Chronic pelvic pain: Pathogenesis and validated ...

3 downloads 0 Views 1MB Size Report
J Sex Med 2014;11:3078–84. [146] Nezhat Ceana, Santolaya Joaquin, Nezhat Farr R, Nezhat · Camran. Comparison of transvaginal sonography and biman-.
Middle East Fertility Society Journal (2016) xxx, xxx–xxx

Middle East Fertility Society

Middle East Fertility Society Journal www.mefsjournal.org www.sciencedirect.com

REVIEW

Chronic pelvic pain: Pathogenesis and validated assessment Ali Yosef a,b, Abdel Ghaffar Ahmed b, Tarek Al-Hussaini b, Mohamad S. Abdellah b, Georgine Cua a, Mohamed A. Bedaiwy a,* a Department of Obstetrics and Gynecology, University of British Columbia, Women’s Health Research Institute, BC Women’s Hospital and Health Centre, Vancouver V6H3N1, Canada b Department of Obstetrics and Gynecology, Assiut University, Egypt

Received 5 May 2016; revised 15 July 2016; accepted 8 August 2016

KEYWORDS Chronic pelvic pain; Endometriosis; Central sensitization

Abstract Chronic pelvic pain (CPP) is a disabling disease that causes distress as the quality of life of CPP patients is vastly diminished. In addition, CPP is a public health crisis and is a burden on healthcare expenditure. In the United States, the annual costs for the diagnosis and treatment of CPP are 2.8 billion US $. Moreover, to the indirect cost resulting from the absence from work and CPP associated family problems add 550 million US $ more making the economic burden more than 3.4 billion US $ (Mathias et al., 1996). Yet, the diagnosis of CPP is usually complicated as there are no gold standard guidelines that clearly define this syndrome. Although we have a limited understanding of its etiology, CPP has been found to be correlated with central sensitization, painful bladder syndrome, irritable bowel syndrome, endometriosis and adhesions. As such, in the evaluation of patients, it is imperative to take a comprehensive patient history. Performing physical examinations and ultrasound imaging is of particular value to elucidate the etiology of pain. As CPP patients are at risk for psychological disorders, psychological assessments are critical to diagnose associated psychological disorders and to take these into account in planning a holistic treatment plan for patients. By such evaluation techniques, we can provide better diagnostic service and patient care to people with CPP. Ó 2016 Middle East Fertility Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author at: Department of Obstetrics and Gynaecology Division of Reproductive Endocrinology & Infertility, Children’s & Women’s Hospital, Room D415A-4500, Oak Street, Vancouver, BC V6H 3N1, Canada. Fax: +1 604 875 2987. E-mail addresses: [email protected] (A. Yosef), [email protected] (A.G. Ahmed), [email protected] (T. Al-Hussaini), [email protected] (M.S. Abdellah), [email protected] (G. Cua), [email protected] (M.A. Bedaiwy). Peer review under responsibility of Middle East Fertility Society.

Production and hosting by Elsevier http://dx.doi.org/10.1016/j.mefs.2016.08.001 1110-5690 Ó 2016 Middle East Fertility Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

2

A. Yosef et al.

Contents 1. 2.

3.

4.

5. 6.

7.

8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Nociceptive pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Inflammatory pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Tumor necrosis factor (TNFa) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Nerve growth factor (NGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Mast cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. Interleukins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Neuropathic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Painful bladder syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Irritable bowel syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Adhesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Endometriosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Adenomyosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Pelvic peritoneal pockets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Endosalpingiosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Pelvic inflammatory disease (PID) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Residual ovary and remnant ovary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Pelvic congestion syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Musculoskeletal causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12. Psychological causes of CPP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient history. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Pain history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Family history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. History of abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psychological assessment and validated questionnaires . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Central sensitization examinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Musculoskeletal examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Pelvic examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Ultrasound. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopic evaluation of CPP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

1. Introduction

2. Pathophysiology of pain

CPP is a common gynecologic complaint affecting about 26% of women [1]. Diagnosing chronic pelvic pain (CPP) is a highly complex process as there is no single definition that comprehensively describes this condition. This is a cause for concern as having varying definitions may hinder physician agreement in diagnosis. In fact, having restricted and narrowed defining criteria limits, and possibly excluding some patients, while having a broad definition may lead to biased diagnosis. In a review article that looked into more than 100 publications on CPP, the authors found varying definitions for CPP [2]. Some factors involved in these varying definitions include the starting point of chronic pain, the duration needed to consider the pain to be chronic, and the location where pain is felt and the specific characteristics of the pain. Table 1 shows commonly used definitions for chronic pelvic pain [3–5].

There are three suggested theories for the origin of chronic pelvic pain mainly nociceptive, inflammatory and neuropathic. Nociceptive pain induced by a noxious stimulus causes tissue injury. Inflammatory pain results from the inflammatory process while neuropathic pain appears due to dysfunction in either the central or the peripheral nervous system. 2.1. Nociceptive pain Specialized receptors for pain include Meissner’s corpuscles for the sense of touch, Pacinian corpuscles for pressure and Ruffini’s corpuscles for proprioception. The physical stimulus is then converted into a biochemical signal transmitted in nerve fibers, mainly in type c nerve fibers.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain Table 1

3

Common definitions of chronic pelvic pain.

Source

Definition

Royal College of Obstetricians and Gynecologists Green-top Guidelines no 41 [3]

Intermittent or continuous pain in the lower abdomen or pelvis for at least six months in duration, not occurring exclusively during menstruation or intercourse and not associated with pregnancy. It may significantly impact the women ability to function. Chronic pelvic pain usually encompasses the following characteristics:  duration of six months or longer  incomplete relief with most treatments  significantly impaired function at home or work  signs of depression, such as early awakening, weight loss, or anorexia  altered family role Non-cyclic pain of six-month duration that involves the pelvis, anterior abdominal wall, or buttocks that is serious enough to cause disability or lead to medical care.(withdrawn)

The Society of Gynecologists and Obstetricians of Canada [4]

The American College of Obstetricians and Gynecologists [5]

Pain can be classified into two major types – somatic and visceral. Visceral pain is mainly diffuse and dull aching. It may be associated with referred pain which occurs at a dermatome supplied by the innervations of the affected viscera. Referred pain may manifest clinically as cutaneous hyperalgesia in which the pain is triggered by stimulus that is less than normal. Referred pain may also lead to allodynia where nonpainful stimulus causes pain. This is more common with chronic pain. Referred pain may also lead to secondary contraction of the skeletal muscles in the referred areas. The persistent contraction of these muscles leads to the appearance of myofascial trigger points [6]. Nociceptive visceral pain can be caused by organ distension, spasms, hemorrhage, inflammation, mesentery traction and neoplasm. There are many studies showing that endometriosis can cause nociceptive visceral pain. Tulandi et al. showed that the peritoneum of women with endometriosis contains more nerve fibers than the control group [7]. Another study showed that endometriotic lesions have a high density of sensory and sympathetic nerve endings [8]. Yet, the most important question remains to revolve around the idea of whether removal of the noxious stimulus will lead to cessation of pain. Abbott et al. showed in randomized control trial that removal of endometriotic lesion led to clinical improvement of pain score [9]. However, it is worth noting that incomplete relief in some cases may be explained by other types of pain mechanism which will be discussed latter. 2.2. Inflammatory pain Inflammation is a common cause of chronic pelvic pain. In fact, endometriosis itself is considered as a chronic inflammatory process [10]. Inflammatory pain is associated with the cross-sensitization phenomenon. Repeated pain impulse from certain organ may lead to false pain sensation from the organ supplied by the same dorsal root ganglion. This may explain the association of chronic pelvic pain with irritable bowel and painful bladder syndromes [11]. Many inflammatory mediators are associated with chronic pelvic pain. These include the following: 2.2.1. Tumor necrosis factor (TNFa) TNFa is a cytokine produced by cells implicated in the inflammation process such as neutrophils, lymphocytes, and natural killer cells. Many studies suggest its great importance in

endometriosis. Bedaiwy et al. showed that the concentration of TNFa is higher in the peritoneal fluid of women with endometriosis than the control group [12]. TNFa may increase the production of prostaglandin E2 and F2a in patients with chronic pain [13]. This idea may have some clinical implications. For example, a randomized controlled trial using infliximab (anti-TNFa) in patients with deep infiltrating endometriosis showed significant improvement [14]. 2.2.2. Prostaglandins The two main types of prostaglandins, E2 and F2a, play an important role in inflammation. They mediate inflammation directly and indirectly by stimulating the release of other inflammatory mediators such as histamine, serotonin and nerve growth factors. Prostaglandins are synthesized by cyclooxygenase (cox) enzyme from arachidonic acid. The cox enzyme exists in two forms. Cox2 is shown to be more important and is present in many inflammatory cells. Many studies showed that the level of cox 2 is higher in tissues from endometriosis patients than in normal endometrium [15]. Moreover, estrogen increases the activity of cox2 [16]. As such, anti-estrogenic drugs may act indirectly to decrease the level of prostaglandins. Surprisingly, although NSAIDS are very commonly used in treatment of chronic pelvic pain, no randomized controlled trials have evaluated their efficacy. The only evidence for the efficacy of analgesic drugs was shown by Kauppila and Ronnberg where naproxen was observed to cause significant pain relief in endometriosis patients more than the control group [17]. However, this study may not be very significant given the small sample size (n = 24). 2.2.3. Nerve growth factor (NGF) NGF plays an important role in mediating pain. It functions to increase pain receptors, small nerve fibers and sympathetic ganglia. NGF also acts as pain mediators by inducing the expression of substance P in the affected areas. Some studies showed high concentrations of NGF in endometriotic lesions [18]. In fact, NGF production is enhanced by estrogen and inhibited by progesterone, as shown in a study on hamsters [19]. As changing hormone levels may affect NGF levels, hormones may be used to modulate pain in the clinical setting. 2.2.4. Mast cells Mast cells are found in connective tissue. They store many inflammatory mediators such as histamine, serotonin and even

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

4 nerve growth factor. Mast cells degranulate and release these factors which cause pain. Anaf et al. found that mast cells increase in the areas affected with endometriosis especially near the nerve endings. Barbara et al. showed that there is a high concentration of mast cells in patients with irritable bowel syndrome [20]. Another study demonstrated the relationship between mast cells and interstitial cystitis [21]. This may clarify the usual association and coexistence of these two conditions. To alleviate pain, mast cell inhibitors such as Pentoxifylline may inhibit the release of inflammatory mediators from the granulocytes. Kamencic and Thiel have showed that this drug, when given postoperative for endometriosis patients, leads to a significant reduction in pain score [22]. 2.2.5. Interleukins Interleukin-1 has been observed in high concentrations in the peritoneal fluid of endometriosis patients [23]. It acts as an inflammatory mediator and may play a role in fibrosis and adhesions. Likewise, interleukin-8 is angiogenic and leads to the induction of inflammatory responses [24]. Other interleukins may also have a role in chronic pain. One such example is interleukin 6 (IL 6), although this is still being disputed. One study concluded that there is no significant difference in peritoneal fluid level of IL-6 between normal and chronic pelvic pain patients [25]. On the other hand, another study showed elevated serum levels of IL-6 in patients with mild to moderate endometriosis [26], suggesting that IL-6 may be used as a serum marker for endometriosis. 2.3. Neuropathic pain Neuropathic pain can be caused by insult to the central or the peripheral nervous system. Peripheral neuropathy is common in diabetic patients. Central sensitization describes a dysfunction in the central nervous system that makes it continue to receive pain signals even after removal of the triggering lesion. Its exact mechanism is still poorly understood. Yet, the main clinical symptoms of central sensitization are cutaneous hyperalgesia which is lowered pain threshold in the affected area, cutaneous allodynia defined as pain from non-painful stimulus, and trigger points which are painful contracted muscle bands. Stratton et al. have showed that these signs are significantly higher in patients with chronic pelvic pain more than the control group [27]. Berkley et al. also found that rats with endometriotic mesenteric cyst suffered from vaginal hyperalgesia although there is no direct anatomic communication between the two sites. This may suggest the role of central neuropathy in this situation [28]. Another evidence on neuropathic pain is that not all women who have endometriosis suffer from pain. Some patients discover endometriosis accidently when doing laparoscopy for other causes. This may suggest variations at the gene level in the neural perception of pain [29]. In some patients with endometriosis the pain persists after removing the lesion [9]. If we can identify these patients, we may avoid the cost and risk of unnecessary surgery. New lines of treatment of neuropathic pain such as neuromodulators such as gabapentin and amitriptyline have promising results. In a randomized trial, 56 patients with chronic pelvic pain showed significant improvement in pain score with the use of gabapentin either on its own or in combination with amitriptyline [30].

A. Yosef et al. 3. Etiology It is worth mentioning that CPP is a complex disorder rather than a single disease. In most of the patients the etiology of CPP is multifactorial and not a single cause. This explains the need for multidisciplinary approach for management of CPP [4,31]. 3.1. Painful bladder syndrome Painful bladder syndrome, previously called interstitial cystitis, is a chronic condition where there is definite bladder pain in the absence of organic causes such as stones or infection. Although its exact etiology is poorly understood, the relationship between CPP and painful bladder syndrome has been illustrated in a previous study where 30% of patients with CPP had painful bladder syndrome [32]. In these patients, CPP was thought to be caused by the activation of Toll-like receptor 4 and inflammatory cytokines [33]. A retrospective study on 60 CPP patients who have undergone both laparoscopy and cystoscopy has shown a strong association between endometriosis and interstitial cystitis in these patients [34]. To aid in diagnosis of interstitial cystitis, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [35] have created guideline criteria, including validated questionnaire aids [36,37] and a potassium sensitivity test, that may be used in diagnosing interstitial cystitis [38]. 3.2. Irritable bowel syndrome The NIDDK have defined irritable bowel syndrome (IBS) as a group of symptoms including pain or discomfort in your abdomen and changes in your bowel movement patterns—that occur together. To definitively diagnose IBS, the Rome III criteria [39] can be used, with the help of the validated Birmingham questionnaire [40]. Irritable bowel syndrome (IBS) is a very common disease in patients with CPP. In fact, Howard estimated that up to 80% of patients with CPP suffer from IBS [41] and such strong correlation also appeared in previous studies [42,43]. Specifically, Matheis et al. showed that there is a strong association between CPP and IBS. However, they related this association to sexual dysfunction [42]. Additionally, a study done by Prior and Whorwell [44] showed that 37 out of 71 patients with CPP visiting the gynecology clinic suffered from IBS. These patients were associated with a worse prognosis than other patients with CPP alone. Due to the similarities of symptoms and strong correlation between CPP and IBS, one group [45] assumed that CPP and IBS are the same clinical entity. This assumption may not hold true, however, as they were less specific in defining CPP. Yet, some have raised the question of common etiology for both CPP and IBS. Malykhina suggested three neural mechanisms for cross-sensitization between pelvic organs and thus, the possible relationship between CPP and IBS. The first mechanism involves neural circuitry through the dorsal root ganglion. The second mechanism involves the level of the spinal cord through the interspinal neurons. The third pathway that has a central mechanism through higher centers of the brain [46], is more important in CPP and may be affected by the psychological status of the patient.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain 3.3. Adhesions Adhesions may have different morphologies – some are filmy and avascular while others are thick and vascular [47]. Although the exact incidence of intraperitoneal adhesions may vary, a common laparoscopic finding in patients with CPP is intraperitoneal adhesions. Some risk factors for adhesions include pelvic inflammatory disease, previous abdominal and pelvic surgeries, endometriosis and a history of the perforated viscus. Treatment of these intraperitoneal adhesion causes a huge economic burden on the healthcare system. In fact, in 1994, the US was estimated to have spent about 1.3 billion USD [48] in treating intraperitoneal adhesions alone. There is a debate on the impact of adhesions on CPP, and as an extension, the value of adhesiolysis in the treatment of CPP. Chan and Wood [49] showed that in 100 patients, there was promising efficacy in adhesiolysis in CPP treatment, where the incidence of pain relief after adhesiolysis was about 65%. However, this retrospective study failed to involve control patients, and as such, may have incurred bias as a result. Another study involved ‘‘randomizing” patients into two groups based on the treatment they would receive – one group being offered surgical adhesiolysis and the other, expectant management. Surprisingly no statistically significant difference in pain reduction was observed between the two groups [50]. Moreover, in another multicenter randomized and blinded clinical trial, 116 patients were recruited and randomized to either surgical treatment by laparoscopy or conservative management. Again, there was no significant difference in the visual analog pain score between the two groups [24]. This may imply surgical adhesiolysis is not useful in managing pain in CPP patients. 3.4. Endometriosis Endometriosis is the presence of endometrial tissue outside the endometrial cavity. Both glands and stroma must be found to prove endometriosis. The exact prevalence of endometriosis in chronic pelvic patients is difficult to estimate that it depends on the criteria we use for endometriosis diagnosis. The most accurate are the histopathological diagnosis. One study showed that the prevalence of endometriosis is about 33% of patients with chronic pelvic pain. On the other hand, in some patients, endometriosis is discovered coincidentally in patients who experience no particular pain [51]. The most common phenotype of endometriosis associated with pain is deep infiltrating endometriosis (DIE). Its prevalence is estimated to be in about 1% of women. It is characterized by penetration of endometriosis more than 5 mm depth of the peritoneum [52]. It affects the rectovaginal septum and other important organs in the pelvis such as the bowel, the bladder and the ureter. Several endocrine changes occur in endometriosis patient. First, estrogen synthesis increases due to the increase in the activity of aromatase enzyme that converts androgen to estrogen. Second, there was an increase in the activity b-hydroxyl steroid dehydrogenase type 1 enzyme that converts estrone into the more active estradiol. Third, estrogen breakdown can also decrease. Fourth, estrogen receptors increase and progesterone receptors decrease. This may be the cause of the resistance in some patients to hormonal treatment [53]. Pain is the cardinal symptom in DIE patients in the form of dysmenorrhea, dyspareunia, dysuria and or dyschezia [54]. A

5 physical examination is a useful tool in the diagnosis of deep infiltrating endometriosis. Transvaginal ultrasound is the best method used in the diagnosis of DIE. Although MRI has a higher sensitivity, the difference is not huge, and the cost effectiveness is in favor of the ultrasound [55]. 3.5. Adenomyosis Adenomyosis is the presence of endometrial gland and stroma in the myometrium. Its incidence varies between 15 and 57% in hysterectomy specimens for benign lesions [56]. Its main symptoms are dysmenorrhea, chronic pelvic pain, and menorrhagia. Adenomyomas can be categorized as localized or diffuse, spreading all over the whole uterus. To diagnose adenomyomas, ultrasound can be used. Certain ultrasound criteria such as uterine enlargement, myometrial wall thickening, anechoic spaces in the myometrium, absent myometrialendometrial border and heterogenous echotexture suggest the presence of adenomyosis [57]. Power Doppler aids in the diagnosis and helps to differentiate between myoma and adenomyosis. In myoma, the vascular supply forms a ring around it but in the case of adenomyosis, the blood supply is diffuse [58]. The sensitivity of transvaginal ultrasound in diagnosing adenomyosis is about 65%. It has the same accuracy as using an MRI, but MRI is more sensitive in cases of myoma concurrent with adenomyosis [57]. The most accurate diagnosis is the pathological diagnosis defined as the presence of endometrial glands in more than one low power field from the basal endometrium [59]. 3.6. Pelvic peritoneal pockets The frequency of pelvic peritoneal pockets is about 7% of patients with chronic pelvic pain [60]. Many theories have been postulated to explain the presence of these pockets. They may be a result of congenital duplication in the Mullerian system [60,61]. It may also be due to peritoneal scaring and operation from chronic inflammation due to endometriosis. Pelvic peritoneal pockets are usually treated by laparoscopic excision. In histopathology, most of them show endometriotic lesions. Vilos et al. showed that laparoscopic excision of these pockets is associated with significant reduction in pain [62]. 3.7. Endosalpingiosis Endosalpingiosis is the presence of ciliated tubular epithelium in the pelvic peritoneum. Its main symptom is pain and grossly it appears as endometriotic lesion. It is similar in the histological structure of the fallopian tube lining [63]. However, the exact origin of endosalpingiosis is not known. In a prospective study on 1107 patients who have done laparoscopy, endosalpingiosis was found in 84 women. 7.9% of all patients had pelvic pain while 7.3% did not have pelvic pain. The authors assumed that endosalpingiosis has little role in the etiology of chronic pelvic pain [64]. In another retrospective study six patients showed endosalpingiosis in the sites corresponding to pain location. However, most of these cases were associated with endometriosis and the small sample size of patients cannot be used for statistical analysis [65]. As such, more studies are needed to assess the relation between endosalpingiosis and chronic pelvic pain.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

6 3.8. Pelvic inflammatory disease (PID) PID is a common gynecologic disease that has many short-term and remote complications. Chronic pelvic pain is considered a long-term complication of PID. In a large study of 813 patients with PID, the incidence of chronic pelvic pain varied from 8.2 to 15%, depending on the level of pain, disability and type of treatment [66]. Pelvic adhesions were thought to be the cause of chronic pelvic pain following PID. However, the exact mechanism for this progression needs further research. 3.9. Residual ovary and remnant ovary syndrome The residual ovary is the whole ovary left on purpose after surgery. It may be unilateral or bilateral. A huge retrospective casecontrol study showed that the incidence of residual ovary syndrome following gynecological surgeries for benign reasons was about 70% [67]. The exact cause of pain is still unknown. Some authors think that postoperative adhesions are the cause of this pain. Others claim that the cause is altered blood supply due to ligation of the uterine artery during hysterectomy. The other condition is the remnant ovary syndrome which is unintentionally leaving a part of ovarian tissue after doing oophorectomy. It is common that in cases with severe pelvic adhesions, or when doing an emergency hysterectomy, the remnant ovary causes a problem in both diagnosis and treatment. The diagnosis usually begins with the history. The patient usually suffers from a unilateral chronic pelvic pain and has no hormonal withdrawal symptoms after ovary removal. Examination may reveal a unilateral pelvic tender mass. Additionally, the patient may have other symptoms as dysuria, dyschezia and dyspareunia [68]. In fact, this disease is more common in young premenopausal women. These remnants may produce hormones and stimulate the growth of endometriotic lesions. The hormonal profile usually helps in diagnosis. Provocative tests by using ovulation induction to stimulate ovarian growth may be used [69]. Different imaging techniques may also be used. In a cohort study, about 80% of cases were diagnosed by ultrasound [70]. However, MRI may be more useful in determining the size and the relation to vital organs and in planning for surgery. Treatment modalities include medical, surgical and radiotherapy. Medical treatment depends mainly on suppression of ovarian function. However, results in most cases were unsatisfactory and its use should be limited for short term and wait for surgical treatment. On the other hand, radiotherapy has risks on adjacent structures. In addition, these remnants may contain hidden malignancies such as adenocarcinomas, that were reported in some cases of ovarian remnant syndrome [71]. Surgery is the definitive treatment in these cases. It is a very difficult surgery and needs an expert surgeon to perform the procedure as careful retroperitoneal dissection, ureterolysis and high ligation of ovarian vessels are necessary [70]. Still, there is a risk of ureteric injury and damage to other vital structures. 3.10. Pelvic congestion syndrome It can be defined as idiopathic pelvic pain of 6 months or more durations with evidence of dilated pelvic veins with evidence of venous reflux [72]. The exact cause is still not known. It may be a congenital weakness of veins or the absence of valves. This occurs in about 15% of patients [73]. It may also be secondary

A. Yosef et al. to vein compression. In addition, this syndrome is common in young multiparous women that is characterized by nonmenstrual dull pain which increases with prolonged standing and decrease on lying down. It is also often accompanied by congestive dysmenorrhea and dyspareunia. On examination, adnexal tenderness and a bluish cervix may also help in diagnosis. Vulvar and thigh varicosities are common findings as well [74]. To diagnose pelvic congestion syndrome, an ultrasound is a good screening method. Findings include dilated ovarian vein and reversed blood flow especially with Valsalva maneuver [75]. Venography is the gold standard method for diagnosis of pelvic congestion syndrome. Findings include dilatation of veins and the slow disappearance of the injected dye [76]. Potential treatments for this syndrome include medical suppression of ovarian function. In a prospective trial on about 47 patients, goserelin was better than medroxyprogesterone acetate in improving the symptoms of pelvic congestion [77]. The main line of treatment is endovascular therapy. However, there are no randomized controlled trials on this particular treatment. Additionally, Laborda et al. made a prospective study on 202 patients suffering from pelvic congestion and have done coil embolization. The success rate was more than 90%. Improvement of pain occurred in less than two months after treatment [78]. 3.11. Musculoskeletal causes Chronic pelvic pain caused by myofascial disorders is a common problem that faces gynecologist almost daily. Tu et al. reported that the estimated prevalence of myofascial induced CPP is up to one fifth of women [79]. The most common of these disorders is trigger points. Trigger points are taut muscle bundles that are tender on pressure. They are caused by chronic injury and repeated minor trauma [80]. Pain is usually poorly localized and may be referred and it is increased with exercise. They appear on ultrasound examination as hypoechoic areas with high vascular resistance [81]. Many treatment modalities were suggested including local injection of trigger points with local anesthetic or botulinum toxins. Pelvic floor muscle disorders include trigger points and pelvic muscle spasm which may be primary or secondary due to local inflammation in the adjacent pelvic viscera. It also includes pelvic floor injury from delivery or accidents. In a previous study on 26 women with CPP and negative laparoscopy, MRI showed injury of levator ani muscle with different degrees [82]. It is worth mentioning here nerve entrapment as a cause of chronic pelvic pain. Pudendal neuralgia or Alcock canal syndrome may be a cause of dull aching chronic pelvic pain. It is suspected when pain is caused by sitting and disappears on standing or sitting on toilet seat [83]. Electromyography and nerve conduction studies may help in its diagnosis. Recent studies on cadavers showed that pudendal nerve has numerous anatomic variations and the adoption of its entrapment as a cause of pain is exaggerated and may not reflect the true cause of pain in these patients [84]. Finally we should not forget the degenerative lumbar disk changes that may cause pelvic pain [85] and the pelvic girdle joints dysfunction that commonly occur with pregnancy and in old age [86]. It is diagnosed with the pelvic girdle pain tests described below. Its treatment needs

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain a multidisciplinary approach with both orthopedic surgeon and physiotherapist. 3.12. Psychological causes of CPP A recent systematic review showed that up to 38% of CPP patients suffer from associated psychiatric illness mainly depression and anxiety [87]. However the problem is that association does not necessary mean causality. In other words CPP may be due to depression but also depression may be a result from CPP. Depression as result of pain can be easily explained by the chronic nature of the disease and that the patients lose hope to be cured and their desire for work and productivity decreases as shown in many studies [88]. Depression may lead to neuropathic pain and central sensitization. In a prospective cohort on about 800 employees in different jobs who were followed up for one year jobs associated with higher stress are twice more suffering from pain in different regions [89]. Thorough psychological assessment of CPP patient is important to diagnose the cause as well as to treat the consequences [4].

7 Table 2 Commonly used questionnaires to assess chronic pelvic pain and their outcome measure. Questionnaire

Outcome measure

Endometriosis health profile (EHP-30) GAD-7 Patient health questionnaire PHQ-9 Pain catastrophizing scale

Quality of life

Tampa scale Chronic pain sleep inventory Female sexual distress scale Pain self-efficacy questionnaire Pain stages of change questionnaire O Leary Sant questionnaire Birmingham questionnaire Visual analog scale Biberoglu and Behrman scale

Generalized anxiety disorder Depression Magnification and exaggeration of symptoms Kinesiophobia Sleep disturbance Sexual disorders Patient ability to work and achieve Ability to accept and adapt to pain Painful bladder syndrome Irritable bowel syndrome Pain score Pain score

4. Patient history 4.2. Ethnicity Taking patient history is a fundamental step in the evaluation of a patient with CPP. Detailed history reviews would include the onset of pain, its pattern as well as its precipitating and relieving factors. History taking may begin before the clinic visit by using online questionnaires. We will point to some items in the patient history record that may be useful for diagnosis. 4.1. Pain history A patient’s pain score provides critical insight into the cause of pain. For example, acute lesions tend to cause more severe pain than chronic lesions. Inflammatory lesions cause more severe pain than any other lesions. Additionally, a change in the pain score can also be used to follow up and understand the progression of pain. As such, we need to understand the characteristics of pain – its duration, frequency, intensity, and location, when it commenced and quality of pain (if the pain is cyclic, continuous, and throbbing). There are a variety of pain scoring systems to comprehend a patient’s pain characteristics, including the most commonly used in the literature, the visual analog scale (VAS) [90], where a patient describes the pain on a scale from zero to ten – zero referring to no pain and ten referring to very severe pain. Although VAS is simple and easy to use, it relies on the patient estimation of pain level which can be rather subjective. Also, if the pain is cyclic, pain levels may vary. This implies uncertainty on our part as to which pain level the patient would describe. Another pain scoring system often used is the two-tiered Biberoglu and Behrman scale [91]. The subjective first part involves symptoms such as dysmenorrhea and dyspareunia while the objective second part depends on signs such as tenderness. However, this scale may not be relevant if the woman does have amenorrhea or is not sexually active. Other concerns for using this scale include uncertainties in the cyclic nature of pain, the relation of pain to sexual activity, and the presence of other types of pain as dysuria or dyschezia.

Ethnicity is very important in elucidating the etiology of CPP. For example, uterine fibroids are known to be more common in the African race while endometriosis is more commonly found in Caucasians [92]. 4.3. Family history Zondervan et al. studied the genetic variations in chronic pelvic pain patients. They concluded that the spectrum of CPP phenotype is very broad, and it may be beneficial to divide the phenotype into subgroups such as fibroid phenotypes and endometriosis phenotypes [93]. In a particular case-control study, the incidence of endometriosis was shown to increase if first degree relatives have the disease [94]. Another large study included more than 1176 families where multiple family members had endometriosis. Genetic study of these families suggested that there is certain gene loci on chromosome 7p that may be responsible for the inheritance of endometriosis in families [95]. Also, familial inheritance of uterine fibroid has been discussed since the 1960s [96]. In fact, one study showed that the presence of uterine fibroid is 2.2 times more common in families that have relatives who have the same disease [97]. 4.4. Smoking Smoking may be a cause or a result of CPP. Some previous studies showed that smoking is the causative agent for all chronic pain syndromes [45]. Several theories have been developed to explain the relation between smoking and chronic pain. One group claimed that smoking is a cause of chronic coughing which may ultimately lead to musculoskeletal pain [98]. Another study explained this association as the effect of nicotine on the pain signaling pathway [99]. 4.5. History of abuse Physical and sexual abuse is strongly related to CPP. It has been suggested that sexual abuse may lead to CPP via the

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

8 trigger point formation or the central sensitization mechanism. One group studied 31 women with CPP, 142 women with pain in other sites and 32 controls. Their history of physical and sexual abuse at different ages was assessed. The results showed that a significantly higher proportion of chronic pelvic pain patients had a history of physical abuse compared to chronic-pain patients and controls [100]. Another case-control study compared two groups of women – one group being women who underwent laparoscopy due to pelvic pain and the second group being women who underwent laparoscopy due to other causes such as tubal sterilization. Their findings suggest that a history of sexual abuse was more common in CPP patients compared to the controls [101]. 5. Psychological assessment and validated questionnaires CPP has a dramatic effect on the patient’s quality of life [11]. Lower educational level had been correlated with higher chronic pelvic pain score, as suggested by the data from a previous study [102]. The CPP patient is also usually depressed and feeling hopeless. In a cross-sectional study of 52 patients with CPP and 54 without CPP, it was implied that CPP patients were associated with a higher level of anxiety and depression, as well as a lower quality of life than a normal person [103]. However, as these studies are merely correlational, it is not clearly understood whether depression is the cause or the result of CPP. Nevertheless, psychiatric evaluation should be a fundamental part of CPP evaluation. The use of validated questionnaires is gaining popularity in the psychiatric evaluation of patients. Many questionnaires are used by different researchers, but we will highlight some questionnaires that had been validated for CPP patients. Table 2 outlines the commonly used questionnaires and the outcome they measure. For assessment of the quality of life, the most common questionnaire is the endometriosis health profile 30 (EHP-30) that was first developed in the UK and was validated in many countries such as the USA and Persia [104,105]. It consists of a core questionnaire divided into five subgroups that assess pain, emotional state, social support, self-image and feel of power as well as a modular questionnaire that cover other aspects of life such as work and sexual life [106]. To assess whether a patient has generalized anxiety disorder (GAD), the GAD-7 validated questionnaire can be used. GAD-7 has been found to be 90% sensitive in distinguishing CPP patients with GAD compared to CPP patients not afflicted by GAD [107]. In a recent study GAD-7 was also used to measure anxiety level in CPP patients [108]. Another validated questionnaire is the PHQ-9, which is used to diagnose depression. A score 10 or higher in the PHQ-9 is indicative of depression with 88% sensitivity [109]. In a retrospective cohort study of CPP patients, it was suggested that depression and anxiety are associated with poor quality of life in CPP patients [103]. To understand the patient’s scale of pain exaggeration, another questionnaire can be used. This describes to us a pain catastrophizing scale [110]. Numerous researches have validated this scale in pain patients [111–114]. As sleep disturbance is common in women with chronic pelvic pain [115], the Pittsburgh sleep quality index [115] and

A. Yosef et al. chronic pain sleep inventory [116] can be used to measure sleep disturbances. Likewise, female sexual function can be assessed using female sexual distress scale [117]. In a cross-sectional study, the incidence of female sexual dysfunction in women with CPP was about two times more than that in women without CPP [118]. Chronic pain, which is associated with fear of movement or kinesiophobia, can also be assessed using Tampa scale which has been validated for many chronic pain conditions [119]. Moreover, the pain self-efficacy questionnaire may be used to measure what patients think about her ability to work and achieve [120]. Pain stages of change questionnaire may be used to measure the ability of patients to accept the diagnosis and tolerate and adapt to a chronic condition [121]. It has been validated for use in patients with chronic musculoskeletal disorders [122]. Other useful questionnaires that can be used include the O’leary Sant questionnaire for painful bladder syndrome [37] and the Birmingham questionnaire for irritable bowel syndrome [40]. In conclusion, these questionnaires can provide powerful and useful tools for assessing the patient’s condition and the prognosis before the initial visit. 6. Physical examination 6.1. Central sensitization examinations Central sensitization is a phenomenon that occurs when the central nervous system is constantly receiving pain signals from a certain area for a long period that pain persists even after the removal of the noxious stimulus [123]. The importance of this hypothesis is coming to the limelight now as it is one of the main causes of the persistence of pain after surgery [124]. The main symptoms associated with central sensitization include cutaneous allodynia (pain from the non-painful stimulus), hyperalgesia (lowered pain threshold in the affected area), and the presence of trigger points (areas of increased sensitivity in skeletal muscles with tonically contracted muscle bundles) due to chronically repeated insults [125]. Regarding trigger points, predisposing factors include repeated trauma and nerve compression due to adhesions or as a result of surgery. Box 1 summarizes some commonly used tests for assessment of central sensitization.

Box 1 Examinations for central sensitization. Tests for central sensitization 1. Central sensitization inventory questionnaire 2. Cutaneous allodynia: cotton tip applicator test 3. Hyperalgesia and trigger points: a. Carnett test b. Abdominal and vaginal pain threshold algometer c. Ultrasound and electromyography for trigger points 4. Brain studies a. Cerebral metabolism b. Gray matter volume changes

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain

9

Table 3 Sensitivity and specificity of imaging techniques used in endometriosis diagnosis in different sites. Type of imaging Ultrasound Ovarian Endometrioma Bowel Endometriosis Uterosacral Ligaments Rectovaginal Septum Vagina Bladder MRI Rectosigmoid Retrocervical

Sensitivity

Specificity

Source

64–89%

89–100%

Moore et al. [148]

91%

98%

53%

93%

Hudelist et al. [149] Guerriero et al. [150]

49%

98%

58% 62%

96% 100%

83% 76%

98% 68%

origin [135]. As such, an examination of the myoskeletal system became a fundamental part of the examination in patients with CPP. Box 2 shows commonly used examinations for diagnosis of pelvic girdle pain.

Box 2 Common tests for pelvic girdle pain. Five common tests of pelvic girdle pain 1. Active straight leg raising test 2. Faber test 3. Posterior pelvic pain provocation test 4. Long dorsal sacroiliac joint tenderness 5. Symphysis pubis tenderness

Abrao et al. [151]

There are many physical tests to assess the symptoms of central sensitization. For example, cutaneous allodynia is most reliably tested using the cotton-tipped applicator test. This test is done by moving gently a cotton tip along the mid clavicular line from subcostal margin down to the symphysis pubis. If this gentle touch can elicit pain in certain area then we can diagnose cutaneous allodynia in this patient. It has been shown that this test has 73% sensitivity, 100% specificity and 98% interobserver reliability in distinguishing patients with CPP compared to those without CPP [126]. To test abdominal wall trigger points, two examinations can be performed. One is the Carnett test [127] where the patient is initially asked to contract her abdominal wall muscles. If the pain declines, the cause of pain is considered to be intraperitoneal. On the other hand, if the pain intensifies, the patient is considered to have abdominal wall trigger points. The Carnett test has been validated to be 78% sensitive in differentiating CPP patients from controls [128]. Another examination can be performed using a pressure algometer where the pain is elicited by pressure lower than normal in the affected area [129]. An algometer had been verified for use on the anterior abdominal wall muscles [27] and on pelvic floor muscles using vaginal pressure algometer [130]. Ultrasound imaging can be used in the diagnosis of central sensitization, and may guide the treatment of trigger points [131]. Stratton et al. showed that central sensitization and myofascial dysfunction signs are more common in women with CPP although there was no significant difference in chronic pain patient with and without endometriosis [27]. Mayer et al. validated a central sensitization inventory questionnaire in many chronic pain syndromes with the highest sensitivity in patients with fibromyalgia; however, it was not validated in chronic pelvic pain patients [132]. Some studies used brain imaging to determine gray matter volume or changes in brain metabolism in patients with central sensitization but such diagnosis methods are still under clinical trials [133,134]. 6.2. Musculoskeletal examination Musculoskeletal pain is a common cause of CPP as up to 22% of patients with CPP described the pain as musculoskeletal in

The examination properly starts with an inspection of gait and posture of the patient followed by an examination of the back and spine. It is often common for these patients to have a history of trauma to joints or skeleton. As pain may increase with prolonged standing or physical effort, the examination should also involve doing several activities to understand the musculoskeletal health of the person. After this, we examine the pelvic girdle. Pelvic girdle pain arises in the area bounded superiorly with the iliac crest and inferiorly with the gluteal fold. This area also involves the sacroiliac joint and the symphysis pubis [136]. Examination of the pelvic girdle can be performed through the posterior pelvic pain provocative test, which can be done by applying pressure on a flexed knee while the patient is lying down in the supine position and hip semi-flexed. Patients are considered to have musculoskeletal pain if this pressure causes pain in the gluteal region of the tested side. In a cross-sectional study of included 72 pregnant women, the test yielded positive for patients with a history of pelvic girdle pain [137]. The second test that can be used is the Faber test. This is performed by applying slight pressure on the flexed knee of a patient in the supine position with the hip abducted and heel rested on the knee of the opposite limb. Patients test positive for the Faber test when slight pressure on the flexed knee causes pain in the hip joint. An observational study on pregnant women with pelvic pain showed that the Faber test was positive in 6 out of 20 women in the CPP group while it was negative in all 20 women in the control group [138]. Also, another test for pelvic girdle pain is through the palpation of the patient’s long dorsal sacroiliac joint to detect tenderness. This test was validated in numerous studies. In fact, Vleeming et al. examined pregnant women with pelvic girdle pain and this test positive in 136 women of 178 women with sensitivity about 86% [139]. Moreover, another examination that can be done is the simple active straight leg raising test. The patient, lying supine, is asked to raise her straight leg up to 30 degrees above the table. The patient tests positive for pelvic pain if this procedure causes pain to the patient. In a cross-sectional study on 50 pregnant women with pelvic pain, this test had a high sensitivity and specificity, making it comparable to other tests such as the posterior pelvic pressure provocative test [140]. Many other tests are prescribed for the diagnosis of pelvic pain, including symphysis pubis palpation, and modified Tren-

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

10

A. Yosef et al.

delenburg test [136]. Surprisingly most studies were done on pregnant women while little or no studies validating the test in non-pregnant women. Imaging techniques such as computed tomography and MRI can also be utilized to facilitate diagnosis in conjunction with a physical examination. The treatments of CPP that are musculoskeletal in origin include pelvic exercises. In a randomized trial on 129 pregnant women, water gym was an effective method for the treatment of low back pain [51]. Another line of treatment that can be used is massage therapy as seen by the promising study where 26 pregnant women who have had massage therapy for six weeks had less back pain than others who were nonpregnant [141]. Additionally, in a retrospective randomized trial performed by Kvorning et al., acupuncture decreased the pain score of 43% of pregnant patients with low back or pelvic pain without side effects [142]. Moreover, another line of treatment is with sacroiliac joint injection with corticosteroids. In a randomized controlled trial sacroiliac, joint injection with steroids and local anesthetic were more effective than injection with local anesthetic alone [143]. Other lines of treatment including prolotherapy, surgery and biofeedback may need more research and evidence of benefits outweighing the costs before these treatments can be approved safe for use. 6.3. Pelvic examination Pelvic examination is fundamental in diagnosing CPP. We usually start with vulvovagival examination for provoked vestibu-

Figure 1

lodynia with Q tip followed by speculum examination. As CPP patients are experiencing a great deal of pain, we initially use a unidigital pain examination for pain mapping. We examine tenderness in right, left pelvic floor, bladder base, cul-de-sac, uterosacral ligaments, cervix, uterus and both adnexa. This is followed by bimanual pain examination. Finally, the pelvic examination ends with a rectal or rectovaginal. Special care should be taken for pelvic floor muscle tenderness, which may indicate the central sensitization pain mechanism. In one retrospective study, it was determined that pelvic floor tenderness was significantly associated with abdominal wall tenderness and superficial dyspareunia in women suffering from chronic pelvic pain [144]. Such association may imply that the presence of the central sensitization mechanism of pain in these patients. In another study, bladder base tenderness detected by an anterior vaginal wall examination, was associated with deep dyspareunia [145]. Moreover, the bimanual examination is particularly useful in the diagnosis of endometriosis. In a retrospective study on 91 patients with endometriosis, bimanual examination had the same accuracy of transvaginal ultrasound in the diagnosis of endometriosis [146]. However, a possible problem with rectovaginal examination may be painful for the patient and of low sensitivity in the diagnosis of endometriosis [147]. A fundamental part of pelvic examination is the screening for sexually transmitted disease (STI). All women with chronic pelvic pain who are sexually active should be screened for STI including Chlamydia and gonorrhea [3] .

Endometriotic nodule in the uterosacral ligament as shown by transvaginal ultrasound.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain 7. Imaging 7.1. Ultrasound Ultrasound aids in the diagnosis of various causes of CPP. Box 3 shows different types, modalities, contrast media and techniques used in ultrasound clinics for CPP etiology diagnosis. In this review, we will focus on the use of ultrasound in the diagnoses of endometriosis.

Box 3 Routes, modalities, media and techniques of ultrasound in endometriosis.

Ultrasound in endometriosis Routes  Transvaginal  Rectal  Transperineal  Combined Rectovaginal Contrast media used  Saline  Barium  Gel Modalities  B mode  Doppler  3D Ultrasound Soft markers  Site specific tenderness guided ultrasound Mobility  Ovarian Mobility  Cervical Sliding Sign  High Uterine Sliding Sign

Endometriosis can be divided into ovarian endometrioma, superficial endometriosis, and deep infiltrating endometriosis. The sensitivity and specificity of ultrasound vary according to the location of endometriosis. Table 3 illustrates the sensitivity and specificity of ultrasound and MRI in the diagnosis of endometriosis in different sites [148–151]. Ovarian endometrioma is typically diagnosed by ultrasound with its classic homogenous ground glass appearance [152]. In a study on 153 patients with adnexal masses, transvaginal ultrasound was 81% sensitive in the diagnosis of endometrioma while the use of color Doppler in transvaginal ultrasound increased the sensitivity to 90% [153]. Variations in shape of endometrioma may also occur when calcification or hemorrhagic areas appear and this may seem as if the endometrioma is mimicking other adnexal lesions. In a prospective study on 71 patients who have done laparoscopy for adnexal cyst, 60% of endometrioma cases were diagnosed sonographically while 40% of cases endometrioma cases were not diagnosed by ultrasound as they did not present with

11 the classic morphology of an endometrioma [154]. Sonographic diagnosis of endometrioma should be taken in combination with other clinical symptoms and diagnostic tools. The second type of endometriosis is deep infiltrating endometriosis. It is characterized by penetration of endometriosis more than 5 mm depth of the peritoneum [52]. It affects the rectovaginal septum and other important organs in the pelvis including the bowel, bladder and ureters. In systematic review over 188 papers, the overall sensitivity of transvaginal ultrasound in the diagnosis of deep infiltrating endometriosis of the bowel was 91% [149]. The route of ultrasound varies it may be transvaginal, transrectal, transperineal or combined. Transvaginal ultrasound may be combined with saline or barium contrast in the rectum to increase the accuracy of diagnosis while the transrectal ultrasound is usually performed after an enema. In a retrospective study looking into endometrioma diagnosis by imaging, the transrectal ultrasound showed higher sensitivity than the transvaginal in the diagnosis of endometriosis in rectovaginal septum but lower sensitivity in vagina and uterosacral[55]. In another prospective study of 90 women with rectovaginal endometriosis, the sensitivity of transvaginal ultrasound with saline contrast in the rectum was higher than without contrast. However, this difference was not considered statistically significant, and the degree of pain was reported to be higher when using contrast [155]. In addition, the double contrast barium enema has proved to have less sensitivity than transvaginal ultrasound in the diagnosis of deep infiltrating endometriosis, as suggested in another study [156]. An alternative combined technique would be the sonorectovaginography which involved injecting saline into the vagina, rectum, and Douglas pouch to increase resolution. However, the need for anesthesia in this procedure limits its value [157]. In sonovaginography, saline infusion in the vagina markedly increased the sensitivity and specificity in the diagnosis of rectovaginal lesions in a prospective study [158]. However it may require tilting of the patient and closure of the vaginal channel with catheter or sonographer hand to prevent the leakage. Considering that transvaginal ultrasound is the most comfortable and least invasive for the patient, the trail was made to increase its accuracy by using different media between the probe and vagina. A newer technique often used is gel sonography where the gel is added in the posterior fornix to increase its resolution. In a prospective study on 189 patients, gel sonography was more than 90% accurate in diagnosing rectovaginal endometriosis [159]. Fig. 1 shows uterosacral nodule behind the uterus. Other routes that can be utilized include the transperineal ultrasonography which may be useful in patients with severe tenderness who cannot tolerate transvaginal ultrasound. In a study of 39 women with endometriosis, 3D transperineal ultrasound had about 95% sensitivity in the diagnosis of rectovaginal lesions [160]. The role of 3D ultrasound is increasing recently in diagnosis of endometriosis especially lesions in the uterosacral ligament as this may be difficult to detect with a 2D ultrasound. However, its use may be limited by higher cost and the need for trained sonographers to operate the new devices [161]. According to the ESHRE guidelines 2014, the value of 3D ultrasound and MRI in diagnosis of deep infiltrating endometriosis is still not established and needs further trials to prove their effectiveness [162].

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

12 In the absence of obvious lesions, other symptoms appear in ultrasound that may guide the diagnosis. These include mobility and tenderness. Mobility may include ovarian mobility, cervical sliding and uterine sliding signs [163]. Ovarian mobility against surrounding structures can give an idea about ovarian adhesion secondary to endometriosis [164]. Uterine sliding is also a good predictor of Douglas pouch obliteration which may make surgery more difficult and increase the incidence of intestinal injury. Signs of uterine sliding can be tested by observing the movement of the cervix against the anterior rectal wall and the movement of the uterus against the intestinal loops. In a study done by six sonographers, this sliding sign has 93% sensitivity in the diagnosis of Douglas pouch obliteration with excellent interobserver reliability [165,166]. Secondly, tenderness guided ultrasonography can also be used to diagnose deep infiltrating endometriosis in CPP patients [167]. This technique involves the sonographer focusing on a point where the patient experiences tenderness. This technique is 91% sensitive and is useful for diagnosis. 7.2. MRI Magnetic resonance imaging (MRI) can be used in diagnosing deep infiltrating endometriosis and bowel infiltrating endometriosis. Although MRI has high sensitivity, it is not cost effectiveness [55]. The sensitivity of MRI in diagnosis of endometriosis was 69% in a prospective trial on 48 women with CPP [168]. MRI is an excellent choice in diagnosis of adenomyosis with sensitivity about 85% [169]. MRI is the first line investigation for sacroiliac joint dysfunction and pelvic girdle pain [136]. Its value in pelvic congestion and syndrome has been discussed before. In spite of its value, its high cost and the need for expert radiologist for interpretation may limit its use. 8. Endoscopic evaluation of CPP Laparoscopy is a best method for investigation of CPP if organic pelvic lesion is suspected. About half of the diagnostic laparoscopies are done due to CPP and about half of them have negative findings [170]. Endometriosis is the most common pathology diagnosed by laparoscopy in CPP patients. In a retrospective cohort of 100 CPP patients endometriosis encountered in 50% of cases [171]. Skilled surgeon must keep in mind the atypical shapes and forms of endometriosis. Thorough examination of the pelvis by topographically divide the pelvis into 4 zones: 2 midline zones and two paired lateral zones [172]. Reporting any abnormality and taking biopsy for histopathological examination are necessary. It is worth mentioning here that physical examination finding not necessarily correlates with laparoscopic findings. Patients with no pain may have laparoscopic abnormalities and vice versa. A new technique is conscious pain mapping where patients undergo laparoscopy under conscious sedation and different areas are palpated by a blunt probe and patient direct up to the most painful area. Swanton et al. did this technique in a prospective trial on 43 CPP patients and success rate of identifying the cause of pain was up to 90% [173]. There are no RCTs done about this techniques and still need more trials but may be used in selected refractory case [174].

A. Yosef et al. 9. Conclusion In this paper we emphasize certain key points in the evaluation of patients with CPP (Box 4). Firstly, the evaluation may start before the initial visit through emailing validated questionnaires to the patient that she can fell out at home. This is particularly important to assess the severity of CPP, impact on quality of life, and capture undiagnosed painful bladder syndrome, irritable bowel syndrome, depression and anxiety. Secondly, in the initial consultation we should take a detailed history, physical examination including psychiatric evaluation and musculoskeletal examination with special emphasis on accurate pain mapping. Central sensitization is being increasingly recognized as an integral component of the pathophysiology of CPP and should be kept in consideration as a potential cause of chronic pain. Ultrasonography evaluation is an integral part of examination to diagnose cul-de-sac obliteration and deep infiltrating endometriosis. This includes soft markers such as uterine sliding sign and tenderness guided pain mapping. This is especially important prior to planning complex endometriosis surgery. New lines including conscious pain mapping still need more trials. Finally, multidisciplinary approach is a key for the evaluation and management of CPP.

Box 4 Take home messages. Before the initial visit 1. Administer validated questionnaires to help in proper diagnosis 2. Give the patient information about the disease During the first visit 1. Detailed history from the patient including pain score, family history, medical and surgical history 2. Discuss the patient’s answers from the questionnaires 3. Musculoskeletal examination including pelvic girdle pain tests 4. Tests for central sensitization 5. Unidigital pain mapping 6. Transvaginal ultrasound as first line of physical investigation 7. Use soft markers as site specific tenderness, uterine and cervical sliding sign 8. MRI (limited value ad expensive) 9. Discuss with the patient possible diagnosis and suitable management 10. Focus on multidisciplinary management Follow up visit 1. Confirm the diagnosis 2. Check the pain score to see the progression of disease

References [1] Ahangari A. Prevalence of chronic pelvic pain among women: an updated review. Pain Physician 2014;17:E141–7.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain [2] Williams RE, Hartmann KE, Steege JF. Documenting the current definitions of chronic pelvic pain: implications for research. Obstet Gynecol 2004;103:686–91. [3] Gynaecologists RCoOa. The initial management of chronic pelvic pain green-top guideline no 41. London: RCOG; 2012. [4] Jarrell JF, Vilos GA, Allaire C, Burgess S, Fortin C, Gerwin R, et al. Consensus guidelines for the management of chronic pelvic pain. J Obstet Gynaecol Can 2005;27:781–826. [5] Bulletins – gynecology ACoP. ACOG practice bulletin No. 51. Chronic pelvic pain. Obstet Gynecol 2004;103:589–605. [6] Slocumb JC. Neurological factors in chronic pelvic pain: trigger points and the abdominal pelvic pain syndrome. Am J Obstet Gynecol 1984;149:536–43. [7] Tulandi T, Felemban A, Chen MF. Nerve fibers and histopathology of endometriosis-harboring peritoneum. J Am Assoc Gynecol Laparosc 2001;8:95–8. [8] Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science 2005;308:1587–9. [9] Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebocontrolled trial. Fertil Steril 2004;82:878–84. [10] Kajihara H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, et al. New insights into the pathophysiology of endometriosis: from chronic inflammation to danger signal. Gynecol Endocrinol 2011;27:73–9. [11] Mathias SD, Kuppermann M, Liberman RF, Lipschutz RC, Steege JF. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol 1996;87:321–7. [12] Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 2002;17:426–31. [13] Chen DB, Yang ZM, Hilsenrath R, Le SP, Harper MJ. Stimulation of prostaglandin (PG) F2 alpha and PGE2 release by tumour necrosis factor-alpha and interleukin-1 alpha in cultured human luteal phase endometrial cells. Hum Reprod 1995;10:2773–80. [14] Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy S. Anti-TNF-alpha treatment for deep endometriosisassociated pain: a randomized placebo-controlled trial. Hum Reprod 2008;23:2017–23. [15] Matsuzaki S, Canis M, Pouly JL, Wattiez A, Okamura K, Mage G. Cyclooxygenase-2 expression in deep endometriosis and matched eutopic endometrium. Fertil Steril 2004;82:1309–15. [16] Giudice LC, Kao LC. Endometriosis. Lancet 2004;364:1789–99. [17] Kauppila A, Ronnberg L. Naproxen sodium in dysmenorrhea secondary to endometriosis. Obstet Gynecol 1985;65:379–83. [18] Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noel JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 2006;86:1336–43. [19] Shi Z, Arai KY, Jin W, Weng Q, Watanabe G, Suzuki AK, et al. Expression of nerve growth factor and its receptors NTRK1 and TNFRSF1B is regulated by estrogen and progesterone in the uteri of golden hamsters. Biol Reprod 2006;74:850–6. [20] Barbara G, Wang B, Stanghellini V, de Giorgio R, Cremon C, Di Nardo G, et al. Mast cell-dependent excitation of visceralnociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007;132:26–37. [21] Sant GR, Kempuraj D, Marchand JE, Theoharides TC. The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology 2007;69:34–40. [22] Kamencic H, Thiel JA. Pentoxifylline after conservative surgery for endometriosis: a randomized, controlled trial. J Minim Invasive Gynecol 2008;15:62–6. [23] Wu MY, Ho HN. The role of cytokines in endometriosis. Am J Reprod Immunol 2003;49:285–96.

13 [24] Pizzo A, Salmeri FM, Ardita FV, Sofo V, Tripepi M, Marsico S. Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol Obstet Invest 2002;54:82–7. [25] Rapkin A, Morgan M, Bonpane C, Martinez-Maza O. Peritoneal fluid interleukin-6 in women with chronic pelvic pain. Fertil Steril 2000;74:325–8. [26] Martinez S, Garrido N, Coperias JL, Pardo F, Desco J, GarciaVelasco JA, et al. Serum interleukin-6 levels are elevated in women with minimal-mild endometriosis. Hum Reprod 2007;22:836–42. [27] Stratton P, Khachikyan I, Sinaii N, Ortiz R, Shah J. Association of chronic pelvic pain and endometriosis with signs of sensitization and myofascial pain. Obstet Gynecol 2015;125:719–28. [28] Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci USA 2004;101:11094–8. [29] Diatchenko L, Nackley AG, Tchivileva IE, Shabalina SA, Maixner W. Genetic architecture of human pain perception. Trends Genet 2007;23:605–13. [30] Sator-Katzenschlager SM, Scharbert G, Kress HG, Frickey N, Ellend A, Gleiss A, et al. Chronic pelvic pain treated with gabapentin and amitriptyline: a randomized controlled pilot study. Wien Klin Wochenschr 2005;117:761–8. [31] Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain 1992;49:221–30. [32] Cheng C, Rosamilia A, Healey M. Diagnosis of interstitial cystitis/bladder pain syndrome in women with chronic pelvic pain: a prospective observational study. Int Urogynecol J 2012;23:1361–6. [33] Schrepf A, Bradley CS, O’Donnell M, Luo Y, Harte SE, Kreder K, et al. Toll-like receptor 4 and comorbid pain in interstitial cystitis/bladder pain syndrome: a multidisciplinary approach to the study of chronic pelvic pain research network study. Brain Behav Immun 2015;49:66–74. [34] Chung MK, Chung RR, Gordon D, Jennings C. The evil twins of chronic pelvic pain syndrome: endometriosis and interstitial cystitis. JSLS 2002;6:311–4. [35] Sant GR, Hanno PM. Interstitial cystitis: current issues and controversies in diagnosis. Urology 2001;57:82–8. [36] O’Leary MP, Sant GR, Fowler Jr FJ, Whitmore KE, SpolarichKroll J. The interstitial cystitis symptom index and problem index. Urology 1997;49:58–63. [37] Kushner L, Moldwin RM. Efficiency of questionnaires used to screen for interstitial cystitis. J Urol 2006;176:587–92. [38] Parsons CL, Greenberger M, Gabal L, Bidair M, Barme G. The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 1998;159:1862–6, discussion 6–7. [39] Drossman DA. The functional gastrointestinal disorders and the Rome II process. Gut 1999;45(Suppl 2):II1–5. [40] Roalfe AK, Roberts LM, Wilson S. Evaluation of the Birmingham IBS symptom questionnaire. BMC Gastroenterol 2008;8:30. [41] Howard FM. Chronic pelvic pain. Obstet Gynecol 2003;101:594–611. [42] Matheis A, Martens U, Kruse J, Enck P. Irritable bowel syndrome and chronic pelvic pain: a singular or two different clinical syndrome? World J Gastroenterol 2007;13:3446–55. [43] Choung RS, Herrick LM, Locke 3rd GR, Zinsmeister AR, Talley NJ. Irritable bowel syndrome and chronic pelvic pain: a population-based study. J Clin Gastroenterol 2010;44:696–701. [44] Prior A, Whorwell PJ. Gynaecological consultation in patients with the irritable bowel syndrome. Gut 1989;30:996–8. [45] Mitchell MD, Mannino DM, Steinke DT, Kryscio RJ, Bush HM, Crofford LJ. Association of smoking and chronic pain syndromes in Kentucky women. J Pain 2011;12:892–9. [46] Malykhina AP. Neural mechanisms of pelvic organ crosssensitization. Neuroscience 2007;149:660–72.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

14 [47] Hammoud A, Gago LA, Diamond MP. Adhesions in patients with chronic pelvic pain: a role for adhesiolysis? Fertil Steril 2004;82:1483–91. [48] Ray NF, Denton WG, Thamer M, Henderson SC, Perry S. Abdominal adhesiolysis: inpatient care and expenditures in the United States in 1994. J Am Coll Surg 1998;186:1–9. [49] Chan CL, Wood C. Pelvic adhesiolysis–the assessment of symptom relief by 100 patients. Aust N Z J Obstet Gynaecol 1985;25:295–8. [50] Peters AA, Trimbos-Kemper GC, Admiraal C, Trimbos JB, Hermans J. 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. [51] Rawson JM. Prevalence of endometriosis in asymptomatic women. J Reprod Med 1991;36:513–5. [52] Koninckx PR, Ussia A, Adamyan L, Wattiez A, Donnez J. Deep endometriosis: definition, diagnosis, and treatment. Fertil Steril 2012;98:564–71. [53] Dassen H, Punyadeera C, Kamps R, Delvoux B, Van Langendonckt A, Donnez J, et al. Estrogen metabolizing enzymes in endometrium and endometriosis. Hum Reprod 2007;22:3148–58. [54] Fauconnier A, Chapron C, Dubuisson JB, Vieira M, Dousset B, Breart G. Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. Fertil Steril 2002;78:719–26. [55] Bazot M, Lafont C, Rouzier R, Roseau G, Thomassin-Naggara I, Darai E. Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis. Fertil Steril 2009;92:1825–33. [56] Vercellini P, Parazzini F, Oldani S, Panazza S, Bramante T, Crosignani PG. Adenomyosis at hysterectomy: a study on frequency distribution and patient characteristics. Hum Reprod 1995;10:1160–2. [57] Bazot M, Cortez A, Darai E, Rouger J, Chopier J, Antoine JM, et al. Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology. Hum Reprod 2001;16:2427–33. [58] Perrot N, Frey I, Mergui JL, Bazot M, Uzan M, Uzan S. Picture of the month. Adenomyosis: power Doppler findings. Ultrasound Obstet Gynecol 2001;17:177–8. [59] Sakhel K, Abuhamad A. Sonography of adenomyosis. J Ultrasound Med 2012;31:805–8. [60] Chatman DL. Pelvic peritoneal defects and endometriosis: AllenMasters syndrome revisited. Fertil Steril 1981;36:751–6. [61] Batt RE, Smith RA. Embryologic theory of histogenesis of endometriosis in peritoneal pockets. Obstet Gynecol Clin North Am 1989;16:15–28. [62] Vilos GA, Vilos AW, Haebe JJ. Laparoscopic findings, management, histopathology, and outcome of 25 women with cyclic leg pain. J Am Assoc Gynecol Laparosc 2002;9:145–51. [63] Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 1927;3(93–110):43. [64] Hesseling MH, De Wilde RL. Endosalpingiosis in laparoscopy. J Am Assoc Gynecol Laparosc 2000;7:215–9. [65] Keltz MD, Kliman HJ, Arici AM, Olive DL. Endosalpingiosis found at laparoscopy for chronic pelvic pain. Fertil Steril 1995;64:482–5. [66] Ness RB, Soper DE, Holley RL, Peipert J, Randall H, Sweet RL, et al. Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial. Am J Obstet Gynecol 2002;186:929–37. [67] Dekel A, Efrat Z, Orvieto R, Levy T, Dicker D, Gal R, et al. The residual ovary syndrome: a 20-year experience. Eur J Obstet Gynecol Reprod Biol 1996;68:159–64.

A. Yosef et al. [68] Magtibay PM, Magrina JF. Ovarian remnant syndrome. Clin Obstet Gynecol 2006;49:526–34. [69] Kho RM, Magrina JF, Magtibay PM. Pathologic findings and outcomes of a minimally invasive approach to ovarian remnant syndrome. Fertil Steril 2007;87:1005–9. [70] Arden D, Lee T. Laparoscopic excision of ovarian remnants: retrospective cohort study with long-term follow-up. J Minim Invasive Gynecol 2011;18:194–9. [71] Donnez O, Squifflet J, Marbaix E, Jadoul P, Donnez J. Primary ovarian adenocarcinoma developing in ovarian remnant tissue ten years after laparoscopic hysterectomy and bilateral salpingooophorectomy for endometriosis. J Minim Invasive Gynecol 2007;14:752–7. [72] Durham JD, Machan L. Pelvic congestion syndrome. Semin Intervent Radiol 2013;30:372–80. [73] Ahlberg NE, Bartley O, Chidekel N. Right and left gonadal veins. An anatomical and statistical study. Acta Radiol Diagn (Stockh) 1966;4:593–601. [74] Beard RW, Reginald PW, Wadsworth J. Clinical features of women with chronic lower abdominal pain and pelvic congestion. Br J Obstet Gynaecol 1988;95:153–61. [75] Park SJ, Lim JW, Ko YT, Lee DH, Yoon Y, Oh JH, et al. Diagnosis of pelvic congestion syndrome using transabdominal and transvaginal sonography. AJR Am J Roentgenol 2004;182:683–8. [76] Beard RW, Highman JH, Pearce S, Reginald PW. Diagnosis of pelvic varicosities in women with chronic pelvic pain. Lancet 1984;2:946–9. [77] Soysal ME, Soysal S, Vicdan K, Ozer S. A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion. Hum Reprod 2001;16:931–9. [78] Laborda A, Medrano J, de Blas I, Urtiaga I, Carnevale FC, de Gregorio MA. Endovascular treatment of pelvic congestion syndrome: visual analog scale (VAS) long-term follow-up clinical evaluation in 202 patients. Cardiovasc Intervent Radiol 2013;36:1006–14. [79] Tu FF, As-Sanie S, Steege JF. Prevalence of pelvic musculoskeletal disorders in a female chronic pelvic pain clinic. J Reprod Med 2006;51:185–9. [80] Alvarez DJ, Rockwell PG. Trigger points: diagnosis and management. Am Fam Physician 2002;65:653–60. [81] Sikdar S, Shah JP, Gebreab T, Yen RH, Gilliams E, Danoff J, et al. Novel applications of ultrasound technology to visualize and characterize myofascial trigger points and surrounding soft tissue. Arch Phys Med Rehabil 2009;90:1829–38. [82] Quinn M. Injuries to the levator ani in unexplained, chronic pelvic pain. J Obstet Gynaecol 2007;27:828–31. [83] Hough DM, Wittenberg KH, Pawlina W, Maus TP, King BF, Vrtiska TJ, et al. Chronic perineal pain caused by pudendal nerve entrapment: anatomy and CT-guided perineural injection technique. AJR Am J Roentgenol 2003;181:561–7. [84] Maldonado PA, Chin K, Garcia AA, Corton MM. Anatomic variations of pudendal nerve within pelvis and pudendal canal: clinical applications. Am J Obstet Gynecol 2015;213(727):e1–6. [85] Oikawa Y, Ohtori S, Koshi T, Takaso M, Inoue G, Orita S, et al. Lumbar disc degeneration induces persistent groin pain. Spine (Phila Pa 1976) 2012;37:114–48. [86] Zelle BA, Gruen GS, Brown S, George S. Sacroiliac joint dysfunction: evaluation and management. Clin J Pain 2005;21:446–55. [87] de Carvalho Ana Carolina Franco, Poli Neto OB, Crippa Jose´ Alexandre de Souza, Hallak JEC, Oso´rio Fla´via de Lima. Associations between chronic pelvic pain and psychiatric disorders and symptoms. Arch Clin Psychiatry 2015;42:5. [88] Pope CJ, Sharma V, Sharma S, Mazmanian D. A systematic review of the association between psychiatric disturbances and endometriosis. J Obstet Gynaecol Can 2015;37:1006–15.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain [89] Nahit ES, Hunt IM, Lunt M, Dunn G, Silman AJ, Macfarlane GJ. Effects of psychosocial and individual psychological factors on the onset of musculoskeletal pain: common and site-specific effects. Ann Rheum Dis 2003;62:755–60. [90] Gurian MB, Mitidieri AM, Rosa ESJC, Poli Neto OB, Nogueira AA, Candido dos Reis FJ. Measures used to assess chronic pelvic pain in randomized controlled clinical trials: a systematic review. J Eval Clin Pract 2015;21:749–56. [91] Vincent K, Kennedy S, Stratton P. Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials. Report from the Art and Science of Endometriosis meeting. Fertil Steril 2010;93:62–7. [92] Jacoby VL, Fujimoto VY, Giudice LC, Kuppermann M, Washington AE. Racial and ethnic disparities in benign gynecologic conditions and associated surgeries. Am J Obstet Gynecol 2010;202:514–21. [93] Zondervan KT, Cardon LR, Kennedy SH, Martin NG, Treloar SA. Multivariate genetic analysis of chronic pelvic pain and associated phenotypes. Behav Genet 2005;35:177–88. [94] Thomas DCEJ. Familial inheritance of endometriosis in a British population. A case control study. J Obstet Gynaecol 1993;13. [95] Zondervan KT, Treloar SA, Lin J, Weeks DE, Nyholt DR, Mangion J, et al. Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13–15. Hum Reprod 2007;22:717–28. [96] Wear LE. Uterine myoma as a hereditary disease. Lancet 1957;272:25–6. [97] Vikhlyaeva EM, Khodzhaeva ZS, Fantschenko ND. Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet 1995;51:127–31. [98] Andersson H, Ejlertsson G, Leden I. Widespread musculoskeletal chronic pain associated with smoking. An epidemiological study in a general rural population. Scand J Rehabil Med 1998;30:185–91. [99] Barton SB, Kofoed BA, Doleys DM. Smoking and narcotics use among chronic pain patients. Psychol Rep 1989;64:1253–4. [100] Rapkin AJ, Kames LD, Darke LL, Stampler FM, Naliboff BD. History of physical and sexual abuse in women with chronic pelvic pain. Obstet Gynecol 1990;76:92–6. [101] Harrop-Griffiths J, Katon W, Walker E, Holm L, Russo J, Hickok L. The association between chronic pelvic pain, psychiatric diagnoses, and childhood sexual abuse. Obstet Gynecol 1988;71:589–94. [102] Roth RS, Punch MR, Bachman JE. Educational achievement and pain disability among women with chronic pelvic pain. J Psychosom Res 2001;51:563–9. [103] Romao AP, Gorayeb R, Romao GS, Poli-Neto OB, dos Reis FJ, Rosa-e-Silva JC, et al. High levels of anxiety and depression have a negative effect on quality of life of women with chronic pelvic pain. Int J Clin Pract 2009;63:707–11. [104] Jenkinson C, Kennedy S, Jones G. Evaluation of the American version of the 30-item Endometriosis Health Profile (EHP-30). Qual Life Res 2008;17:1147–52. [105] Nojomi M, Bijari B, Akhbari R, Kashanian M. The assessment of reliability and validity of Persian version of the endometriosis health profile (EHP-30). Iran J Med Sci 2011;36:84–9. [106] Jones G, Kennedy S, Barnard A, Wong J, Jenkinson C. Development of an endometriosis quality-of-life instrument: the endometriosis health profile-30. Obstet Gynecol 2001;98:258–64. [107] Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006;166:1092–7. [108] Brunahl CA, Riegel B, Hoink J, Kutup A, Eichelberg E, Lowe B. Psychosomatic aspects of chronic pelvic pain syndrome. Psychometric results from the pilot phase of an interdisciplinary outpatient clinic. Schmerz 2014;28:311–8.

15 [109] Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001;16:606–13. [110] Osman A, Barrios FX, Kopper BA, Hauptmann W, Jones J, O’Neill E. Factor structure, reliability, and validity of the Pain Catastrophizing Scale. J Behav Med 1997;20:589–605. [111] Meyer K, Sprott H, Mannion AF. Cross-cultural adaptation, reliability, and validity of the German version of the Pain Catastrophizing Scale. J Psychosom Res 2008;64:469–78. [112] Morris LD, Grimmer-Somers KA, Louw QA, Sullivan MJ. Cross-cultural adaptation and validation of the South African Pain Catastrophizing Scale (SA-PCS) among patients with fibromyalgia. Health Qual Life Outcomes 2012;10:137. [113] D’Eon JL, Harris CA, Ellis JA. Testing factorial validity and gender invariance of the pain catastrophizing scale. J Behav Med 2004;27:361–72. [114] Cho S, Kim HY, Lee JH. Validation of the Korean version of the Pain Catastrophizing Scale in patients with chronic non-cancer pain. Qual Life Res 2013;22:1767–72. [115] Cosar E, Cakir Gungor A, Gencer M, Uysal A, Hacivelioglu SO, Ozkan A, et al. Sleep disturbance among women with chronic pelvic pain. Int J Gynaecol Obstet 2014;126:232–4. [116] Kosinski M, Janagap CC, Gajria K, Schein J. Psychometric testing and validation of the Chronic Pain Sleep Inventory. Clin Ther 2007;29(Suppl):2562–77. [117] Derogatis L, Clayton A, Lewis-D’Agostino D, Wunderlich G, Fu Y. Validation of the female sexual distress scale-revised for assessing distress in women with hypoactive sexual desire disorder. J Sex Med 2008;5:357–64. [118] Verit FF, Verit A, Yeni E. The prevalence of sexual dysfunction and associated risk factors in women with chronic pelvic ’pain: a cross-sectional study. Arch Gynecol Obstet 2006;274: 297–302. [119] Lame IE, Peters ML, Kessels AG, Van Kleef M, Patijn J. Test– retest stability of the Pain Catastrophizing Scale and the Tampa Scale for Kinesiophobia in chronic pain over a longer period of time. J Health Psychol 2008;13:820–6. [120] Briet JP, Bot AG, Hageman MG, Menendez ME, Mudgal CS, Ring DC. The pain self-efficacy questionnaire: validation of an abbreviated two-item questionnaire. Psychosomatics 2014;55:578–85. [121] Evans JR, Jastrowski Mano K, Guite JW, Weisman SJ, Hainsworth KR. Psychometric properties of the pain stages of change questionnaire: new insights on the measurement of readiness to change in adolescents, mothers, and fathers. J Pain 2015;16:645–56. [122] Roe C, Damsgard E, Fors T, Anke A. Psychometric properties of the pain stages of change questionnaire as evaluated by Rasch analysis in patients with chronic musculoskeletal pain. BMC Musculoskelet Disord 2014;15:95. [123] Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152:S2–S15. [124] Jarrell J, Ross S, Robert M, Wood S, Tang S, Stephanson K, et al. Prediction of postoperative pain after gynecologic laparoscopy for nonacute pelvic pain. Am J Obstet Gynecol 2014;211(360):e1–8. [125] Travell JG, Simons DG. Myofascial pain and dysfunction. The trigger point manual. Lippincott Williams & Wilkins; 1999; Volume 1. Upper Half of Body. [126] Nasr-Esfahani M, Jarrell J. Cotton-tipped applicator test: validity and reliability in chronic pelvic pain. Am J Obstet Gynecol 2013;208(52):e1–5. [127] Suleiman S, Johnston DE. The abdominal wall: an overlooked source of pain. Am Fam Physician 2001;64:431–8. [128] Srinivasan R, Greenbaum DS. Chronic abdominal wall pain: a frequently overlooked problem. Practical approach to diagnosis and management. Am J Gastroenterol 2002;97:824–30.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

16 [129] Fischer AA. Algometry in diagnosis of musculoskeletal pain and evaluation of treatment outcome: an update. J Musculoskelet Pain 1998;6:5–32. [130] Tu FF, Fitzgerald CM, Kuiken T, Farrell T, Norman Harden R. Vaginal pressure-pain thresholds: initial validation and reliability assessment in healthy women. Clin J Pain 2008;24:45–50. [131] Kumbhare DA, Elzibak AH, Noseworthy MD. Assessment of Myofascial Trigger Points Using Ultrasound. Am J Phys Med Rehabil 2016;95:72–80. [132] Mayer TG, Neblett R, Cohen H, Howard KJ, Choi YH, Williams MJ, et al. The development and psychometric validation of the central sensitization inventory. Pain Pract 2012;12:276–85. [133] Tu CH, Niddam DM, Chao HT, Liu RS, Hwang RJ, Yeh TC, et al. Abnormal cerebral metabolism during menstrual pain in primary dysmenorrhea. Neuroimage 2009;47:28–35. [134] Tu CH, Niddam DM, Chao HT, Chen LF, Chen YS, Wu YT, et al. Brain morphological changes associated with cyclic menstrual pain. Pain 2010;150:462–8. [135] Gyang A, Hartman M, Lamvu G. Musculoskeletal causes of chronic pelvic pain: what a gynecologist should know. Obstet Gynecol 2013;121:645–50. [136] Vleeming A, Albert HB, Ostgaard HC, Sturesson B, Stuge B. European guidelines for the diagnosis and treatment of pelvic girdle pain. Eur Spine J 2008;17:794–819. [137] Ostgaard HC, Zetherstrom G, Roos-Hansson E. The posterior pelvic pain provocation test in pregnant women. Eur Spine J 1994;3:258–60. [138] Wormslev M, Juul AM, Marques B, Minck H, Bentzen L, Hansen TM. Clinical examination of pelvic insufficiency during pregnancy. An evaluation of the interobserver variation, the relation between clinical signs and pain and the relation between clinical signs and physical disability. Scand J Rheumatol 1994;23:96–102. [139] Vleeming A, de Vries HJ, Mens JM, van Wingerden JP. Possible role of the long dorsal sacroiliac ligament in women with peripartum pelvic pain. Acta Obstet Gynecol Scand 2002;81:430–6. [140] Mens JM, Vleeming A, Snijders CJ, Koes BW, Stam HJ. Reliability and validity of the active straight leg raise test in posterior pelvic pain since pregnancy. Spine (Phila Pa 1976) 2001;26:1167–71. [141] Field T, Hernandez-Reif M, Hart S, Theakston H, Schanberg S, Kuhn C. Pregnant women benefit from massage therapy. J Psychosom Obstet Gynaecol 1999;20:31–8. [142] Kvorning N, Holmberg C, Grennert L, Aberg A, Akeson J. Acupuncture relieves pelvic and low-back pain in late pregnancy. Acta Obstet Gynecol Scand 2004;83:246–50. [143] Luukkainen RK, Wennerstrand PV, Kautiainen HH, Sanila MT, Asikainen EL. Efficacy of periarticular corticosteroid treatment of the sacroiliac joint in non-spondylarthropathic patients with chronic low back pain in the region of the sacroiliac joint. Clin Exp Rheumatol 2002;20:52–4. [144] Yong PJ, Mui J, Allaire C, Williams C. Pelvic floor tenderness in the etiology of superficial dyspareunia. J Obstet Gynaecol Can 2014;36:1002–9. [145] Nourmoussavi M, Bodmer-Roy S, Mui J, Mawji N, Williams C, Allaire C, et al. Bladder base tenderness in the etiology of deep dyspareunia. J Sex Med 2014;11:3078–84. [146] Nezhat Ceana, Santolaya Joaquin, Nezhat Farr R, Nezhat Camran. Comparison of transvaginal sonography and bimanual pelvic examination in patients with laparoscopically confirmed endometriosis. J Am Assoc Gynecol Laparosc 1994;2:127–30. [147] Dragisic KG, Padilla LA, Milad MP. The accuracy of the rectovaginal examination in detecting cul-de-sac disease in patients under general anaesthesia. Hum Reprod 2003;18:1712–5.

A. Yosef et al. [148] Moore J, Copley S, Morris J, Lindsell D, Golding S, Kennedy S. A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet Gynecol 2002;20:630–4. [149] Hudelist G, English J, Thomas AE, Tinelli A, Singer CF, Keckstein J. Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2011;37:257–63. [150] Guerriero S, Ajossa S, Minguez JA, Jurado M, Mais V, Melis GB, et al. Accuracy of transvaginal ultrasound for diagnosis of deep endometriosis in uterosacral ligaments, rectovaginal septum, vagina and bladder: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2015;46:534–45. [151] Abrao MS, Goncalves MO, Dias Jr JA, Podgaec S, Chamie LP, Blasbalg R. Comparison between clinical examination, transvaginal sonography and magnetic resonance imaging for the diagnosis of deep endometriosis. Hum Reprod 2007;22:3092–7. [152] Mais V, Guerriero S, Ajossa S, Angiolucci M, Paoletti AM, Melis GB. The efficiency of transvaginal ultrasonography in the diagnosis of endometrioma. Fertil Steril 1993;60:776–80. [153] Guerriero S, Ajossa S, Mais V, Risalvato A, Lai MP, Melis GB. The diagnosis of endometriomas using colour Doppler energy imaging. Hum Reprod 1998;13:1691–5. [154] Asch E, Levine D. Variations in appearance of endometriomas. J Ultrasound Med 2007;26:993–1002. [155] Valenzano Menada M, Remorgida V, Abbamonte LH, Nicoletti A, Ragni N, Ferrero S. Does transvaginal ultrasonography combined with water-contrast in the rectum aid in the diagnosis of rectovaginal endometriosis infiltrating the bowel? Hum Reprod 2008;23:1069–75. [156] Savelli L, Manuzzi L, Coe M, Mabrouk M, Di Donato N, Venturoli S, et al. Comparison of transvaginal sonography and double-contrast barium enema for diagnosing deep infiltrating endometriosis of the posterior compartment. Ultrasound Obstet Gynecol 2011;38:466–71. [157] Bignardi T, Condous G. Sonorectovaginography: a new sonographic technique for imaging of the posterior compartment of the pelvis. J Ultrasound Med 2008;27:1479–83. [158] Dessole S, Farina M, Rubattu G, Cosmi E, Ambrosini G, Nardelli GB. Sonovaginography is a new technique for assessing rectovaginal endometriosis. Fertil Steril 2003;79:1023–7. [159] Reid S, Lu C, Hardy N, Casikar I, Reid G, Cario G, et al. Office gel sonovaginography for the prediction of posterior deep infiltrating endometriosis: a multicenter prospective observational study. Ultrasound Obstet Gynecol 2014;44:710–8. [160] Pascual MA, Guerriero S, Hereter L, Barri-Soldevila P, Ajossa S, Graupera B, et al. Diagnosis of endometriosis of the rectovaginal septum using introital three-dimensional ultrasonography. Fertil Steril 2010;94:2761–5. [161] Guerriero S, Saba L, Ajossa S, Peddes C, Angiolucci M, Perniciano M, et al. Three-dimensional ultrasonography in the diagnosis of deep endometriosis. Hum Reprod 2014;29:1189–98. [162] Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400–12. [163] Reid S, Condous G. Transvaginal sonographic sliding sign: accurate prediction of pouch of Douglas obliteration. Ultrasound Obstet Gynecol 2013;41:605–7. [164] Marasinghe JP, Senanayake H, Saravanabhava N, Arambepola C, Condous G, Greenwood P. History, pelvic examination findings and mobility of ovaries as a sonographic marker to detect pelvic adhesions with fixed ovaries. J Obstet Gynaecol Res 2014;40:785–90. [165] Reid S, Lu C, Casikar I, Mein B, Magotti R, Ludlow J, et al. The prediction of pouch of Douglas obliteration using offline analysis of the transvaginal ultrasound ‘sliding sign’ technique: inter- and intra-observer reproducibility. Hum Reprod 2013;28:1237–46.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Evaluation of chronic pelvic pain [166] Leon M, Alcazar JL. High sliding sign: a new soft marker of uterine fundus compromise in deep infiltrating endometriosis. Ultrasound Obstet Gynecol 2015;45:624. [167] Guerriero S, Ajossa S, Gerada M, D’Aquila M, Piras B, Melis GB. ‘‘Tenderness-guided” transvaginal ultrasonography: a new method for the detection of deep endometriosis in patients with chronic pelvic pain. Fertil Steril 2007;88:1293–7. [168] Stratton P, Winkel C, Premkumar A, Chow C, Wilson J, HearnsStokes R, et al. Diagnostic accuracy of laparoscopy, magnetic resonance imaging, and histopathologic examination for the detection of endometriosis. Fertil Steril 2003;79:1078–85. [169] Novellas S, Chassang M, Delotte J, Toullalan O, Chevallier A, Bouaziz J, et al. MRI characteristics of the uterine junctional zone: from normal to the diagnosis of adenomyosis. AJR Am J Roentgenol 2011;196:1206–13.

17 [170] Howard FM. The role of laparoscopy in the evaluation of chronic pelvic pain: pitfalls with a negative laparoscopy. J Am Assoc Gynecol Laparosc 1996;4:85–94. [171] Kresch AJ, Seifer DB, Sachs LB, Barrese I. Laparoscopy in 100 women with chronic pelvic pain. Obstet Gynecol 1984;64:672–4. [172] Bedaiwy MA, Henry D, Liu J, Falcone T. Standardization of laparoscopic pelvic examination. Fertil Steril 2013;99:e11. [173] Swanton A, Iyer L, Reginald PW. Diagnosis, treatment and follow up of women undergoing conscious pain mapping for chronic pelvic pain: a prospective cohort study. BJOG 2006;113:792–6. [174] Yunker A, Steege J. Practical guide to laparoscopic pain mapping. J Minim Invasive Gynecol 2010;17:8–11.

Please cite this article in press as: Yosef A et al. Chronic pelvic pain: Pathogenesis and validated assessment, Middle East Fertil Soc J (2016), http://dx.doi.org/ 10.1016/j.mefs.2016.08.001

Suggest Documents