Endometriosis (Volume 3) Pankaj Desai, Purvi Patel
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Epidemiology of Endometriosis1

Suman Bijlani
Pundalik Sonawane
 
INTRODUCTION
Endometriosis, defined as the presence of endometrial tissue outside the uterus, is a leading cause of pelvic pain and infertility among women. It is the third leading cause of gynecologic hospitalization1 and the number one cause of infertility in the United States and affects an estimated 8 to 10% of women in the reproductive age group. It accounts for 2–10% of outpatient gynecological consultations and is an indication for approximately 20% of laparoscopies.
Previously deemed a curse of affluence, we now know that endometriosis cuts across the socioeconomic barrier. With about 100 million women across the globe suffering from endometriosis, the economic impact of this disease is staggering. Probably the most far-reaching of the consequences of endometriosis, however, is its effects on mental health. Though not immediately life threatening, the disease affects the quality of life of the woman (pain, dyspareunia and infertility, Table 1-1) and can frustrate the patient and her physician alike by its propensity to recur throughout her reproductive life span. Numerous groups have been formed worldwide to provide support and information to sufferers and their families.
 
ENDOMETRIOSIS—THE ETERNAL DILEMMA
It is interesting to note that despite its increasing incidence over the decades and frenzied research in the field, investigators have not been able to solve the puzzle of endometriosis.
Various theories have been proposed over the years to explain its pathogenesis and newer hypotheses continue to be formulated. The most popular theory remains the ‘Sampson's Retrograde Menstruation Theory’ which suggests that endometriotic lesions result from reflux of viable endometrial tissue through the fallopian tubes which subsequently implants on 2peritoneal surface or pelvic organs.
Table 1-1   Distribution of symptoms among endometriosis patients
Chief Complaint
N
%
Cyclical urinary complaints
1
0.1%
Cyclical intestinal complaints
33
3.7%
None (asymptomatic)
23
2.6%
Dysmenorrhea
555
62.2%
Deep dyspareunia
19
2.1%
Chronic pelvic pain
119
13.3%
Infertility
125
14.0%
Total
892
100.0%
Table adapted from Bellelis et al. 2 A retrospective study of 892 post-laparoscopy patients with histologically confirmed diagnosis of endometriosis.
The peritoneal lesions, thus, would be attributed to the survival, adhesion, proliferation, invasion and vascularization of the regurgitated endometriotic tissue, an idea referred to as the ‘Implantation Theory’.
However, this theory fails to explain the pathogenesis of ovarian and specific forms of deep endometriosis as well as distant endometriosis. It also fails to explain why only some women develop the disease although some degree of menstrual reflux is a ubiquitous phenomenon.
According to some authors, peritoneal endometriosis, endometriosis of the ovary and rectovaginal endometriosis must be considered as three separate entities with different pathogeneses (The ‘Metaplasia Theory’).3 Today one of the main sources of debate is whether or not the different forms of the disease have a unique common etiology or conversely, represent three separate entities with different pathogeneses.
Whatever be the source of the lesions, immunological-inflammatory factors are implicated in the pathogenesis. Implantation of menstrual effluent in the peritoneal cavity could be due to the failure of immune mechanisms to eliminate these cells from extraneous sites.
It has also been found that women with endometriosis had at least one type of autoantibody present in serum, with statistical elevations in ANA, sm antibodies, anticardiolipin antibodies and lupus anticoagulant as compared to controls.4 These auto-reactive antibodies could, however, be a natural by-product of inflammation and local tissue destruction, and may be implicated in miscarriage in patients with endometriosis.5 Women with endometriosis 3have elevated cellular and non-cellular markers of inflammation, and oxidative stress in the follicular and peritoneal environments, suggesting that oxidative stress plays an integral role in the pathogenesis of endometriosis although it is not clear whether inflammation is the effect rather than the cause.
In addition, the fact that endometriosis is predominantly a condition of the reproductive life span suggests a strong estrogenic influence in its genesis. However, postmenopausal endometriosis is now a known entity, though rare.
 
AN EPIDEMIOLOGICAL APPROACH TO ENDOMETRIOSIS
Much can be learnt from the characterization of endometriosis patients, as family history, personal history, habits and lifestyle are all likely to affect disease development. The study of the epidemiology of endometriosis is thus a critical tool for the understanding of its etio-pathogenesis. Unfortunately, the evaluation of the incidence, prevalence, and risk factors of endometriosis is fraught with difficulties.
 
IS ENDOMETRIOSIS ALWAYS A DISEASE?
The answer to this question could be the key to many a mystery surrounding endometriosis. Asymptomatic endometriosis is being increasingly identified in women undergoing laparoscopy for unrelated indications such as tubal sterilization (prevalence of 2–18% in women diagnosed incidentally at tubal sterilization)6,7 and many researchers are of the opinion that occult endometriosis is a common, in fact, normal occurrence in many women and may represent a physiological process. Johannes LH Evers has said, “Endometriosis does not exist; all women have endometriosis.” For the many visible lesions, there may exist many invisible ones, perhaps waiting to develop into visible endometriosis. In fact, surgical pathology of blind biopsies of visually normal peritoneum in endometriosis patients has shown 14% occult endometriotic lesions. In non-endometriosis patients, the corresponding figure is 6%.8,9 For this reason, some authors have suggested that epidemiological studies should be directed only to advanced or at least symptomatic endometriosis.10 This view has however not been universally accepted.11
Some gynecologists have suggested that endometriosis be defined not only by the presence of ectopic endometrium, but also by evidence that the lesions are ‘active cellularly’ or have affected normal physiology.12
There is much controversy also as to whether minimal to mild endometriosis in the absence of anatomic distortion should be considered a cause of infertility and treated as such.
4
 
CHANGING DEFINITIONS OF ENDOMETRIOSIS
This brings us face to face with one of the major dilemmas in estimating endometriosis incidence and prevalence. Isn't it obviously difficult to figure out ‘how much’ is endometriosis if we are not even clear about ‘what’ constitutes endometriosis? Is it a symptom complex (pain, subfertility), or is it visible lesions within the peritoneal cavity with or without symptoms, or is it histologically proven endometrial tissue outside the uterus? How does one prove that the lesion is ‘cellularly active’? Does adenomyosis constitute a type of endometriosis?
The definition of endometriosis has evolved over the years, and from being described as “a disorder causing pain and requiring surgery” in the early 20th century, we now know that endometriosis is characterized by different types of peritoneal and extra-peritoneal lesions which have specific histological characteristics. The relatively recent identification of more subtle forms of lesions on laparoscopy (non-pigmented, vesicular, flame-like and finally microscopic) has resulted in an increased reporting of prevalence over the years.
So it depends on the definition you use and the meticulousness with which you scrutinize the peritoneal cavity whether endometriosis occurs frequently, always, or not at all!
 
PITFALLS IN EPIDEMIOLOGICAL RESEARCH INTO ENDOMETRIOSIS
We now know that, in the absence of a uniform definition, standardization of results from various studies on endometriosis is an uphill task. Yet, that is not all.
The precise timing of onset of endometriosis is generally not known. The time from onset of symptoms to diagnosis is often many years. Hence it is extremely difficult to determine the incidence of the disease.
One of the biggest obstacles is the absence of a non-invasive tool for diagnosing endometriosis. Direct visualization (laparoscopy or laparotomy) is the gold-standard technique for this purpose. However, limiting the definition of endometriosis to women with a laparoscopic diagnosis may introduce a selection bias. It is possible that patients with greater access to medical care or with more advanced or aggressive disease may be more likely to undergo laparoscopy and another segment of cases is likely to go unreported. This includes women with pelvic pain or infertility, who never resort to laparoscopy for various reasons.
Not to mention that the recognition of this condition at laparoscopy varies with the level of training and experience of the surgeon. Deep infiltrating 5lesions may not always be recognized and sub-diaphragmatic lesions often missed. Although larger lesions can be diagnosed by contrast enema, or by trans-vaginal or trans-rectal ultrasound, or MRI, for none of these imaging techniques the sensitivity of detecting smaller lesions have been reported. Biopsy of the lesions to nail the diagnosis, though ideal, is not always feasible due to technical difficulties. Histopathological confirmation rarely exceeds 80%.13 Even when biopsies have been taken, it remains unclear how women with subtle lesions which have not been confirmed by biopsy, should be classified.
Cystic ovarian endometriosis further presents the difficulty that, clinically and on ultrasound, it may not be possible to distinguish it from a hemorrhagic corpus luteum.
To add to the confusion, the widely used rAFS classification has never been validated as a tool to score infertility or pain.13 The patient's symptoms too, may not always correlate with the severity or extent of disease.
Taken together, the absence of a uniform definition, an easy non-invasive diagnostic tool and a validated classification system, preclude valid statistical evaluation of data obtained from various studies.
Few well-designed epidemiologic studies of risks factors for endometriosis exist. Eskenazi et al1 conducted a review of more than 100 published studies and found that only 6 (1 cohort and 5 case control studies) including a surgically confirmed case group, provided clear criteria for control selection and considered potential confounding factor in the analysis.
The populations studied also vary widely and include women with pelvic pain, infertile women, those undergoing hysterectomy (vaginal or abdominal) or tubal sterilization or laparoscopy for an unrelated indication, and women unexposed to spermatozoa.
It is a small wonder then, that medical literature shows wide discrepancy in the reporting of incidence and prevalence rates of endometriosis. In all likelihood, the current reported prevalence is an underestimation.
 
REPORTED PREVALENCE AMONGST GENERAL POPULATION
Currently, more than 10 million women in the US are known to have endometriosis and 400,000 hysterectomies are attributed to it every year. However, prevalence data in the general population is less readily available due to the ethical constraint of performing laparoscopy to diagnose the disease in healthy women (Table 1-2). Understandably such studies are limited in numbers as well as show varying results depending on the diagnostic criteria applied and the type of study population (women attending family planning 6clinics, study of hospital discharges, self-reported cases in surveys, incidental diagnosis or unselected population).
Table 1-2   Prevalence and incidence of endometriosis from large hospital based studies or from population based studies
Author(year)
Total (n)
N with endometriosis
Prevalence/incidence
Houston (1987) (hospital based study)15
1970 census (N=14,472) 1980 census (N=17,231)
388 total
171(HC)
81(SV)
121(CPR)
15(CPO)
Incidence (per 100,000 person-years) 108.8 (HC) 160.4 (HC+SV) 237.4 (HC, SV,+CPR) 246.9 (HC, SV, CPR,+CPO)
Boling (1988) (hospital based study)17
1,04,129 laparoscopy or laparotomy charts
6456
6.20%
Wheeler(1988) (hospital based study)18
13354 total)
1. 1860 anastomosis
2. 3060 tubal ligation
3. 5511 hysterectomy (abdominal)
4. 2065 laparoscopy 5.858 hysterectomy (vaginal)
1374 total
1. 13
2. 49
3. 622
4. 619
5. 71 (Histologic diag)
10.30%
Vessey et al (1993) (hospital based study)14
17,032 diagnosis of endometriosis on laparoscopy or laparotomy
By end of 1990(~41-61 year olds)142 primary diagnosis 171 any diagnosis 313 total
0.80%1% 1.80%
Velebil et al (1995) (hospital based study)19
5,067,500 hospital discharges
5,66,400
11.2% prevalence (32.4/10,000 women of reproductive age average annual rate)
Kjerulff et al (1996) (population based study)16
Self-reported 31,617
211 endometriosis (1666 menstrual disorder)
6.9/1000 women with endometriosis (53.0/1000 women with menstrual disorder)
HC—histological confirmed
SV—surgically visualized
CPR—clinically probable (with pain and positive examination)
CPO—clinically possible (positive examination)
Table adapted from Eskenazi et al. 1
7
Medical literature reports prevalence rates varying from 1.8% to 3.3% in the general population for surgically or histologically confirmed endometriosis.14,15 The incidence was found vary between 1.6 per 1000 new cases per year to 6.9 per 1000 white women.16 If clinically probable endometriosis were to be accounted for, the rates would double. Add to that asymptomatic cases, and the prevalence would be still higher.
In a recent study (2011), Buck Louis, et al20 reported the incidence as 0.7% for only histology, 7% for only MRI and 41% for visualised disease. They concluded that the incidence of endometriosis is dependent on the diagnostic method and the choice of sampling framework. They estimated that 11% of women have undiagnosed endometriosis at the population level.
 
REPORTED PREVALENCE AMONGST SELECTED POPULATION
 
Endometriosis in Infertile Women
Prevalence of endometriosis is 25 to 40% among infertile women. Endometriosis is associated with twentyfold odds of infertility with about 40% of endometriotic patients suffering from primary or secondary infertility. Women with endometriosis are likely to report fewer prior pregnancies, elective abortions and ectopic pregnancies compared to women seeking care for infertility, who do not have endometriosis.21 Miscarriage does not appear to be a risk factor for the development of endometriosis (Table 1-3).2
 
Endometriosis and Chronic Pelvic Pain
The 2004 American College of Obstetrics and Gynecology clinical management guideline states that the prevalence of endometriosis is approximately 33% in women with chronic pelvic pain (CPP). However, endometriosis is probably responsible for more than half cases of CPP. Endometriosis prevalence for women admitted to hospital for pelvic pain is 5–21%.2225
Pain is the prominent feature in deep infiltrating endometriosis (DIE), especially if the lesions penetrate deeper than 5mm or infiltrate nerves. There is a clear-cut relation between posterior DIE and deep dyspareunia, as well as between pelvic adhesions and dysmenorrhea. The evidence for a relationship between cystic ovarian endometriosis and painful symptoms is poor.
Demographic and epidemiologic parameters in women with endometriosis differ, depending whether chronic pelvic pain or infertility are the presenting symptoms. In the pain group, diagnostic delay is longer and endometriosis 8at diagnostic laparoscopy more advanced, indicating progressiveness of the disease (Table 1-3).
Table 1-3   Prevalence of endometriosis during laparoscopy by indication for surgery
Total (N)
N with endometriosis
%
Range in %
% with minimal /mild disease
Range in%
Pelvic pain
2400
588
24.5
4.5–82.0
69.9
61–100
Infertility
14,371
2812
19.6
2.1–78.0
65.6
16.3–95
Tubalsterilization
10,634
433
4.1
0.7–43.0
91.7
20–100
Table Adapted from Eskenazi B, et al. 1
 
Endometriosis in Adolescents
Endometriosis is the most common pathologic condition in adolescents with pelvic pain, and has been reported in 25–38% of adolescents with pelvic pain.26,27 The prevalence of endometriosis among adolescents undergoing laparoscopy for pelvic pain refractory to medical therapy has been reported to be 50-70%.28,29 Many providers, including pediatricians, family physicians and gynecologists may not be well versed with the symptoms of endometriosis in young women leading to delay in the diagnosis, which may result in advanced disease at the time of surgery. Early diagnosis and intervention are critical in this segment to avoid long-term morbidity.
 
Endometriosis after Menopause
There is a small risk of recurrence or de novo occurrence of endometriosis after the menopause. Doubts have been raised in the past that pathophysiology of postmenopausal endometriosis is different to premenopausal disease. However, a recent study30 confirmed similar immunohistochemical profile in the two situations and inferred that it is the same process, which has the potential to reactivate given the appropriate stimulus. Thus, postmenopausal patients who take hormone therapy (HT); especially estrogen only therapy (ET) are at a relative risk of developing endometriosis.
The risk of malignant transformation of premenopausal endometriosis is around 1%. The risk of malignant transformation appears to be increased in postmenopausal women and is further elevated in patients who take ET compared to those taking combined HT, although this subject is not fully 9elucidated. This suggests that hormone replacement therapy should generally be reserved for patients with severe climacteric complaints, and if indicated, combined therapy should be used.31
 
RISK FACTORS
Endometriosis is a complex trait with significant environmental and genetic influences that are likely to affect expression. One of the key roles of epidemiological studies is to find associations of the said disease with various causative agents. Population-based analyses on endometriosis have brought to light many unique and interesting components to the disease.
 
Age
Endometriosis is a disease of the reproductive age group. It is rare before menarche and after menopause. Interestingly, John Huffman first related the diagnosis of endometriosis to thelarche. Based on the findings of endometriosis in girls between thelarche and menarche, some researchers32 have suggested that the theory of embryonic Müllerian rests be added to the currently accepted pathogenesis of endometriosis.
 
Race
Most studies have found ethnic differences with higher prevalence among Caucasian and Japanese women, but not statistically significant ones, suggesting that racial factors may not play a major role in endometriosis development.
 
Education and Socioeconomic Status
Women with higher education and those higher in the social rung may be at a higher risk of developing endometriosis. It is possible that superior health awareness and access to health care services in this class of women gives them a better chance at being diagnosed thus leading to higher ‘reported’ prevalence.
 
Menstrual and Reproductive Factors
In addition to their relation to the hormonal milieu, menstrual cycle characteristics and reproductive history may influence the total ‘bulk‘ of endometrial cells released into peritoneal cavity. The risk of endometriosis has been found to increase with increased exposure to menstruation, such as menstrual cycles shorter than 27 days, longer duration of flow (greater than 7 days) and early menarche. Late menarche (after the age of 14) is 10strongly and inversely correlated with subsequent endometriosis.33 The association of irregular cycles and heavy menstrual flow with endometriosis is less clear.
Literature reports a prevalence of endometriosis up to 76% among dysmenorrheal women in women, with linear increase in risk with the severity of symptoms. It has also been reported that women who report an early history of dysmenorrhea are at an increased risk. However, dysmenorrhea may be symptom of the disease rather than a risk factor.34,35
Greater parity is consistent with lower risk of endometriosis.11 This further strengthens the menstrual reflux theory as each pregnancy means fewer cycles of menstruation in a lifetime. Nulliparity has been consistently reported to be strongly associated with endometriosis, although it is impossible to determine whether it increases the risk or it is just an extension of the fact that women with endometriosis find it harder to conceive.
It has been suggested that women who use tampons exclusively may have less chances of developing endometriosis, possibly as tampon use is a likely deterrent to sexual indulgence during menstruation and avoiding this behavior might protect against the disease.36,37 However, the general consensus is that the type of sanitary protection used does not impact the development of endometriosis.
 
Contraceptive Choices and Endometriosis
The effect of oral contraceptive pill (OCP) usage on endometriosis is controversial, with some studies showing protective and others showing an increased risk. Inconsistent findings are probably the result of the dual effect of OCPs on endometriosis. The effect of inhibiting ovulation and decreasing menstrual blood flow reduces the risk while exogenous hormonal exposure possibly increases the chances of implantation and lesion growth. There is, to date, no convincing evidence of association between IUD usage and endometriosis development.1,14
 
Body Habitus
There is a weak inverse association between endometriosis and weight and body mass index (both at the time of diagnosis and historically, i.e. during childhood and young adulthood), suggesting that there may be a childhood origin for endometriosis.38,39
An inverse correlation between endometriosis and waist-to-hip ratio has been suggested for women below the age of 30.40,41 Body fat distribution is a good marker of endogenous estrogen levels in premenopausal women, as women 11with a higher ratio of androgens to estrogens appear to concentrate body fat centrally and those with a relatively high estrogen level have more peripheral accumulation of fat.
Height has been implicated as a positive risk factor for endometriosis34 possibly as a result to the higher follicular phase plasma estradiol levels that have been noted among taller women.42
Some authors have suggested that an ‘endometriosis phenotype’ be identified. This may consist of early menarche, short cycles, painful periods, subfertility and possibly tall stature and leanness. These could be candidates for the identification of genetic markers so that a particular genotype may be correlated with these factors even if a formal diagnosis of endometriosis has not been made.43
 
Lifestyle and Environmental Factors
It has been found that influences that enhance the estrogen milieu tend to increase endometriosis risk while those that suppress it, tend to decrease the risk.
Heavy smokers (one or more pack a day), especially those who had begun before the age of 17, may have a lower risk due to their relative estrogen deficient state. However, this association is not consistent44 and needs to be tested further.
Alcohol and caffeine intake may increase the risk.45 Moderate intake of alcohol has been shown to increase total and bioavailable estrogen. Regular strenuous exercise, which may reduce estrogen levels, has been associated with reduced risk of endometriosis.46
Environmental exposure to polychlorinated biphenyl or dioxin-based compounds has been implicated in endometriosis development through their effect on the immune system.47 However, there is insufficient evidence to support the same.48
The role of diet in endometriosis genesis is under study with some evidence that green vegetables and fresh fruits are protective while red meats and ham increase the risk.49
 
Mullerian Anomalies
There is a higher incidence of endometriosis among women with Mullerian anomalies than controls. Obstructive anomalies are associated with more endometriosis than non-obstructive anomalies, again hinting at menstrual reflux as an important component of endometriosis development.50 The association of non-obstructive anomalies with endometriosis is less clear. 12One recent study has suggested a higher incidence of endometriosis in patients with septate uterus.51
 
Intrauterine Environment
Very early influences as early as intrauterine life may play an important role in determining the female fetus' risk for the development of future endometriosis. Limited studies have demonstrated an inverse correlation between endometriosis incidence and birth weight. It has been suggested that women who are born as one of a multiple gestation may be at an increased risk. In utero exposure to DES increases the risk to the tune of 80%. There is no correlation between preterm birth with endometriosis.52 Whether breastfed babies are relatively protected from endometriosis in later life, is not clear.
 
Familial Clustering
Endometriosis does seem to cluster in families with the type of inheritance being polygenic or multifactorial. A number of studies have demonstrated that first degree relatives of endometriosis patients are 5 to 7 times more likely to have surgically confirmed disease.53,54 There is an increased concordance for endometriosis in mono-versus di-zygotic twins.55 Endometriosis in families tends to be more severe and occurs at an earlier age as compared to sporadic cases, which suggests more genetic liability in individuals with severe disease.56
It is however, important to remember that familial clustering may not always reflect a genetic etiology, but could represent other risk factors for the disease common to families, such as lifestyle or diet or an intermediate factor associated with the development of endometriosis that is inherited, such as age at menarche.
 
Genetic Predisposition
Genomic studies suggest that endometriosis is the result of abnormal expression or regulation of certain key genes. Linkage studies using sub-pair analysis of individuals with surgically confirmed endometriosis and their families have revealed a peak of linkage on chromosome 10 and suggestive peaks on chromosome 20 and chromosome 7p.57 However, given the wide spectrum of symptomology in endometriosis, it is unlikely that one or few polymorphisms would account for all causes of endometriosis and for its variable age at onset. If susceptibility-conferring DNA variants do exist, they are either likely to be responsible for only a small portion of endometriosis or are individually of small marginal importance and of high frequency, and are characterized by extensive heterogeneity.13
Recent studies indicate that endometriosis is an epigenetic disease wherein HOXA20 is aberrantly methylated in the endometrium,58 PR-B is aberrantly methylated in ectopic endometrium59 and that genes coding for DNA methyltransferases are aberrantly expressed in ectopic endometrium.60
However, the presumption that major susceptibility genes exist for endometriosis still needs careful scrutiny.
 
Comorbidities
Studies have demonstrated an increased frequency of endometroid carcinoma of the ovary in patients with endometriosis. There may also be an association between family history of cancer and the development of endometriosis.61
Fibromyalgia, chronic fatigue syndrome, autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, hypo- and hyperthyroidism and multiple sclerosis), allergies and asthma occur more frequently in women with endometriosis than in women in the general population.62
There has also been reported a significantly higher proportion of uterine leiomyoma among patients with endometriosis compared with controls.63
These data suggest an association between endometriosis and other disorders and indicate the need to consider the coexistence of other comorbid conditions in women with endometriosis (Table 1-4).
 
Epidemiology of Recurrence
It is with good reason that we include the topic of recurrence in our chapter. One reason is that the ability of endometriosis to recur after medical or surgical treatments offers one of its biggest challenges. Secondly, studies that have attempted to study this aspect of endometriosis provide valuable insights into the pathogenesis, as we shall soon elucidate.
A few clinically relevant questions which come to mind with respect to endometriosis recurrence are: What is the profile of patients most likely to relapse? After the surgery, in which time period is the patient most prone to recurrence? Similarly, is it true that the patient is less likely to recur once she remains to be recurrence-free for one or two years?
The answer to these questions lies in the answer to the biggest question of all: Is recurrence a ‘de novo’ phenomenon or ‘in situ’ disease?
While the identification of risk factors for recurrence may tell us which particular patient subgroups are most prone to recurrence, the understanding of the recurrence patterns may help us identify which time period after surgery has higher risk of recurrence. Obviously, these two approaches offer entirely different perspective, and the combination of the two should help shed more lights on the causes and possibly mechanisms of recurrence.
14
Table 1-4   Summary of risk factors for endometriosis
Risk factor
Direction and consistency of effect
MENSTRUAL AND REPRODUCTIVE FACTORS
Earlier age of menarche
↑ ↑ Consistent
Shorter menstrual cycle length
↑ ↑ Consistent
Heavy menstrual flow
Limited studies
Irregular cycle duration
Inconsistent
Tampon use
Inconsistent
Oral contraceptive use
Inconsistent
Greater parity
↓ ↓ Consistent
BODY HABITUS
Greater height
Inconsistent
Greater weight
Inconsistent
Greater body mass index
Consistent
Greater waist-to-hip ratio
Limited studies
Red hair
↓ ↓ Limited studies
White race
↑ ↑ Limited studies
LIFESTYLE AND ENVIRONMENTAL FACTORS
Regular exercise
Limited studies
Cigarette smoking
Inconsistent
Alcohol use
Limited studies
Caffeine intake
Limited studies
PCB, dioxin exposure
Consistent inprimates but inconsistent in women
IMMUNE DISORDER COMORBIDITY
Diagnosis with an immune disorder
↑ ↑ limited studies
Arrows indicate the approximate magnitude of the relation
slight to moderate increase risk;
↑ ↑ moderate to large increase in risk;
slight to moderate decrease risk;
↓ ↓ moderate to large decrease in risk;
no association
Table adapted from Missmer SA, Cramer DW. 12
15
Few studies on endometriosis have studied recurrence patterns. In an interesting study,64 investigators found a constant hazard rate in the first 28-30 months after surgery, indicating that the recurrence in that period is completely random. After that period, the hazard rate increased dramatically. The existence of a completely random recurrence period may be a universal phenomenon, with its duration and the magnitude of recurrence risk determined by patient characteristics and quality of care. The second phase of much higher recurrence risk may reflect successful reseeding, reimplantation, and regrowth of ectopic endometrium. Indeed, it took a minimum of about 4 years from the onset of menarche to the first surgery for ovarian endometrioma (Liu et al, unpublished observation). In view of the documented diagnostic delay of (and subsequent surgery for) endometriosis in women with complaints of chronic pelvic pain, it is reasonable to speculate that it might take approximately 2 years to develop de novo ovarian endometrioma. Future studies with longer follow-up and careful documentation as to whether recurrent ovarian endometrioma occurs de novo or in situ will be thus helpful to further illuminate this issue.
No consensus has been reached for risk factors for recurrence either.
Studies on recurrence concur that postoperative pregnancy is a favourable prognostic factor.65,66 On the contrary, a history of previous medical management prior to surgery is a strong risk factor for recurrence.64,65 Possibly, pre-operative medication may result in morphological changes in the lesions such as edema, atrophy or reduction in size, rendering them hard to detect at surgery. These undetected lesions may be the source of later recurrence. Alternatively, it is possible that hormonal ablative therapy may alter certain genomic characteristics of the endometriotic lesions leading to a greater chance of recurrence.
The total rAFS score, not stage is a risk factor,64 but stage IV disease may be associated with higher recurrence.67 This finding highlights certain fallacies of the rAFS classification, which despite its plus points, is not based on any empirical evidence that it would correlate with endometrioma recurrence.68 Besides, the rAFS stage may not distinguish subgroups of patients who have different recurrence risks.
Younger age64 correlates with higher estrogen levels and possibly younger age at onset represents a more aggressive form of disease and may, thus, be associated with higher relapse rates, though all researchers do not concur on that.65 Previous surgery for endometrioma (perhaps indicating a more 16aggressive form of disease) may be an unfavorable prognostic factor.64,65,67 The effect of cyst size on recurrence of endometrioma is controversial.64,65 The number of cysts or bilateral disease and the association of pain or infertility have not been proven to affect the chances of recurrence.65
A point of note is that the risk factors for recurrence were similar for endometriosis at different sites.66 However, deep infiltrating disease may have a higher propensity for recurrence,66 though this is not a universal finding.64
 
Epidemiological Insights into Endometriosis
Epidemiological studies, as seen above, have sought out the various influences, interplays and associations that go into the making of and recurrence of endometriosis. There has been recently increased interest in genomic studies and immune system research into endometriosis. The latest information that a number of epigenetic markers are altered in endometriosis may provide some interesting answers to the riddle of endometriosis. Yet, given its multifaceted manifestation and multifactorial etiology, we are still a long way from “getting to the bottom” of this enigmatic disorder.
The genesis of endometriosis could well represent a “seed and soil” analogy wherein later life influences work upon a genetically susceptible individual to cause a derangement in the normal milieu. The determinants of endometriosis may, thus, be genetic with hormonal, immunological and environmental inputs from the early years, even intrauterine life playing a modulating role. Why some of these women develop florid symptoms and anatomical distortion, while others lead perfectly normal lives, remains a mystery. Whether ‘asymptomatic (non-disease) endometriosis’ and ‘disease endometriosis’ have different origins or whether these two are the two ends of the spectrum of the different stages of the disease, is debatable.
The role of the immune system as a modulator of endometriosis is strongly suspected, but as yet uncertain and more research is warranted before arriving at a consensus on an immunological basis for the disease.
 
Is Endometriosis a Malignancy?
Endometriosis is a neoplastic process, which shows some similarity with malignancy, that is local invasion and angiogenesis. The key challenge remains, however, to find an answer to the question whether endometriosis is a normal endometrial cell or an abnormal-a modified endometrial cell. This is important to understand prevention, which can be prevention of implantation, or prevention of cellular damage. Also for therapy this would 17constitute a fundamental difference, since a modified endometrial cell could have a specific point of attack, without damaging the endometrium.
 
Economic Burden of Endometriosis
Endometriosis impairs quality of life and work productivity across countries and ethnicities. In one study, each affected woman lost on average 10.8 hours (SD 12.2) of work weekly, mainly owing to reduced effectiveness while working. Loss of work productivity translated into significant costs per woman/week, from US$4 in Nigeria to US$456 in Italy.69
American businesses lose billions of dollars each year in lost productivity and work time because of the disease. Annual health care costs and costs of productivity loss associated with endometriosis have been estimated as $2801 and $1023 per patient, respectively. Assuming a 10% prevalence rate, annual cost of endometriosis in the U.S. was estimated at $22 billion in 2002.70
To date it has not been possible to determine whether a medical approach is less expensive than a surgical approach to patients of endometriosis presenting with chronic pelvic pain. Evidence of endometriosis costs in infertile patients is largely lacking.70
 
Impact on Mental Health
A recent survey data from women with self-reported, surgically diagnosed endometriosis showed that living with endometriosis may be characterized by physical limitations that disrupt health, work and daily life.71 In another survey, 16 50% of women who reported endometriosis had required bed rest for at least one day during the past year on account of the disease, the average number of bed rest days being 17.8!
The suffering is compounded by the frequent delay from the onset of symptoms to a confirmed diagnosis, which may average 6 years or more.72 Due to their non-specific nature, early symptoms are often overlooked or the family physician consulted. The time to referral to a specialist is often months to years and even then a conservative approach is usually the preferred management option and laparoscopy the last resort. Women presenting with infertility or pain are most often diagnosed in their early thirties. The mean age at diagnosis of endometriosis was found to be 33.2 years in a recent series.2
It is rather unfortunate that, in many a case, the patient, her family and her doctor are completely baffled by a disease whose only proof of existence is the patient's own symptoms. Sadly such a woman may be labeled psycho-somatic 18until, hopefully, a definitive diagnosis of endometriosis is reached.
One can understand then, the emotional burden of this ‘benign’ disorder, especially in the Indian society, where awareness of the disease is even more restricted and women's health is often not priority. Incapacitated by pain in performing her familial obligations (housework) and limited in her sexual and reproductive performance, the average Indian patient stands little chance at receiving empathy, support and access to the best medical care.
 
Trends in Endometriosis
Although no consistent information is available on the incidence of the disease, temporal trends suggest an increase among women of reproductive age. This could be explained—at least in part-by changing lifestyle and reproductive habits.73 Besides, improved awareness and diagnosis could be responsible for better reporting. During the last 15 years, diagnostic delay has steadily decreased and the frequency of advanced endometriosis at first diagnosis declined.
 
Trends in Endometriosis Research
Interest in endometriosis is on the rise as is evidenced by the number of publications on endometriosis over the decades. From 119 publications per year in 1968, the number rose to 715 in 2008 and is still increasing (Fig. 1-1).
zoom view
Fig. 1-1: Number of scientific articles published on endometriosis since 1950. Figure adapted from Matthew Rosser. Endometriosis Update 21.06.2011: http://endo-update.blogspot.com/2011/06/trendy_21.html
19
A closer look at the studies suggests that the focus areas of research are diagnosis and drug treatment. This is a clear reflection of the need of the hour for better diagnostic tools and treatment modalities (Fig. 1-2).
zoom view
Fig. 1-2: Number of publications by focus areas of research Figure adapted from Matthew Rosser. Endometriosis Update 21.06.2011: http://endo-update.blogspot.com/2011/06/trendy_21.html
The quest for understanding the etiology and pathogenesis of endometriosis continues. Of late, the role of genetic, epigenetic and immune mechanisms in the genesis, sustenance and progression of endometriosis are being investigated with fervor (Fig. 1-3).
zoom view
Fig. 1-3: Number of publications by study of various influences in endometriosis Figure adapted from Matthew Rosser. Endometriosis Update 21.06.2011: http://endo-update.blogspot.com/2011/06/trendy_21.html
20
An interesting observation is while a majority of research work is being published in the US and UK, research is being conducted in various countries across the globe, including a few third world nations. As it would appear, endometriosis is finally being recognized as a global problem.
 
CONCLUSION
In this chapter, we have tried to highlight the magnitude of the problem of endometriosis, in terms of women's physical and emotional health as well as the economic encumbrance it poses on the health care system. Endometriosis negatively impacts work and social relationships. Misdiagnosis and under-diagnosis of endometriosis are not only because of a limitation of diagnostic tools, but also due to a lack of recognition of symptoms by the patient and physicians.
The precise incidence and prevalence of endometriosis remains elusive for a multitude of reasons outlined above. However, it is heartening to note that trends in research show an awakening of the medical profession to the predicament of women suffering from endometriosis. Internet sites, blogs and support groups are helping disseminate information and create awareness among women.
Newer insights into etiological factors and pathogenesis are likely to translate into preventive tools in the near future. An understanding of whether deep, pelvic and ovarian endometriosis are all manifestations of a similar process, or represent different entities which behave differently, would go a long way in tying the knots of endometriosis.
There is an urgent need to find a non-invasive tool for the diagnosis of endometriosis to minimize diagnostic delays. There is also an equal urgency to standardize disease definitions and end-points for defining study results. Fortunately, the commitment of the medical profession and governments towards the cause of endometriosis research gives hope that it won't be long before women suffering from endometriosis can look forward to a brighter future.
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