic pain. J Psychosom Obstet Gynecol 2003;24:87–98. 5. Giamberardino MA, De Laurentis S, Affaitati G, et al. Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women. Neurosci Lett 2001;304:61–64. 6. Doggweiler-Wiygul R. Chronic pelvic pain. World J Urol 2001;19: 155–156. 7. Bajaj P, Bajaj P, Madsen H, et al. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain 2003;4:372–380. 8.


Gynecology_Novak

Gynecology_Novak. 7. Bajaj P, Bajaj P, Madsen H, et al. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain 2003;4:372–380. 8. Diatchenko L, Nackley AG, Slade GD, et al. Idiopathic pain disorders pathways of vulnerability. Pain 2006;123:226–230. 9. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152[Suppl]:S2–S15 10. Winnard KP, Dmitrieva N, Berkley KJ. Cross-organ interactions between reproductive, gastrointestinal, and urinary tracts: modulation by estrous stage and involvement of the hypogastric nerve. Am J Physiol Regul Integr Comp Physiol 2006;291:R1592–R1601. 11. Howard FM. The role of laparoscopy in the chronic pelvic pain patient. Clin Obstet Gynecol 2003;4:749–766. 12. Bouyer J, Job-Spira N, Pouly J, et al. Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a population-based study. Br J Obstet Gynaecol 2000;107:714– 721. 13.


Gynecology_Novak

Gynecology_Novak. 13. Murray H, Baakdah H, Bardell T, et al. Diagnosis and treatment of ectopic pregnancy. CMAJ 2005;173:905–912. 14. Huchon C, Fauconnier A. Adnexal torsion: a literature review. Eur J Obstet Gynecol Reprod Biol 2010;150:8–12. 15. Oltmann SC, Fischer A, Barber R, et al. Cannot exclude torsion—a 15-year review. J Pediatr Surg 2009;44:1212. 16. Oelsner G, Cohen S, Soriano D, et al. Minimal surgery for the twisted ischaemic adnexa can preserve ovarian function. Human Reprod 2003;18:2599–2602. 17. Cates W Jr, Wasserheit JN. Genital chlamydial infections: epidemiology and reproductive sequelae. Am J Obstet Gynecol 1991;164:1771–1781. 18. Ness RB, Hillier SL, Kipp K, et al. Bacterial vaginosis and risk of pelvic inﬂammatory disease. Obstet Gynecol 2004;104:761–769. 19. Ness RB, Kip KE, Hillier SL, et al. A cluster analysis of bacterial vaginosis-associated microﬂora and pelvic inﬂammatory disease. Am J Epidemiol 2005;162:585–590.


Gynecology_Novak

Gynecology_Novak. 19. Ness RB, Kip KE, Hillier SL, et al. A cluster analysis of bacterial vaginosis-associated microﬂora and pelvic inﬂammatory disease. Am J Epidemiol 2005;162:585–590. 19a. Centers for Disease Control and Prevention. Update to CDC’s Sexually Trnasmitted Diseases Treatment Guideline, 2006. MMWR 2006;55:RR-11. 20. Hiller N, Sella T, Lev-Sagi A, et al. Computed tomographic features of tuboovarian abscess. J Reprod Med 2005;50:203. 21. Landers DV, Sweet RL. Tubo-ovarian abscess: contemporary approach to management. Rev Infect Dis 1983;5:876–884. 22. Reed SD, Landers DV, Sweet RL. Antibiotic treatment of tuboovarian abscess: comparison of broad-spectrum beta-lactam agents versus clindamycin-containing regimens. Am J Obstet Gynecol 1991;164: 1556. 23. Gjelland K, Ekerhovd E, Granberg S. Transvaginal ultrasound-guided aspiration for treatment of tubo-ovarian abscess: a study of 302 cases. Am J Obstet Gynecol 2005;193:1323. 24.


Gynecology_Novak

Gynecology_Novak. 23. Gjelland K, Ekerhovd E, Granberg S. Transvaginal ultrasound-guided aspiration for treatment of tubo-ovarian abscess: a study of 302 cases. Am J Obstet Gynecol 2005;193:1323. 24. Krivak TC, Cooksey C, Propst A. Tubo-ovarian abscess: diagnosis, medical and surgical management. Compr Ther 2004;30:93– 100. 25. Ferrero S, Abbamonte LH, Giordano M, et al. Uterine myomas, dyspareunia, and sexual function. Fertil Steril 2006;86:1504. 26. Lippman SA, Warner M, Samuels S, et al. Uterine fibroids and gynecologic pain symptoms in a population-based study. Fertil Steril 2003;80:1488–1494. 27. Dueholm M, Lundorf E, Hansen ES, et al. Accuracy of magnetic resonance imaging and transvaginal ultrasonography in the diagnosis, mapping, and measurement of uterine myomas. Am J Obstet Gynecol 2002;186:409–415. 28. Addiss DG, Shaffer N, Fowler BS, et al. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol 1990;132:910–925. 29.


Gynecology_Novak

Gynecology_Novak. 28. Addiss DG, Shaffer N, Fowler BS, et al. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol 1990;132:910–925. 29. SCOAP Collaborative, Cuschieri J, Florence M, et al. Negative appendectomy and imaging accuracy in the Washington State Surgical Care and Outcomes Assessment Program. Ann Surg 2008;248: 557–563. 30. Rao PM, Rhea JT. Colonic diverticulitis: evaluation of the arrowhead sign and the inﬂamed diverticulum for CT diagnosis. Radiology 1998;209:775–779. 31. Echols RM, Tosiello RL, Haverstock DC, et al. Demographic, clinical, and treatment parameters inﬂuencing the outcome of acute cystitis. Clin Infect Dis 1999;29:113–119. 32. Takahashi S, Hirose T, Satoh T, et al. Efficacy of a 14-day course of oral ciproﬂoxacin therapy for acute uncomplicated pyelonephritis. J Infect Chemother 2001;7:255–257. 33.


Gynecology_Novak

Gynecology_Novak. 32. Takahashi S, Hirose T, Satoh T, et al. Efficacy of a 14-day course of oral ciproﬂoxacin therapy for acute uncomplicated pyelonephritis. J Infect Chemother 2001;7:255–257. 33. Harris RD, Holtzman SR, Poppe AM. Clinical outcome in female patients with pelvic pain and normal pelvic US findings. Radiology 2000;216:440–443. 34. Burnett MA, Antao V, Black A, et al. Prevalence of primary dysmenorrhea in Canada. J Obstet Gynaecol Can 2005;27:765–770. 35. Dawood MY. Primary dysmenorrhea: advances in pathogenesis and management. Obstet Gynecol 2006;108:428. 36. Jabbour HN, Sales KJ. Prostaglandin receptor signaling and function in human endometrial pathology. Trends Endocrinol Metab 2004;15:398–404. 37. Milsom I, Minic M, Dawood MY, et al. Comparison of the efficacy and safety of nonprescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen, and placebo in the treatment of primary dysmenorrhea: a pooled analysis of five studies. Clin Ther 2002;24:1384. 38.


Gynecology_Novak

Gynecology_Novak. 38. Marjoribanks J, Proctor ML, Farquhar C. Nonsteroidal anti-inﬂammatory drugs for primary dysmenorrhoea. Cochrane Database Syst Rev 2003;4:CD001751. 39. Proctor ML, Roberts H, Farquhar C. Combined oral contraceptive pill (OCP) as treatment for primary dysmenorrhoea. Cochrane Database Syst Rev 2001;4:CD002120. 40. Edelman AB, Gallo MF, Jensen JT, et al. Continuous or extended cycle vs. cyclic use of combined oral contraceptives for contraception. Cochrane Database Syst Rev 2005;3:CD004695. 41. White AR. A review of controlled trials of acupuncture for women’s reproductive health care. J Fam Plan Reprod Health Care 2003;29:233–236. 42. Proctor ML, Smith CA, Farquhar C, et al. Transcutaneous electrical nerve stimulation and acupuncture for primary dysmenorrhoea. Cochrane Database Syst Rev 2002;1:CD002123. 43. Akin MD, Weingand KW, Hengehold DA, et al. Continuous low-level topical heat in the treatment of dysmenorrhea. Obstet Gynecol 2001;97:343–349. 44.


Gynecology_Novak

Gynecology_Novak. 43. Akin MD, Weingand KW, Hengehold DA, et al. Continuous low-level topical heat in the treatment of dysmenorrhea. Obstet Gynecol 2001;97:343–349. 44. Proctor ML, Latthe PM, Farquhar CM, et al. Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005;4:CD001896. 45. Vercellini P, Parazzini F, Oldani S, et al. Adenomyosis at hysterectomy: a study on frequency distribution and patient characteristics. Hum Reprod 1995;10:1160–1162. 46. Lee NC, Dikcer RC, Rubin GL, et al. Confirmation of the preoperative diagnoses for hysterectomy. Am J Obstet Gynecol 1984;150:283– 287. 47. Templeman C, Marshall SF, Ursin G, et al. Adenomyosis and endometriosis in the California Teachers Study. Fertil Steril 2008;90:415. 48. Levgur M. Diagnosis of adenomyosis: a review. J Reprod Med 2007;52:177. 49.


Gynecology_Novak

Gynecology_Novak. 48. Levgur M. Diagnosis of adenomyosis: a review. J Reprod Med 2007;52:177. 49. Kim MD, Kim S, Kim NK, et al. Long-term results of uterine artery embolization for symptomatic adenomyosis. AJR Am J Roentgenol 2007;188:176. 50. Giudice LC, Kao LC. Endometriosis. Lancet 2004;364:1789– 1799. 51. Cornillie FJ, Oosterlynck D, Lauweryns JM, et al. Deeply infiltrating pelvic endometriosis: histology and clinical significance. Fertil Steril 1990;53:978–983. 52. Al-Jefout M, Dezarnaulds G, Cooper M, et al. Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Hum Reprod 2009;24:3019–3024. 53. Allen C, Hopewell S, Prentice A. Non-steroidal anti-inﬂammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev 2005;4:CD004753. 54. Hughes E, Brown J, Collins JJ, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev 2007;3:CD000155. 55.


Gynecology_Novak

Gynecology_Novak. 54. Hughes E, Brown J, Collins JJ, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev 2007;3:CD000155. 55. Vercellini P, Frontino G, De Giorgi O, et al. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003;80:305. 56. Somigliana E, Vigano P, Barbara G, et al. Treatment of endometriosis-related pain: options and outcomes. Front Biosci (Elite Ed) 2009;1:455–465. 57. Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993. 58. Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Obstet Gynecol 1998;91:16–24. 59.


Gynecology_Novak

Gynecology_Novak. 58. Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Obstet Gynecol 1998;91:16–24. 59. Ferrero S, Camerini G, Seracchioli R, et al. Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis. Hum Reprod 2009;24:3033–3041. 60. Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol 2008;26:1051– 1057. 61. Vercellini P, Barbara G, Abbiati A, et al. Repetitive surgery for recurrent symptomatic endometriosis: what to do? Eur J Obstet Gynecol Reprod Biol 2009;146:15–21. 62.


Gynecology_Novak

Gynecology_Novak. 61. Vercellini P, Barbara G, Abbiati A, et al. Repetitive surgery for recurrent symptomatic endometriosis: what to do? Eur J Obstet Gynecol Reprod Biol 2009;146:15–21. 62. Seracchioli R, Mabrouk M, Manuzzi L, et al. Post-operative use of oral contraceptive pills for prevention of anatomical relapse or symptom-recurrence after conservative surgery for endometriosis. Hum Reprod 2009;24:2729–2735. 63. Vercellini P, Crosignani PG, Somigliana E, et al. Medical treatment for rectovaginal endometriosis: what is the evidence? Hum Reprod 2009;24:2504–2514. 64. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol 2004;103:589–605. 65. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990–1997. Obstet Gynecol 2002;99:229–234. 66. Cervero F, Laird JM. Understanding the signaling and transmission of visceral nociceptive events. J Neurobiol 2004;61:45–54. 67.


Gynecology_Novak

Gynecology_Novak. 66. Cervero F, Laird JM. Understanding the signaling and transmission of visceral nociceptive events. J Neurobiol 2004;61:45–54. 67. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009;10:895–926. 68. International Pelvic Pain Society. Pelvic pain assessment form. Available at http://www.pelvicpain.org/pdf/History and Physical Form/IPPS-H&PformR-MSW.pdf. Accessed April 27, 2011. 69. Meltzer-Brody S, Leserman J, Zolnoun D, et al. Trauma and post-traumatic stress disorder in women with chronic pelvic pain. Obstet Gynecol 2007;109:902–908. 70. Walling MK, O’Hara MW, Reiter RC, et al. Abuse history and chronic pain in women: II. A multivariate analysis of abuse and psychological morbidity. Obstet Gynecol 1994;84:200–206. 71. Rapkin AJ, Kames LD, Darke LL, et al. History of physical and sexual abuse in women with chronic pelvic pain. Obstet Gynecol 1990;76:92–96. 72.


Gynecology_Novak

Gynecology_Novak. 71. Rapkin AJ, Kames LD, Darke LL, et al. History of physical and sexual abuse in women with chronic pelvic pain. Obstet Gynecol 1990;76:92–96. 72. Lorencatto C, Petta CA, Navarro MJ, et al. Depression in women with endometriosis with and without chronic pelvic pain. Acta Obstet Gynecol Scand 2006;85:88–92. 73. Randolph ME, Reddy DM. Sexual functioning in women with chronic pelvic pain: the impact of depression, support, and abuse. J Sex Res 2006;43:38–45. 74. Srinivasan R, Greenbaum DS. Chronic abdominal wall pain: a frequently overlooked problem. Practical approach to diagnosis and management. Am J Gastroenterol 2002;97:3207. 75. Wykes CB, Clark TJ, Khan KS. Accuracy of laparoscopy in the diagnosis of endometriosis: a systematic quantitative review. BJOG 2004;111:1204–1212. 76. Vercellini P, Frontino G, Pietropaolo G, et al. Deep endometriosis: definition, pathogenesis, and clinical management. J Am Assoc Gynecol Laparosc 2004;11:153–161. 77.


Gynecology_Novak

Gynecology_Novak. 76. Vercellini P, Frontino G, Pietropaolo G, et al. Deep endometriosis: definition, pathogenesis, and clinical management. J Am Assoc Gynecol Laparosc 2004;11:153–161. 77. Fedele L, Parazzini F, Bianchi S, et al. Stage and localization of pelvic endometriosis and pain. Fertil Steril 1990;53:155–158. 78. Fukaya T, Hoshiai H, Yajima A. Is pelvic endometriosis always associated with chronic pain? A retrospective study of 618 cases diagnosed by laparoscopy. Am J Obstet Gynecol 1993;169:719–722. 79. Donnez J, Squifﬂet J. Laparoscopic excision of deep endometriosis. Obstet Gynecol Clin North Am 2004;31:567–580, ix. 80. Konincky RP, Meuleman C, Demeyere S, et al. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril 1991;55:759–765. 81. Porpora MG, Koninckx PR, Piazze J, et al. Correlation between endometriosis and pelvic pain. J Am Assoc Gynecol Laparosc 1999;6:429–434. 82.


Gynecology_Novak

Gynecology_Novak. 81. Porpora MG, Koninckx PR, Piazze J, et al. Correlation between endometriosis and pelvic pain. J Am Assoc Gynecol Laparosc 1999;6:429–434. 82. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science 2005;308:1587–1589. 83. Stratton P, Berkley K. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update 2011;17:327–346. 84. Tokushige N, Markham R, Russell P, et al. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Fertil Steril 2007;88:795–803. 85. Stout AL, Steege JF, Dodson WC, et al. Relationship of laparoscopic findings to self-report of pelvic pain. Am J Obstet Gynecol 1991;164[Pt 1]:73–79. 86. Rapkin AJ. Adhesions and pelvic pain: a retrospective study. Obstet Gynecol 1986;68:13–15. 87. Steege JF, Scott AL. Resolution of chronic pelvic pain after laparoscopic lysis of adhesions. Am J Obstet Gynecol 1991;165:278–283. 88.


Gynecology_Novak

Gynecology_Novak. 87. Steege JF, Scott AL. Resolution of chronic pelvic pain after laparoscopic lysis of adhesions. Am J Obstet Gynecol 1991;165:278–283. 88. Swank DJ, Swank-Bordewijk SC, Hop W, et al. Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomized controlled multi-centre trial. Lancet 2003;361:1247–1251. 89. Swank DJ, Van Erp WF, Repelaer Van Driel O, et al. A prospective analysis of predictive factors on the results of laparoscopic adhesiolysis in patients with chronic abdominal pain. Surg Laparosc Endosc Percutan Tech 2003;13:88–94. 90. Hammoud A, Gago LA, Diamond M. Adhesions in patients with chronic pelvic pain: a role for adhesiolysis? Fertil Steril 2004;82:1483–1491. 91. Peters AAW, Trimbos-Kemper GCM, Admiral C, et al. A randomized clinical trial on the benefit of adhesiolysis in patients with intraperitoneal adhesions and chronic pelvic pain. Br J Obstet Gynaecol 1992;99:59–62. 92.


Gynecology_Novak

Gynecology_Novak. 92. Howard FM, El-Minawi AM, Sanchez R. Conscious pain mapping by laparoscopy in women with chronic pelvic pain. Obstet Gynecol 2000;96:934–939. 93. Gupta A, McCarthy S. Pelvic varices as a cause for pelvic pain: MRI appearance. Magn Reson Imaging 1994;12:679–681. 94. Soysal ME. A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion. Hum Reprod 2001;16:931–939. 95. Farquhar CM, Rogers V, Franks S, et al. A randomized controlled trial of medroxyprogesterone acetate and psychotherapy for the treatment of pelvic congestion. Br J Obstet Gynaecol 1989;96:1153– 1162. 96. Kim HS, Malhotra AD, Rowe PC, et al. Embolotherapy for pelvic congestion syndrome: long-term results. J Vasc Interv Radiol 2006;17:289. 97. Tu FF, Hahn D, Steege JF. Pelvic congestion syndrome-associated pelvic pain: a systematic review of diagnosis and management. Obstet Gynecol Surv 2010;65:332–340. 98.


Gynecology_Novak

Gynecology_Novak. 97. Tu FF, Hahn D, Steege JF. Pelvic congestion syndrome-associated pelvic pain: a systematic review of diagnosis and management. Obstet Gynecol Surv 2010;65:332–340. 98. Magtibay PM, Nyholm JL, Hernandez JL, et al. Ovarian remnant syndrome. Am J Obstet Gynecol 2005;193:2062–2066. 99. Carey MP, Slack MC. GnRH analogue in assessing chronic pelvic pain in women with residual ovaries. BJOG 1996;103:150–153. 100. Kho RM, Magrina JF, Magtibay PM. Pathologic findings and outcomes of a minimally invasive approach to ovarian remnant syndrome. Fertil Steril 2007;87:1005. 101. Nezhat C, Kearney S, Malik S, et al. Laparoscopic management of ovarian remnant. Fertil Steril 2005;83:973. 102. Williams RE, Hartmann KE, Sandler R, et al. Prevalence and characteristics of irritable bowel syndrome among women with chronic pelvic pain. Obstet Gynecol 2004;104:452–458. 103.


Gynecology_Novak

Gynecology_Novak. 102. Williams RE, Hartmann KE, Sandler R, et al. Prevalence and characteristics of irritable bowel syndrome among women with chronic pelvic pain. Obstet Gynecol 2004;104:452–458. 103. Williams RE, Hartmann KE, Sandler RS, et al. Recognition and treatment of irritable bowel syndrome among women with chronic pelvic pain. Am J Obstet Gynecol 2005;192:761 104. Mertz HR. Irritable bowel syndrome. N Engl J Med 2003;349:2136– 2146. 105. Mayer EA. Irritable bowel syndrome. N Engl J Med 2008;358:1692– 1699. 106. Drossman DA. Rome III: the new criteria. Chin J Dig Dis 2006;7: 181–185. 107. Kaur H, Arunkalaivanan AS. Urethral pain syndrome and its management. Obstet Gynecol Surv 2007;62:348–351. 108. Costantini E, Zucchi A, Del Zingaro M, et al. Treatment of urethral syndrome: a prospective randomized study with Nd:YAG laser. Urol Int 2006;76:134–138. 109.


Gynecology_Novak

Gynecology_Novak. 108. Costantini E, Zucchi A, Del Zingaro M, et al. Treatment of urethral syndrome: a prospective randomized study with Nd:YAG laser. Urol Int 2006;76:134–138. 109. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167. 110. Parsons CL. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 2007;69:S9. 111. Wesselmann U. Interstitial cystitis: a chronic visceral pain syndrome. Urology 2001;57:32. 111a. Chancellor MB. A Multidisciplinary Consensus Meeting on IC/PBS Outcome of the Consensus Meeting on Interstitial Cystitis/Painful Bladder Syndrome, February 10, 2007, Washington, DC. Rev Urol 2007 9: 81–83. 112.


Gynecology_Novak

Gynecology_Novak. 112. Parsons CL. The potassium sensitivity test: a new gold standard for diagnosing and understanding the pathophysiology of interstitial cystitis. JUrol 2009;182:432–434. 113. Chancellor MB, Yoshimura N. Neurophysiology of stress urinary incontinence. Rev Urol 2004;6[Suppl 3]:S19–S28. 114. Dimitrakov J, Kroenke K, Steers WD, et al. Pharmacologic management of painful bladder syndrome/interstitial cystitis: a systematic review. Arch Intern Med 2007;167:1922. 115. Welk BK, Teichman JM. Dyspareunia response in patients with interstitial cystitis treated with intravesical lidocaine, bicarbonate, and heparin. Urology 2008:71:67–70. 116. Moldwin RM, Evans RJ, Stanford EJ, et al. Rational approaches to the treatment of patients with interstitial cystitis. Urology 2007;69[Suppl]:73–81. 117. Maher CF, Carey MP, Dwyer PL, et al. Percutaneous sacral nerve root neuromodulation for intractable interstitial cystitis. JUrol 2001;165:884–886. 118.


Gynecology_Novak

Gynecology_Novak. 117. Maher CF, Carey MP, Dwyer PL, et al. Percutaneous sacral nerve root neuromodulation for intractable interstitial cystitis. JUrol 2001;165:884–886. 118. Rahn DD, Phelan JN, Roshanravan SM, et al. Anterior abdominal wall nerve and vessel anatomy: clinical implications for gynecologic surgery. Am J Obstet Gynecol 2010;202:234.e1–5. 119. Fardin F, Benettello P, Negrin P. Iatrogenic femoral neuropathy: considerations on its prognosis. Electromyogr Clin Neurophysiol 1980;20:153–155. 120. Reiter RC. Occult somatic pathology in women with chronic pelvic pain. Clin Obstet Gynecol 1990;33:154–160. 121. Bohrer JC, Chen CC, Walters MD. Pudendal neuropathy involving the perforating cutaneous nerve after cystocele repair with graft. Obstet Gynecol 2008;112:496. 122. Labat JJ, Riant T, Robert R, et al. Diagnostic criteria for pudendal neuralgia by pudendal nerve entrapment (Nantes criteria). Neurourol Urodyn 2008;27:306. 123.


Gynecology_Novak

Gynecology_Novak. 122. Labat JJ, Riant T, Robert R, et al. Diagnostic criteria for pudendal neuralgia by pudendal nerve entrapment (Nantes criteria). Neurourol Urodyn 2008;27:306. 123. Slocumb JC. Neurological factors in chronic pelvic pain: trigger points and the abdominal pelvic pain syndrome. Am J Obstet Gynecol 1984;149:536–543. 124. Travell J. Myofascial trigger points: clinical view. Adv Pain Res Ther 1976;1:919–926. 125. Doggweiler-Wiygul R. Urologic myofascial pain syndromes. Curr Pain Headache Rep 2004;8:445–451. 126. Affaitati G, Fabrizio A, Savini A, et al. A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. Clin Ther 2009;31:705–720. 127. Butrick CW. Pelvic ﬂoor hypertonic disorders: identification and management. Obstet Gynecol Clin North Am 2009;36:707–722. 128.


Gynecology_Novak

Gynecology_Novak. 127. Butrick CW. Pelvic ﬂoor hypertonic disorders: identification and management. Obstet Gynecol Clin North Am 2009;36:707–722. 128. FitzGerald MP, Anderson RU, Potts J, et al. Randomized multi-center feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. JUrol 2009;182: 570. 129. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;292:2388. 130. Tough EA, White AR, Cummings TM, et al. Acupuncture and dry needling in the management of myofascial trigger point pain: a systematic review and meta-analysis of randomised controlled trials. Eur J Pain 2009;13:3–10. 131. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007;147:478. 132.


Gynecology_Novak

Gynecology_Novak. 132. Keefe FJ, Rumble ME, Scipio CD, et al. Psychological aspects of persistent pain: current state of the science. J Pain 2004;5:195– 211. 133. Duleba AJ, Jubanyik KJ, Greenfield DA, et al. Changes in personality profile associated with laparoscopic surgery for chronic pelvic pain. J Am Assoc Gynecol Laparosc 1998;5:389–395. 133a. Beck AT. Depression: Causes and Treatment. Philadelphia: University of Pennsylvania Press. 2006;ISBN0-8122-1032-8. 134. Masheb RM, Kerns RD, Lozano C, et al. A randomized clinical trial for women with vulvodynia: cognitive-behavioral therapy vs. supportive psychotherapy. Pain 2009;141:31–40. 135. Sullivan M, Thorn B, Haythornthwaite J, et al. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain 2001;17:5–64. 136. Albert H. Psychosomatic group treatment helps women with chronic pelvic pain. J Psychosom Obstet Gynecol 1999;20:216–225. 137.


Gynecology_Novak

Gynecology_Novak. 136. Albert H. Psychosomatic group treatment helps women with chronic pelvic pain. J Psychosom Obstet Gynecol 1999;20:216–225. 137. Rapkin AJ, Kames LD. The pain management approach to chronic pelvic pain. J Reprod Med 1987;32:323–327. 138. Peters AAW, van Dorst E, Jellis B, et al. A randomized clinical trial to compare two different approaches in women with chronic pelvic pain. Obstet Gynecol 1991;77:740. 139. Sator-Katzenschlager SM, Scharbert G, Kress HG, et al. Chronic pelvic pain treated with gabapentin and amitriptyline: a randomized controlled pilot study. Wien Klin Wochenschr 2005;117:761–768. 140. Rapkin AJ, Hartshorn TG, Partownavid P. Pain management. Clin Update Womens Health Care 2011; in press. 141. Tu FF, Holt J, Gonzales J, et al. Physical therapy evaluation of patients with chronic pelvic pain: a controlled study. Am J Obstet Gynecol 2008;198:272.e1–7. 142.


Gynecology_Novak

Gynecology_Novak. 141. Tu FF, Holt J, Gonzales J, et al. Physical therapy evaluation of patients with chronic pelvic pain: a controlled study. Am J Obstet Gynecol 2008;198:272.e1–7. 142. Elcombe S, Gath D, Day A. The psychological effects of laparoscopy on women with chronic pelvic pain. Psychol Med 1997; 27:1041–1050. 143. Daniels J, Gray R, Hills RK, et al. LUNA Trial Collaboration. Laparoscopic uterosacral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial. JAMA 2009;302:955–961. 144. Swank DJ, Jeekel H. Laparoscopic adhesiolysis in patients with chronic abdominal pain. Curr Opin Obstet Gynecol 2004;16:313– 318. 145. Reiter RC, Gambone JC, et al. Availability of a multidisciplinary pelvic pain clinic and frequency of hysterectomy for pelvic pain. J Psychosom Obstet Gynecol 1991;12[Suppl]:109. 146. Reiter RC, Lench JB, Gambone JC. Clinical commentary: consumer advocacy, elective surgery, and the “golden era of machine.” Obstet Gynecol 1989;74:815–817. 147.


Gynecology_Novak

Gynecology_Novak. 146. Reiter RC, Lench JB, Gambone JC. Clinical commentary: consumer advocacy, elective surgery, and the “golden era of machine.” Obstet Gynecol 1989;74:815–817. 147. Stovall TG, Ling FW, Crawford DA. Hysterectomy for chronic pelvic pain of presumed uterine etiology. Obstet Gynecol 1990;75:676–679. 148. Hillis SD, Marchbanks PA, Peterson HB. The effectiveness of hysterectomy for chronic pelvic pain. Obset Gynecol 1995;86:941–945. 149. Carlson KJ, Miller BA, Fowler FJ Jr. The Maine Women’s Health Study: I. Outcomes of hysterectomy. Obstet Gynecol 1994;83:556– 565. 150. ACOG Criteria Set. Hysterectomy, abdominal or vaginal for chronic pelvic pain. Number 29, November 1997. Committee on Quality Assessment. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1998;60:316–317. 151. El-Toukhy TA, Hefni M, Davies A, et al. The effect of different types of hysterectomy on urinary and sexual functions: a prospective study. J Obstet Gynaecol 2004;24:420–425.


Gynecology_Novak

Gynecology_Novak. 151. El-Toukhy TA, Hefni M, Davies A, et al. The effect of different types of hysterectomy on urinary and sexual functions: a prospective study. J Obstet Gynaecol 2004;24:420–425. Thomas M. D’Hooghe Endometriosis is diagnosed by visual inspection of the pelvis during laparoscopy, ideally with histological confirmation; positive histology confirms the diagnosis, but negative histology does not exclude it. Endometriosis can be associated with subfertility, pelvic pain, i.e., dysmenorrhea, dyspareunia and nonmenstrual pain, and reduced quality of life. Severe or deeply infiltrating endometriosis should be managed in a facility with the necessary expertise to provide treatment in a multidisciplinary context, including advanced laparoscopic surgery and laparotomy. Classification systems for endometriosis are subjective and correlate poorly with pain symptoms, but have some value in determining the prognosis and management of infertility.


Gynecology_Novak

Gynecology_Novak. Classification systems for endometriosis are subjective and correlate poorly with pain symptoms, but have some value in determining the prognosis and management of infertility. Suppression of ovarian function for 6 months reduces pain associated with endometriosis. Hormonal drugs are equally effective in reducing pain but have differing side effects and cost. Ablation of endometriotic lesions with laparoscopic uterine nerve ablation (LUNA) in minimal to moderate disease reduces pain associated with endometriosis; however, because LUNA used alone has no effect on dysmenorrhea associated with endometriosis, there is no evidence that LUNA is a necessary component of treatment. Ablation of endometriotic lesions plus adhesiolysis in minimal to mild endometriosis is more effective than diagnostic laparoscopy alone in improving fertility. Suppression of ovarian function is not effective in improving subsequent fertility in patients with endometriosis.


Gynecology_Novak

Gynecology_Novak. Suppression of ovarian function is not effective in improving subsequent fertility in patients with endometriosis. Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterus. The most frequent sites of implantation are the pelvic viscera and the peritoneum. Endometriosis varies in appearance from a few minimal lesions on otherwise intact pelvic organs, to massive ovarian endometriotic cysts that distort tubo-ovarian anatomy and extensive adhesions involving bowel, bladder, and ureter. It is estimated to occur in 10% of reproductive-age women and is associated with pelvic pain and infertility. Considerable progress in understanding the pathogenesis, spontaneous evolution, diagnosis, and treatment of endometriosis has occurred. The European Society for Human Reproduction and Embryology (ESHRE) guidelines for the clinical management of endometriosis are published and regularly updated to present emerging clinical evidence (1).


Gynecology_Novak

Gynecology_Novak. Prevalence Endometriosis is found predominantly in women of reproductive age but is reported in adolescents and in postmenopausal women receiving hormonal replacement (2). It is found in women of all ethnic and social groups. Estimates of the frequency of endometriosis vary widely, but the prevalence of the condition is assumed to be around 10% (3,4). Although no consistent information is available on the incidence of the disease, temporal trends suggest an increase among women of reproductive age (4).


Gynecology_Novak

Gynecology_Novak. In women with pelvic pain or infertility, a high prevalence of endometriosis (from a low of 20% to a high of 90%) is reported (5,6). In women with unexplained subfertility with or without pain (regular cycle, partner with normal sperm), the prevalence of endometriosis is reported to be as high as 50% (7). In asymptomatic women undergoing tubal ligation (women of proven fertility), the prevalence of endometriosis ranges from 3% to 43% (8–13). This variation in the reported prevalence may be explained by several factors. First, it may vary with the diagnostic method used: laparoscopy, the operation of choice for diagnosis, is a better method than laparotomy for diagnosing minimal to mild endometriosis. Second, minimal or mild endometriosis may be more thoroughly evaluated in a symptomatic patient given general anesthesia than in an asymptomatic patient during tubal sterilization. Third, the interest and experience of the surgeon is important because there is a wide variation in the


Gynecology_Novak

Gynecology_Novak. patient given general anesthesia than in an asymptomatic patient during tubal sterilization. Third, the interest and experience of the surgeon is important because there is a wide variation in the appearance of subtle endometriosis implants, cysts, and adhesions. Most studies that evaluate the prevalence of endometriosis in women of reproductive age lack histologic confirmation (8–10,14–19).


Gynecology_Novak

Gynecology_Novak. The following are identified risk factors for endometriosis: infertility, red hair, early age at menarche, shorter menstrual cycle length, hypermenorrhea, nulliparity, m¨ullerian anomalies, birth weight (less than 7 pounds), one of multiple fetal gestation, diethylstilbestrol (DES) exposure, endometriosis in first-degree relative, tall height, dioxin or polychlorinated biphenyls (PCB) exposure, a diet high in fat and red meat, and prior surgeries or medical therapy for endometriosis (20). Prior use of contraception or intrauterine device (IUD), or smoking is not associated with increased risk of endometriosis (21,22). Protective factors against the development of endometriosis include multiparity, lactation, tobacco exposure in utero, increased body mass index, increased waist-to-hip ratios and exercise, and diet high in vegetables and fruits (20). Some evidence suggests that women with a “pinpoint cervix” have an increased risk for endometriosis, but more studies are needed to


Gynecology_Novak

Gynecology_Novak. ratios and exercise, and diet high in vegetables and fruits (20). Some evidence suggests that women with a “pinpoint cervix” have an increased risk for endometriosis, but more studies are needed to confirm this observation (23).


Gynecology_Novak

Gynecology_Novak. Several publications link endometriosis with an increased risk for certain gynecologic and nongynecologic cancers (24,25). These associations are controversial and no data exist to inform clinicians regarding the best management of patients who might be at risk of developing such cancers (1). Endometriosis should not be considered a medical condition associated with a clinically relevant risk of any specific cancer (26). Data from large cohort and case-control studies indicate an increased risk of ovarian cancers in women with endometriosis. The observed effect sizes are modest, varying between 1.3 and 1.9 (27). Evidence from clinical series consistently demonstrates that the association is confined to the endometrioid and clear-cell histologic types of ovarian cancer (28). A causal relationship between endometriosis and these specific histotypes of ovarian cancer should be recognized, but the low magnitude of the risk observed is consistent with the view that ectopic endometrium


Gynecology_Novak

Gynecology_Novak. between endometriosis and these specific histotypes of ovarian cancer should be recognized, but the low magnitude of the risk observed is consistent with the view that ectopic endometrium undergoes malignant transformation with a frequency similar to its eutopic counterpart (29). Evidence for an association with melanoma and non-Hodgkin’s lymphoma is increasing but needs to be verified, whereas an increased risk for other gynecologic cancer types is not supported (28).


Gynecology_Novak

Gynecology_Novak. Although signs and symptoms of endometriosis were described since the 1800s, its widespread occurrence was acknowledged only during the 20th century. Endometriosis is an estrogen-dependent disease. Three theories were proposed to explain the histogenesis of endometriosis: 1. Ectopic transplantation of endometrial tissue 2. 3. The induction theory No single theory can account for the location of endometriosis in all cases.


Gynecology_Novak

Gynecology_Novak. Transplantation Theory The transplantation theory, originally proposed by Sampson in the mid-1920s, is based on the assumption that endometriosis is caused by the seeding or implantation of endometrial cells by transtubal regurgitation during menstruation (30). Substantial clinical and experimental data support this hypothesis (5,31). Retrograde menstruation occurs in 70% to 90% of women, and it may be more common in women with endometriosis than in those without the disease (8,32). The presence of endometrial cells in the peritoneal ﬂuid, indicating retrograde menstruation, is reported in 59% to 79% of women during menses or in the early follicular phase, and these cells can be cultured in vitro (33,34). The presence of endometrial cells in the dialysate of women undergoing peritoneal dialysis during menses supports the theory of retrograde menstruation (35). Endometriosis is most often found in dependent portions of the pelvis—the ovaries, the anterior and posterior cul-de-sac, the


Gynecology_Novak

Gynecology_Novak. during menses supports the theory of retrograde menstruation (35). Endometriosis is most often found in dependent portions of the pelvis—the ovaries, the anterior and posterior cul-de-sac, the uterosacral ligaments, the posterior uterus, and the posterior broad ligaments (36). The menstrual reﬂux theory combined with the clockwise peritoneal ﬂuid current explains why endometriosis is predominantly located on the left side of the pelvis (reﬂuxed endometrial cells implant more easily in the rectosigmoidal area) and why diaphragmatic endometriosis is found more frequently on the right side (reﬂuxed endometrial cells implant there by the falciform ligament) (37,38).


Gynecology_Novak

Gynecology_Novak. Endometrium obtained during menses can grow when injected beneath abdominal skin or into the pelvic cavity of animals (39,40). Endometriosis was found in 50% of Rhesus monkeys after surgical transposition of the cervix to allow intra-abdominal menstruation (41). Increased retrograde menstruation by obstruction of the outﬂow of menstrual ﬂuid from the uterus is associated with a higher incidence of endometriosis in women and in baboons (42–44). Women with shorter intervals between menstruation and longer duration of menses are more likely to have retrograde menstruation and are at higher risk for endometriosis (45). Menstruation is associated with intraperitoneal inﬂammation in both women and baboons, but a limited quantity of endometrial cells can be identified in peritoneal ﬂuid during menstruation in women, possibly because endometrial–peritoneal attachment is reported to occur within 24 hours (46–48). Ovarian endometriosis may be caused by either retrograde menstruation or by


Gynecology_Novak

Gynecology_Novak. menstruation in women, possibly because endometrial–peritoneal attachment is reported to occur within 24 hours (46–48). Ovarian endometriosis may be caused by either retrograde menstruation or by lymphatic ﬂow from the uterus to the ovary; metaplasia and bleeding from a corpus luteum may be a critical event in the development of some endometriomas (49–51).


Gynecology_Novak

Gynecology_Novak. Deeply infiltrative endometriosis, with a depth of at least 5 mm beneath the peritoneum, can present as nodules in the cul-de-sac, rectosigmoid, and bladder area and occurs with other forms of peritoneal or ovarian endometriosis (52). According to anatomic, surgical, and pathologic findings, deep endometriotic lesions originate intraperitoneally rather than extraperitoneally. The lateral asymmetry in the occurrence of ureteral endometriosis is compatible with the menstrual reﬂux theory and with the anatomic differences of the left and right hemipelvis (37). Adolescents and young women can have peritoneal disease (53). This observation, together with evidence from the development and spontaneous evolution of endometriosis in baboons, supports the notion that endometriosis starts as peritoneal disease and that the three different phenotypes and locations of endometriosis (peritoneal, ovarian, and deep) represent a homogenous disease continuum with a single origin (i.e., regurgitated


Gynecology_Novak

Gynecology_Novak. disease and that the three different phenotypes and locations of endometriosis (peritoneal, ovarian, and deep) represent a homogenous disease continuum with a single origin (i.e., regurgitated endometrium), rather than three different disease entities, as advocated by some investigators (37,54,55).


Gynecology_Novak

Gynecology_Novak. Extrapelvic endometriosis, although rare (1% to 2%), may result from vascular or lymphatic dissemination of endometrial cells to many gynecologic (vulva, vagina, cervix) and nongynecologic sites. The latter include bowel (appendix, rectum, sigmoid colon, small intestine, hernia sacs), lungs and pleural cavity, skin (episiotomy or other surgical scars, inguinal region, extremities, umbilicus), lymph glands, nerves, and brain (56).


Gynecology_Novak

Gynecology_Novak. Coelomic Metaplasia The transformation (metaplasia) of coelomic epithelium into endometrial tissue is a proposed mechanism for the origin of endometriosis. One study evaluating structural and cell surface antigen expression in the rete ovarii and epoophoron reported little commonality between endometriosis and ovarian surface epithelium, suggesting that serosal metaplasia is unlikely in the ovary (57). The results of another study involving the genetic induction of endometriosis in mice suggest that ovarian endometriotic lesions may arise directly from the ovarian surface epithelium through a metaplastic differentiation process induced by activation of an oncogenic K-ras allele (50).


Gynecology_Novak

Gynecology_Novak. Induction Theory The induction theory is an extension of the coelomic metaplasia theory. It proposes that an endogenous (undefined) biochemical factor can induce undifferentiated peritoneal cells to develop into endometrial tissue. This theory is supported by experiments in rabbits but is not substantiated in women or nonhuman primates (58,59).


Gynecology_Novak

Gynecology_Novak. Genetic Factors Increasing evidence suggests that endometriosis is partially a genetic disease. Recent findings that support this association include evidence of familial clustering in humans and in Rhesus monkeys, a founder effect detected in the Icelandic population, concordance in monozygotic twins, a similar age at onset of symptoms in affected nontwin sisters, a six-to nine-times increased prevalence of endometriosis among first-degree relatives of women compared with the general population, and a 15% prevalence of magnetic resonance imaging (MRI) findings suggestive of endometriosis in the first-degree relatives of women with stage III or IV disease based on the classification of the American Society of Reproductive Medicine (60). The induction of humanlike endometriosis by genetic activation of an oncogenic K-ras allele lends further support to the genetic basis of this disorder (50).


Gynecology_Novak

Gynecology_Novak. Population Studies The risk of endometriosis is seven times greater if a first-degree relative is affected by endometriosis (61). Because no specific Mendelian inheritance pattern is identified, multi-factorial inheritance is postulated. A relative risk for endometriosis of 7.2 was found in mothers and sisters, and a 75% (six in eight) incidence was noted in homozygotic twins of patients with endometriosis (62). In another study of twins, 51% of the variance of the latent liability to endometriosis may be attributable to additive genetic inﬂuences (63). Other investigators reported that 14 monozygotic twin pairs were concordant for endometriosis, and two pairs were discordant (64). Of these twin pairs, nine had moderate to severe endometriosis. A relationship was shown between endometriosis and systematic lupus erythematosus, dysplastic nevi, and a history of melanoma in women of reproductive age (65,66). Endometriosis is linked to the presence of individual human leukocyte antigens


Gynecology_Novak

Gynecology_Novak. and systematic lupus erythematosus, dysplastic nevi, and a history of melanoma in women of reproductive age (65,66). Endometriosis is linked to the presence of individual human leukocyte antigens (67–69). Genome-wide association studies show that the risk of endometriosis is associated with a mutation on the short arm of chromosome 7 (7p15.2) in women of European ancestry and that this association is the strongest for moderate to severe disease (70).


Gynecology_Novak

Gynecology_Novak. A number of studies investigated genetic polymorphisms as a possible factor contributing to the development of endometriosis. About 50% of the studies in one review demonstrated positive correlations between different polymorphisms and endometriosis (71). This relation was seen most clearly in groups 1 (cytokines and inﬂammation), 2 (steroid-synthesizing enzymes and detoxifying enzymes and receptors), 4 (estradiol metabolism), 5 (other enzymes and metabolic systems), and 7 (adhesion molecules and matrix enzymes). Group 8 (apoptosis, cell-cycle regulation, and oncogenes) seemed to be negatively correlated with the disease, whereas groups 3 (hormone receptors), 6 (growth factor systems), and especially 9 (human leukocyte antigen system components) showed a relatively strong correlation. As many results were contradictory, the review concluded that genetic polymorphisms might have a limited value in assessing possible development of endometriosis (71). Future studies should include large


Gynecology_Novak

Gynecology_Novak. results were contradictory, the review concluded that genetic polymorphisms might have a limited value in assessing possible development of endometriosis (71). Future studies should include large numbers of women with laparoscopically and histologically confirmed endometriosis and women with a laparoscopically confirmed normal pelvis as controls, taking into account ethnic variability.


Gynecology_Novak

Gynecology_Novak. Aneuploidy Epithelial cells of endometriotic cysts are monoclonal on the basis of phosphoglycerate kinase gene methylation, and normal endometrial glands are monoclonal (72,73). In a comparison of endometriotic tissue with eutopic endometrium, ﬂow cytometric DNA analysis failed to show aneuploidy (74). Studies using comparative genomic hybridization, or multicolor in situ hybridization, showed aneuploidy for chromosomes 11, 16, and 17, increased heterogeneity of chromosome 17 aneuploidy, and losses of 1p and 22q (50%), 5p (33%), 6q (27%), 70 (22%), 9q (22%), and 16 (22%) of 18 selected endometriotic tissues (75–77). In another study, trisomies 1 and 7, and monosomies 9 and 17 were found in endometriosis, ovarian endometrioid adenocarcinoma, and normal endometrium (78). The proportions of aneusomic cells were significantly higher in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (p <0.001), suggesting a role of the ovarian stromal milieu in the


Gynecology_Novak

Gynecology_Novak. aneusomic cells were significantly higher in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (p <0.001), suggesting a role of the ovarian stromal milieu in the induction of genetic changes, which may lead to invasive cancer in isolated cases (78).


Gynecology_Novak

Gynecology_Novak. Microsatellite DNA assays reveal an allelic imbalance (loss of heterozygosity) in p16 (Ink4), GALT, p53, and APOA2 loci in patients with endometriosis and in stage II of endometriosis (79). Another report found a loss of heterozygosity in 28% of endometriotic lesions at one or more sites: chromosomes 9p (18%), 11q (18%), and 22q (15%) (73).


Gynecology_Novak

Gynecology_Novak. Although retrograde menstruation appears to be a common event in women, not all women who have retrograde menstruation develop endometriosis. The immune system may be altered in women with endometriosis, and it is hypothesized that the disease may develop as a result of reduced immunologic clearance of viable endometrial cells from the pelvic cavity (80,81). Endometriosis can be caused by decreased clearance of peritoneal ﬂuid endometrial cells resulting from reduced natural killer (NK) cell activity or decreased macrophage activity (82). Decreased cell-mediated cytotoxicity toward autologous endometrial cells is associated with endometriosis (82–86). These studies used techniques that have considerable variability in target cells and methods (87,88). Whether NK cell activity is lower in patients with endometriosis than in those without endometriosis is controversial. Some reports demonstrate reduced NK activity and others found no increase in NK activity in women with moderate to


Gynecology_Novak

Gynecology_Novak. in patients with endometriosis than in those without endometriosis is controversial. Some reports demonstrate reduced NK activity and others found no increase in NK activity in women with moderate to severe disease (84– 86,89–94). There is great variability in NK cell activity among normal individuals that may be related to variables such as smoking, drug use, and exercise (87).


Gynecology_Novak

Gynecology_Novak. In contrast, endometriosis can be considered a condition of immunologic tolerance, as opposed to ectopic endometrium, which essentially is self-tissue (80). It can be questioned why viable endometrial cells in the peritoneal ﬂuid would be a target for NK cells or macrophages. Auto-transplantation of blood vessels, muscles, skin grafts, and other tissues is extremely successful (83–85). There is no in vitro evidence that peritoneal ﬂuid macrophages actually attack and perform phagocytosis of viable peritoneal ﬂuid endometrial cells. High-dose immunosuppression can increase slightly the progression of spontaneous endometriosis in baboons (95). There is no clinical evidence that the prevalence of endometriosis is increased in immunosuppressed patients. The fact that women with kidney transplants, who undergo chronic immunosuppression, are not known to have increased infertility problems can be considered indirect evidence that these patients do not develop extensive endometriosis.


Gynecology_Novak

Gynecology_Novak. Substantial evidence suggests that endometriosis is associated with a state of subclinical peritoneal inﬂammation, marked by an increased peritoneal ﬂuid volume, increased peritoneal ﬂuid white blood cell concentration (especially macrophages with increased activation status), and increased inﬂammatory cytokines, growth factors, and angiogenesispromoting substances. It is reported in baboons that subclinical peritoneal inﬂammation occurs during menstruation and after intrapelvic injection of endometrium (93). A higher basal activation status of peritoneal macrophages in women with endometriosis may impair fertility by reducing sperm motility, increasing sperm phagocytosis, or interfering with fertilization, possibly by increased secretion of cytokines such as tumor necrosis factor-α (TNF-α) (96–100). Tumor necrosis factor may facilitate the pelvic implantation of ectopic endometrium (99,100). The adherence of human endometrial stromal cells to mesothelial cells in vitro is increased


Gynecology_Novak

Gynecology_Novak. (96–100). Tumor necrosis factor may facilitate the pelvic implantation of ectopic endometrium (99,100). The adherence of human endometrial stromal cells to mesothelial cells in vitro is increased by the pretreatment of mesothelial cells with physiologic doses of TNF-α (101). Macrophages or other cells may promote the growth of endometrial cells by secretion of growth and angiogenetic factors such as epidermal growth factor (EGF), macrophage-derived growth factor (MDGF), fibronectin, and adhesion molecules such as integrins (101–107). After attachment of endometrial cells to the peritoneum, subsequent invasion and growth appear to be regulated by matrix metalloproteinases (MMP) and their tissue inhibitors (108,109).


Gynecology_Novak

Gynecology_Novak. There is increasing evidence that local inﬂammation and secretion of prostaglandins (PG) is related to differences in endometrial aromatase activity between women with and without endometriosis. Expression of aromatase cytochrome P450 protein and mRNA is present in human endometriotic implants but not in normal endometrium, suggesting that ectopic endometrium produces estrogens, which may be involved in the tissue growth interacting with the estrogen receptor (110). Inactivation of 17β-estradiol is impaired in endometriotic tissues because of deficient expression of 17β-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrium in response to progesterone (111). The inappropriate aromatase expression in endometriosis lesions can be stimulated by prostaglandin E2 (PGE2). This reaction leads to local production of E2, which stimulates PGE2 production, resulting in a positive-feedback system between local inﬂammation and estrogen-driven local growth of


Gynecology_Novak

Gynecology_Novak. E2 (PGE2). This reaction leads to local production of E2, which stimulates PGE2 production, resulting in a positive-feedback system between local inﬂammation and estrogen-driven local growth of ectopic endometrium (112).


Gynecology_Novak

Gynecology_Novak. The subclinical pelvic inﬂammatory status associated with endometriosis is reﬂected in the systemic circulation. Increased concentrations of C-reactive protein, serum amyloid A (SAA), TNF-α, membrane cofactor protein-1, interleukin-6 (IL-6), IL-8, and chemokine (C-C motif) receptor 1 (CCR1) are observed in peripheral blood samples of patients with endometriosis when compared with controls (113). This observation offers a basis for the development of noninvasive diagnostic tests. Both hypothesis-driven research and system biology approaches using mRNA microarray and proteomic techniques studies show that eutopic endometrium is biologically different in women with endometriosis when compared to controls with respect to proliferation, apoptosis, angiogenesis, and inﬂammatory pathways (114–117). Several studies show a higher prevalence of nerve fibers and neurotrophic factors in the eutopic endometrium from women with endometriosis when compared to controls (46,118).


Gynecology_Novak

Gynecology_Novak. study, monkeys exposed over 12 months to low-dose dioxin (0.71 ng/kg/day) had endometriosis implants with smaller maximal and minimal diameters and similar survival rate when compared with endometriotic lesions in unexposed controls, suggesting no effect of dioxin on endometriosis (127). After 12 months of exposure to high-dose dioxin (17.86 ng/kg/day), larger diameters and a higher survival rate of endometriosis implants were observed in exposed Rhesus monkeys compared with unexposed controls. The second randomized study performed in 80 Rhesus monkeys compared those with no treatment with those treated with 0, 5, 20, 40, and 80 μgof Aroclor (1,254 kg per day) for 6 years. Endometriosis occurred in 37% of controls and in 25% of treated monkeys as determined by laparoscopy and necropsy data (128). No association was observed between endometriosis severity and PCB exposure. These data question the importance of dioxin exposure, except at high doses, in the development of endometriosis


Gynecology_Novak

Gynecology_Novak. (128). No association was observed between endometriosis severity and PCB exposure. These data question the importance of dioxin exposure, except at high doses, in the development of endometriosis in primates.


Gynecology_Novak

Gynecology_Novak. Rodents Continuous exposure to 2,3,7,8-tetrachlorodibenzo-P-dioxin inhibited the growth of surgically induced endometriosis in ovariectomized mice treated with high-dose estradiol. No correlation was observed between the dose of dioxin and survival of endometrial implants, adhesions, and serum E2 levels (129). In ovariectomized mice induced with endometriosis, similar stimulating effects of estrone and 4-chlorodiphenyl ether (4-CDE) were observed on survival rates of endometriotic mice, suggesting an estrogen-like effect of 4-CDE (130). Potential mechanisms mediating dioxin action to promote endometriosis in rodents are complex and probably different in rats and mice, and furthermore in women. The mouse appears to be a better model to elucidate these mechanisms, but both models have important limitations (131,132).


Gynecology_Novak

Gynecology_Novak. Stem Cells Endometrial stem cells are identified, are bone marrow derived, can differentiate into neurogenic or pancreatic-β cells, may contribute to the development of endometriosis in a murine model, and their potential role in the pathogenesis of endometriosis needs to be investigated (133–136).


Gynecology_Novak

Gynecology_Novak. Future Research The study of endometriosis is compounded by the need to determine the presence or absence of pathology. The pathogenesis of endometriosis, the pathophysiology of related infertility, and the spontaneous evolution of endometriosis are being studied. At the time of diagnosis, most patients with endometriosis had the disease for an unknown period, making it difficult to initiate clinical experiments that would determine the etiology or progression of the disease (31). Because endometriosis occurs naturally only in women and nonhuman primates, and invasive experiments cannot be performed easily, it is difficult to undertake properly controlled studies. There is a need for the development of a good animal model with spontaneous endometriosis. The main advantage of the rat and rabbit models used to study endometriosis is their low cost relative to primates, but the disadvantages are numerous (137–140). In both models, the type of lesion appears to be quite different from the


Gynecology_Novak

Gynecology_Novak. models used to study endometriosis is their low cost relative to primates, but the disadvantages are numerous (137–140). In both models, the type of lesion appears to be quite different from the variety of pigmented and nonpigmented lesions observed in women (137–139). Primates are phylogenetically close to humans, have a comparable menstrual cycle, are afﬂicted with spontaneous endometriosis, and when induced with endometriosis, develop macroscopic lesions that are similar to those found in human disease (41,141–145). Spontaneous endometriosis in the baboon is minimal and disseminated, similar to the different stages of endometriosis in women (141,146–148).


Gynecology_Novak

Gynecology_Novak. Immunomodulatory drugs inhibiting pelvic inﬂammation associated with endometriosis may offer new approaches to medical treatment and can be studied in these models (149–153). In a consensus workshop following the 10th World Congress on Endometriosis in 2008, it was agreed that multidisciplinary expertise is required to advance our understanding of this disease, and 25 recommendations for research were developed (154). Clinical Presentation Endometriosis should be suspected in women with subfertility, dysmenorrhea, dyspareunia, or chronic pelvic pain, although these symptoms can be associated with other diseases. Endometriosis may be asymptomatic, even in women with more advanced disease, (i.e., ovarian endometriosis or deeply invasive rectovaginal endometriosis).


Gynecology_Novak

Gynecology_Novak. Endometriosis may be asymptomatic, even in women with more advanced disease, (i.e., ovarian endometriosis or deeply invasive rectovaginal endometriosis). Risk factors for endometriosis include short cycle length, heavier menstruation, and longer ﬂow duration, probably related to a higher incidence of retrograde menstruation (45,155,156). Patient height and weight are positively and negatively, respectively, associated with the risk of endometriosis (157). Endometriosis can be associated with significant gastrointestinal symptoms (pain, nausea, vomiting, early satiety, bloating and distention, altered bowel habits). A characteristic motility change (ampulla of Vater–duodenal spasm, a seizure equivalent of the enteric nervous system, along with bacterial overgrowth), is documented in most women with the disease (158). Women of reproductive age with endometriosis are not osteopenic (159).


Gynecology_Novak

Gynecology_Novak. The average delay between onset of pain symptoms and surgically confirmed endometriosis is quite long: 8 years or longer in the United Kingdom and 9 to 12 years in the United States (160). Similar durations were observed in Scandinavia and in Brazil (161,162). A delay in diagnosis of endometriosis of 6 and 3 years in women with pain and women with infertility, respectively, was reported. Over the past two decades, there was a steady decrease in the delay in diagnosis and a decline in the prevalence of advanced endometriosis at first diagnosis (163). Patient awareness of endometriosis was increased. Many patients’ quality of life is affected by pain, emotional impact of subfertility, anger about disease recurrence, and uncertainty about the future regarding repeated surgeries or long-term medical therapy and its side effects (164).


Gynecology_Novak

Gynecology_Novak. Endometriosis should be perceived as a chronic disease, at least in a subset of highly symptomatic women, and quality-of-life issues should be evaluated using reliable and valid questionnaires (165). Pain In adult women, dysmenorrhea may be especially suggestive of endometriosis if it begins after years of pain-free menses. Dysmenorrhea often starts before the onset of menstrual bleeding and continues throughout the menstrual period. In adolescents, the pain may be present after menarche without an interval of pain-free menses. Evidence suggests that absenteeism from school and both the incidence and duration of oral contraceptive use for severe primary dysmenorrhea during adolescence is higher in women who later develop deeply infiltrative endometriosis than in women without deeply infiltrative endometriosis (166).


Gynecology_Novak

Gynecology_Novak. The distribution of pain is variable but most often is bilateral. Local symptoms can arise from rectal, ureteral, and bladder involvement, and lower back pain can occur. Some women with extensive disease have no pain, whereas others with only minimal to mild disease may experience severe pelvic pain. All endometriosis lesion types are associated with pelvic pain, including minimal to mild endometriosis (167). Endometriomas are not associated with dysmenorrheal severity, and dysmenorrhea is less frequent in women with only ovarian endometriomas compared with other locations (168,169). Endometriomas can be considered a marker for greater severity of deeply infiltrative lesions (170). Deeply infiltrative lesions are consistently associated with pelvic pain, gastrointestinal symptoms, and painful defecation (171). The role of adhesions in pain and endometriosis is poorly understood (172).


Gynecology_Novak

Gynecology_Novak. Many studies failed to detect a correlation between the degree of pelvic pain and the severity of endometriosis (11,169,173). Some studies reported a positive correlation between endometriosis stage and endometriosis-related dysmenorrhea or chronic pelvic pain (174,175). In one study, a significant but weak correlation was observed between endometriosis stage and severity of dysmenorrhea and nonmenstrual pain, whereas a strong association was found between posterior cul-de-sac lesions and dyspareunia (176).


Gynecology_Novak

Gynecology_Novak. Possible mechanisms causing pain in patients with endometriosis include local peritoneal inﬂammation, deep infiltration with tissue damage, adhesion formation, fibrotic thickening, and collection of shed menstrual blood in endometriotic implants, resulting in painful traction with the physiologic movement of tissues (177,178). The character of pelvic pain is related to the anatomic location of deeply infiltrating endometriotic lesions (171). Severe pelvic pain and dyspareunia may be associated with deep infiltrating subperitoneal endometriosis (6,177,179). In rectovaginal endometriotic nodules, a close histologic relationship was observed between nerves and endometriotic foci and between nerves and the fibrotic component of the nodule (180). Increasing evidence suggests a close relationship between the density of innervation of endometriotic lesions and pain symptoms (176).


Gynecology_Novak

Gynecology_Novak. Subfertility Many arguments support the hypothesis that there is a causal relationship between the presence of endometriosis and subfertility (181). The following factors have been reported: 1. Increased prevalence of endometriosis in subfertile women (33%) when compared to women of proven fertility (4%), a reduced monthly fecundity rate (MFR) in baboons with mild to severe (spontaneous or induced) endometriosis when compared to those with minimal endometriosis or a normal pelvis. 2. Trend toward a reduced monthly fecundity rate in infertile women with minimal to mild endometriosis when compared to women with unexplained infertility. 3. Endometriotic ovarian cysts that negatively affect the rate of spontaneous ovulation (182). 4. Dose–effect relationship: a negative correlation between the r-AFS stage of endometriosis and the monthly fecundity rate and cumulative pregnancy rate (181,183). 5.


Gynecology_Novak

Gynecology_Novak. 4. Dose–effect relationship: a negative correlation between the r-AFS stage of endometriosis and the monthly fecundity rate and cumulative pregnancy rate (181,183). 5. Reduced monthly fecundity rate and cumulative pregnancy rate after donor sperm insemination in women with minimal to mild endometriosis when compared to those with a normal pelvis. 6. Reduced monthly fecundity rate after husband sperm insemination in women with minimal to mild endometriosis when compared to those with a normal pelvis. 7. Reduced implantation rate per embryo after in vitro fertilization (IVF) in women with endometriosis when compared to women with tubal factor infertility (181,184). 8. Increased monthly fecundity rate and cumulative pregnancy rate after surgical removal of minimal to mild endometriosis.


Gynecology_Novak

Gynecology_Novak. 8. Increased monthly fecundity rate and cumulative pregnancy rate after surgical removal of minimal to mild endometriosis. When endometriosis is moderate or severe, involving the ovaries and causing adhesions that block tubo-ovarian motility and ovum pickup, it is associated with subfertility (182,185). This effect was shown in primates, including cynomolgus monkeys and baboons (144,186). Numerous mechanisms (ovulatory dysfunction, luteal insufficiency, luteinized unruptured follicle syndrome, recurrent abortion, altered immunity, and intraperitoneal inﬂammation) are proposed as explanations, but an association between fertility and minimal or mild endometriosis remains controversial (187).


Gynecology_Novak

Gynecology_Novak. Spontaneous Abortion A possible association between endometriosis and spontaneous abortion was suggested in uncontrolled or retrospective studies. Some controlled studies evaluating the association between endometriosis and spontaneous abortion have important methodologic shortcomings: heterogeneity between cases and controls, analysis of the abortion rate before the diagnosis of endometriosis, and selection bias of study and control groups (80,188,189). Based on controlled prospective studies, there is no evidence that endometriosis is associated with (recurrent) pregnancy loss or that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate (190–192). Some data suggest that miscarriage rates may be increased after treatment with assisted reproductive technology (193).


Gynecology_Novak

Gynecology_Novak. Endometriosis is associated with anovulation, abnormal follicular development with impaired follicle growth, reduced circulating E2 levels during the preovulatory phase, disturbed luteinizing hormone (LH) surge patterns, premenstrual spotting, luteinized unruptured follicle syndrome, and galactorrhea and hyperprolactinemia (194). Increased incidence and recurrence of the luteinized unruptured follicle syndrome is reported in baboons with mild endometriosis, but not in primates with minimal endometriosis or a normal pelvis (195). Luteal insufficiency with reduced circulating E2 and progesterone levels, out-of-phase endometrial biopsies, and aberrant integrin expression was reported in the endometrium of women with endometriosis by some researchers, but these findings were not confirmed by other investigators (194,196,197). No convincing data exist to conclude that the incidence of these endocrine abnormalities is increased in women who have endometriosis.


Gynecology_Novak

Gynecology_Novak. Extrapelvic Endometriosis Extrapelvic endometriosis, although often asymptomatic, should be suspected when symptoms of pain or a palpable mass occur outside the pelvis in a cyclic pattern. Endometriosis involving the intestinal tract (especially colon and rectum) is the most common site of extrapelvic disease and may cause abdominal and back pain, abdominal distention, cyclic rectal bleeding, constipation, and obstruction. Ureteral involvement can lead to obstruction and result in cyclic pain, dysuria, and hematuria. Pulmonary endometriosis can manifest as pneumothorax, hemothorax, or hemoptysis during menses. Umbilical endometriosis should be suspected when a patient has a palpable mass and cyclic pain in the umbilical area (56).


Gynecology_Novak

Gynecology_Novak. Treatment of extragenital endometriosis will depend on the site. If complete excision is possible, this is the treatment of choice; when this is not possible, long-term medical treatment is necessary using the same principles of medical treatment for pelvic endometriosis (1). Appendicular endometriosis is usually treated by appendectomy. Surgical treatment of bladder endometriosis is usually in the form of excision of the lesion and primary closure of the bladder wall. Ureteral lesions may be excised after stenting the ureter; in the presence of intrinsic lesions or significant obstruction, segmental excision with end-to-end anastomosis or reimplantation may be necessary. Abdominal wall and perineal endometriosis is usually treated by complete excision of the nodule (1).


Gynecology_Novak

Gynecology_Novak. Clinical Examination In many women with endometriosis, no abnormality is detected during the clinical examination. However, the vulva, vagina, and cervix should be inspected for any signs of endometriosis, although the occurrence of endometriosis in these areas is rare (e.g., episiotomy scar). The presence of a narrow pinpoint cervical ostium can be a risk factor for endometriosis (23). Other signs of possible endometriosis include uterosacral or cul-desac nodularity, lateral or cervical displacement caused by uterosacral scarring, painful swelling of the rectovaginal septum, and unilateral ovarian cystic enlargement (198). In more advanced disease, the uterus is often in fixed retroversion, and the mobility of the ovaries and fallopian tubes is reduced. Evidence of deeply infiltrative endometriosis (deeper than 5 mm under the peritoneum) in the rectovaginal septum with cul-de-sac obliteration or cystic ovarian endometriosis should be suspected when there is clinical documentation of


Gynecology_Novak

Gynecology_Novak. (deeper than 5 mm under the peritoneum) in the rectovaginal septum with cul-de-sac obliteration or cystic ovarian endometriosis should be suspected when there is clinical documentation of uterosacral nodularities during menses, especially if CA125 serum levels are higher than 35 IU/mL (199–201). In these cases, black-blue colored lesions can sometimes be observed in the vagina during speculum examination.


Gynecology_Novak

Gynecology_Novak. The clinical examination may have false-negative results. The diagnosis of endometriosis should be confirmed by visual inspection during laparoscopy and by histological confirmation of endometriosis in biopsied lesions.


Gynecology_Novak

Gynecology_Novak. Ultrasound Peritoneal endometriosis cannot be reliably visualized by imaging techniques. Compared to laparoscopy, transvaginal ultrasound has no value in diagnosing peritoneal endometriosis, but it is useful in making or excluding the diagnosis of an ovarian endometrioma (1,202). Either transvaginal or transrectal ultrasonography can be used with high sensitivity and specificity for the diagnosis of ovarian endometrioma (202–204). The typical ultrasound features of an endometriotic ovarian cyst in premenopausal women were described as “ground glass echogenicity of the cyst ﬂuid, one to four locules and no solid parts” (205). Transvaginal ultrasound may have a role in the diagnosis of endometriosis nodules with a diameter of 1 cm involving the bladder or rectum, but this is dependent on the interest and experience of the ultrasonographer and the quality and resolution of the ultrasound equipment.


Gynecology_Novak

Gynecology_Novak. Local guidelines for the management of suspected ovarian malignancy should be followed in cases of ovarian endometrioma (1). Ultrasound scanning with or without serum CA125 testing is usually used to try to identify rare instances of ovarian cancer; however, CA125 levels are frequently elevated in the presence of endometriomas, so this approach is often not useful (1). Other Imaging Other imaging techniques, including computed tomography (CT) and MRI, can be used to provide additional and confirmatory information, but they cannot be used for primary diagnosis (1,206). These techniques are more costly than ultrasonography, and their added value is unclear. Hysterosalpingography is not recommended as a diagnostic test for endometriosis, although the presence of filling defects (presence of hypertrophic or polypoid endometrium) has a significant positive correlation with endometriosis (positive and negative predictive values of 84% and 75%, respectively) (207).


Gynecology_Novak

Gynecology_Novak. Imaging to Assess Intestinal and Urologic Involvement If there is clinical evidence of deeply infiltrating endometriosis, ureteral, bladder, and bowel involvement should be assessed. Ureteral involvement may be asymptomatic in up to 50% of patients with deeply infiltrative endometriosis (208). Consideration should be given to performing ultrasound (transrectal, transvaginal or renal), a CT urogram, or an MRI. A barium enema study might be useful, depending on the individual circumstances, to map the extent of disease present, which may be multifocal (1). There is no proof that one technique is superior to another; it is recommended that the technique that is most familiar to the radiologist involved be used.


Gynecology_Novak

Gynecology_Novak. Blood and Other Tests There is no specific blood test for the diagnosis of endometriosis. A general endometriosis screening test may be neither appropriate (risk for overdiagnosis) nor feasible. A blood test with a high sensitivity would be useful if that would identify women with symptomatic endometriosis (pelvic pain, infertility) that is not detectable by ultrasound imaging (209). This would include all cases of minimal to mild endometriosis and those cases of moderate to severe endometriosis without detectable ovarian endometriotic cysts or nodules (210). These are patients who could benefit from laparoscopic surgery to reduce endometriosis-associated pain and infertility or to diagnose and treat other pelvic causes of pelvic pain or infertility, like pelvic adhesions. From that perspective, a lower specificity would be acceptable because the main goal of such a test would be to rule in all women with potential endometriosis or other pelvic disease who might benefit from surgery


Gynecology_Novak

Gynecology_Novak. a lower specificity would be acceptable because the main goal of such a test would be to rule in all women with potential endometriosis or other pelvic disease who might benefit from surgery (211).


Gynecology_Novak

Gynecology_Novak. CA125 Levels of CA125, a glycoprotein from coelomic epithelium and common to most nonmucinous epithelial ovarian carcinomas, are significantly higher in women with moderate or severe endometriosis and normal in women with minimal or mild disease (212,213). It is presumed that endometriosis lesions produce peritoneal irritation and inﬂammation and this leads to an increased shedding of CA125 (213). During menstruation, an increase in CA125 levels was shown in women with and without endometriosis (214–218). Other studies did not find an increase during menses, or found an increase only with moderate to severe endometriosis (219–222). The levels of CA125 vary widely: in patients without endometriosis (8–22 U/mL in the nonmenstrual phase), in those with minimal to mild endometriosis (14–31 U/mL in the nonmenstrual phase), and in those with moderate to severe disease (13–95 U/mL in the non-menstrual phase). Compared with laparoscopy, measurement of serum CA125 levels has no value as a