The classification of endometriosis has been an evolving process. In 1978, the American Fertility Society (AFS, now called the American Society for Reproductive Medicine) classified four stages (stages I-IV) and used an arbitrarily weighted point score that included assessment of the extent of endometriosis in two dimensions and the presence and extent of adhesions in the peritoneum, ovaries, and tubes. It also took into account whether the endometriosis was unilateral or bilateral. The size of the endometrioma was considered along with the presence of filmy vs. dense adhesions. In 1985 and again in 1996 (R-AFS), further revisions were made to the original AFS classification [7] (◘ Fig. 24.2). An endometrioma that is larger than 3 cm in diameter is at least stage III disease. Despite the improvements, the correlation between the stage of endometriosis and the likelihood of pregnancy or degree of pain is poor, and future improvement in the classification is both warranted and likely.

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

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

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

Ovarian endometriosis or endometriomas increase with age and are generally associated with a more advanced stage of the disease [2]. This form of endometriosis can be diagnosed with a high level of accuracy by serial ultrasounds. They may be confused with a hemorrhagic corpus luteum, which will disappear over the course of a few months. These ovarian forms of endometriosis often have associated peritoneal implants (77% of the time and 85.4% of these women experienced pelvic pain whereas only 38.3% of those with an isolated endometrioma experienced pain [9]). Only a small percentage of patients with peritoneal implants will eventually develop an endometrioma. Endometriomas can be uniloculated or multiloculated. They are more commonly localized in the left ovary, as with peritoneal implants, likely due to the natural peritoneal fluid flow subsequent to menstrual regurgitation.

Invasion of endometriotic cells deeper than 5 mm has been associated with increased pain [10]. A rectovaginal exam during the menstrual period in the office setting or a thorough exam under anesthesia prior to laparoscopy may alert the surgeon to the presence of these types of lesions. In a study looking at 93 women with deep infiltrating peritoneal endometriosis, 61% had concomitant superficial implants and 51% had endometriomas. Deep nodules were the only form of the disease in just 7% of the women.

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

Endometriosis is mainly present duri ng the reproductive years (average age of 28) and usually regresses during menopause, suggesting that the development and growth of endometriosis is estrogen dependent. Accordingly, the Nurses’ Health Study prospectively assessed predisposing factors for endometriosis and observed an association with early age of menarche, shorter length of menstrual cycles during late adolescence, and nulliparity. Furthermore, women with low estrogen levels and low body mass index, who use alcohol, who are infertile smokers, and who exercise intensely appear to be at decreased risk [11].

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

Managing endometriosis receives the lion share of attention, although investigation into the genesis of the disease does not lag far behind. In fact, it is likely that only with the discovery of the true pathogenesis of endometriosis will more efficacious therapy emerge as well as preventative measures for younger women. The three different endometriosis entities—endometriomas, implants, and retrocervical septum disease—could develop along distinct routes, but overlapping mechanisms are probably at play for at least some of these. The disease has multitudinous theories for pathogenesis, yet only a handful continue to be proffered as valid: (1) retrograde menstruation (Sampson’s theory), (2) metaplastic transformation (Meyer’s theory), (3) lymphatic or hematogenous embolization (Halban’s theory), (4) tissue relocation (i.e., iatrogenic surgical displacement of endometrium during laparoscopy or cesarean section), and (5)immune dysregulation leading to deficient clearance of ectopic endometrial tissue.

Over the years each theory has received indirect corroboration. Retrograde menstruum from the fallopian tubes into the pelvis and beyond has been supported by identifying menstrual tissue refluxing from the fallopian tubes during surgery and the identification of fresh endometrial lesions during menstrual phase laparoscopy. In addition, the baboon model of endometriosis is, in effect, iatrogenic retrograde menses invariably leading to the development of scattered lesions [12]. Lastly, a greater frequency of lesions in the right subphrenic region and left hemipelvis/ovary supports retrograde menses, since these locations follow the natural tendency of intra-abdominal peritoneal flow and obstruction via the falciform ligament. Unclear, however, is why endometriosis is not then found in all women, given the ubiquitous nature of retrograde menstruation.

Metaplasia of the coelomic epithelium seems equitable given that both peritoneal and endometrial tissues emanate from coelomic cells. Zheng et al. have shown histologic, morphologic evidence of transitioning ovarian surface epithelium into endometriotic cells, corroborating a metaplastic process [13]. A corollary to this postulate is that of the embryogenetic theory or Müllerianosis : misplaced endometrial tissue during the embryologic period of organogenesis. Signorile et al. demonstrated the presence of ectopic endometrium in 9% of 101 human female fetuses [14]. With endogenous estradiol stimulation later in life, this tissue could grow and thus present as ectopic implants. Theoretically, deep retrocervical septum lesions could derive from such abnormal embryogenesis.

Newer, exciting pathophysiology theories borrow from the traditional theories and, most significantly, build upon these premises in order to better grasp the true etiology. For instance, stem cells originating from the bone marrow (Meyer’s theory) have been found to populate eutopic endometrium (Halban’s theory) that may then be shed (Sampson’s theory) into the peritoneal cavity. Vercellini et al. provided another concept for the development of endometriomas when they described how a hemorrhagic corpus luteum may progress to an endometrioma [15]. If this were truly an endometrioma, then retrograde menses (Sampson’s theory) would be a prerequisite to seed the cyst contents with endometrial cells.

Underlying virtually all of these theories is the molecular underpinnings of the disease and, in particular, the inherent immune dysfunction that could at once promote and sustain endometriosis [16]. The aberrant immune factors found in women affected with endometriosis could explain why some develop the disease while others do not. The chronic inflammatory milieu can impair normal clearance of endometrial tissue and encourage adherence/invasion, angiogenesis, and nerve fiber innervation [17].

Even though there is a purported association between infertility and endometriosis, the mechanism of this association remains complex and is not completely understood [18]. A population based cohort study using record linkage comparing 5375 women with surgically confirmed endometriosis with outcomes in 8710 women without endometriosis revealed an increased risk of miscarriage [19]. The following factors may explain a diminished fecundity:

Pain associated with endometriosis is quite complex. Pain associated with advanced disease can be caused by extensive adhesions, ovarian cysts, or deeply infiltrating endometriosis. Expression of nerve growth factor is associated with endometriosis pain. Sensory nerve fibers have been found more frequently in the functional layer of the endometrium of women with endometriosis than those unaffected by the disease. Finally, discrete changes in the central pain system (i.e., regional gray matter volume) may contribute to chronic pain in women with endometriosis [20].

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