To improve the still fragmented understanding of endometriosis, a life cycle approach was adopted that revealed unexpected aspects of the natural history of the disease throughout a woman’s life. Three age-related stages of endometriosis are distinguished. In premenarcheal and adolescent endometriosis, 2 types can be distinguished: a classic form that can occur before menarche, and a congenital obstructive form that is caused by uterine anomaly and outflow obstruction. The lesions include superficial peritoneal implants, but adhesions and endometrioma can also occur. It is suggested that premenarcheal and possibly adolescent endometriosis develop by activation of resting stem cells shed at the time of neonatal retrograde uterine bleeding. In the adult, endometriosis can be related to uterine preconditioning by cyclic menstruations acting as a priming mechanism for deep placentation. In adult life, the typical lesions are peritoneal, ovarian, and deep or adenomyotic endometriosis. More recently, endometriosis has been associated with endometrial dysfunction and myometrial junctional zone hyperplasia. These uterine changes can be linked with some major obstetrical syndromes. In postmenopause, endometriosis can develop or be reactivated both in the presence or absence of exogenous estrogens and can spread to a variety of organs and structures causing constrictive lesions.
Thomas Cullen was the first to describe, under the common name of “adenomyoma,” the full morphological and clinical picture of the conditions identified today as endometriosis and adenomyosis ; he defined adenomyoma as the presence of endometrial-like tissue in myometrial wall, rectovaginal septum, hilus of the ovary, uterine ligaments, rectal wall, and umbilicus.
The name “endometriosis” was created by John A. Sampson 7 years after his fundamental paper on ovarian endometriomas when, operating on women at the time of menstruation and observing bleeding of the lesions, he advanced the first theory on the pathogenesis, postulating that presence of lesions outside the uterus was due to tubal regurgitation and dissemination of eutopic endometrial cells.
Peritoneal lesions became the signature of endometriosis and the introduction of laparoscopy in the 1960s added a golden tool for an accurate diagnosis and surgical treatment. As a result, endometriosis became a separate nosological entity vis-à-vis adenomyosis (and the uterus) and research became focused on how fragments of menstrual endometrium can implant on peritoneal surfaces and invade the underlying tissues. Besides the classic theory, alternative mechanisms have been proposed, such as coelomic metaplasia, transportation through veins or lymphatics, the presence of embryonic vestiges, and more recently the transformation of bone marrow and endometrial stem cells ; but–to this day–menstrual regurgitation with the subsequent implantation of endometrial cells under facilitating circumstances still explains most ectopic localizations.
During the last century, clinical interest and research have been largely focused on lesions and their direct consequences and endometriosis has been considered fundamentally a disease of the fertile period and more specifically of adulthood, while the significance of its presence in other periods of a woman’s life has not received proper attention.
Here, we wish to draw attention to the fact that understanding endometriosis (and to some extent also adenomyosis) requires a life cycle approach granting significance to its presence before menarche, during adolescence, in adulthood, and in postmenopause. Taking such an approach also means revisiting the specific impact of the uterus itself on the development of the condition during the various stages of life.
Methods
The published literature was searched using Scopus and PubMed focusing on the terms “endometriosis,” “menarche,” “adolescence,” “reproduction,” “adult,” “adenomyosis,” and “menopause.” In addition, the references of major publications were included in the search.
After this search we restricted further work on studies of endometriosis published in peer-reviewed gynecological journals reporting data in function of the different age groups. These were critically appraised and summarized.
One point that should be stressed is the lack–to our knowledge–of epidemiological studies on adolescent or postmenopausal endometriosis. At best, there are relatively small series that can provide no basis for an epidemiological evaluation. Even in the case of adult disease, the lack of affordable, noninvasive diagnostic methods makes it impossible to evaluate its true incidence.
Results
Premenarcheal and adolescent endometriosis
Premenarcheal endometriosis occurs in the normal young girl before menarche and needs to be distinguished from a congenital obstructive form that appears after menarche and is caused by complete outflow obstruction in the menstruating young girl.
Marsh and Laufer carefully documented a classic form of endometriosis in 5 premenarcheal girls aged between 8.5-13 years and with breast development from Tanner I-III having chronic pelvic pain for >6 months. In none of them could an obstructive abnormality of the reproductive tract be suspected. At laparoscopy, all 5 girls had clear and red lesions of peritoneal endometriosis. On biopsy the lesions included stroma (but no endometrial-like glands), vascular proliferation, hemosiderin deposits, macrophage proliferation, inflammation, ciliated epithelium, and/or adhesions ( Table ). In all of them the clinical situation improved substantially after surgical removal of the lesions. Because of a relapse of pelvic pain not responsive to hormonal therapy, in 2 girls–6 and 8 years later–a second-look laparoscopy was performed and the presence of endometriosis with glandular structures and stroma was confirmed by biopsy. Recently, more cases have been described of peritoneal endometriosis in a 9-year-old premenarcheal girl with cyclic pelvic pain since her 8th year of life and ovarian endometrioma in an 11-year-old premenarcheal girl and an 18-year-old woman.
| Age group | Localization | Type of lesions |
|---|---|---|
| Adolescent | Peritoneum | Angiogenesis, subtle |
| Ovarian surface | Endometrioma | |
| Adult | Peritoneum | Typical, adhesions |
| Ovary | Endometrioma | |
| Rectovaginal septum | Deep adenomyoma | |
| Postmenopausal | Ovary | Endometrioma |
| Extrapelvis | Obstructive |
Adolescent endometriosis can occur in association with obstructive müllerian anomalies (eg, unicornuate uterus with rudimentary horn, or uterine didelphys with obstructed hemivagina, often present with pelvic pain secondary to hematometra or hematocolpos). The reported incidence in teenagers with genital tract anomalies varies between 11-40%. In 64 women with müllerian anomalies, the hypothesis was tested that the development of endometriosis depends upon the amount of retrograde menstruation and the ability of the immune response to remove the debris. Surgery confirmed the presence of endometriosis in 10 of 13 women with functioning endometrium, patent tubes, and outflow obstruction and in only 16 of 43 women with no obstruction (77% vs 37%, P < .01). An interesting case was a 12-year-old white girl with extensive unilateral endometriosis in association with uterus didelphys and unilateral wall fusion defect at laparoscopy; after correction of the vaginal obstruction a subsequent laparotomy showed no evidence of endometriosis. Recently, Yang et al in 15 cases with a genital tract malformation noted a much earlier disease onset; in addition, the ovaries were involved in 14 of these girls.
Traditionally, endometriosis has been thought to occur only rarely in adolescence, but an increasing awareness of the disease among the medical community, as well as the public, is making an early diagnosis more frequent. Although its true incidence is difficult to quantify, estimates have been attempted; they vary among different studies between 19-73%. Although a majority of women with endometriosis report symptoms starting in adolescence, diagnosis is often delayed in this patient population and often the younger the women are at onset of symptoms, the longer the period before a diagnosis is posed. Endometriosis occurs in approximately 70% of adolescent girls with chronic pelvic pain not responding to conventional medical therapy and the majority of patients have stage I disease.
The lesions
The different appearances of peritoneal endometriosis are classified as early-active (red, glandular, or vesicular), advanced (black, puckered), and healed (white, fibrotic) implants ( Figure 1 and Table ). Visually, active peritoneal endometriosis shows intense angiogenesis that can be clearly observed during hydroflotation ( Figure 2 ). The anatomic distribution of peritoneal endometriosis supports Sampson’s hypothesis of retrograde menstruation as the primary model of development of endometriosis. The clinical significance of these minor manifestations has remained controversial. In adolescence, most disease is atypical and transient, with subtle lesions suddenly emerging and then vanishing.
Pathogenesis of premenarcheal and adolescent endometriosis
Commenting on the publication by Marsh and Laufer, the editor of Obstetrical and Gynecological Survey speculated that the girls may have had antecedents to endometriosis rather than the classic form of the disorder and suggested that endometrial cells may be activated by a process of angiogenesis even long before menarche. While vascular endothelial growth factor (VEGF) expression produced by the endometrial cell varies with the phase of the menstrual cycle and is higher in the proliferative than in the secretory phase, the estrogenic effect of maternal steroids or the prepubertal estrogen secretion might be sufficient for stimulating angiogenesis in the neonatal implants to develop into early endometriosis.
There is also the possibility that endometriosis may develop by mechanisms other than retrograde menstruation and implantation, such as coelomic metaplasia, embryonic müllerian rests, or even the persistence of the forms of embryonic endometriosis as recently described. More generally, mesenchymal stem cells may be the principal source of endometriosis outside of the peritoneal cavity when they differentiate into endometrial cells in these locations. The study of endometrial stem cells has made great progress and their existence has now been confirmed through different approaches. Since adult stem cells can reconstruct endometrial tissue in vivo, their possible involvement in the etiology of endometriosis has been suggested. Premenarcheal and even adolescent endometriosis may also develop from stem cells originating from retrograde neonatal uterine bleeding.
Neonatal uterine bleeding: a source of endometrial stem cells?
The phenomenon of uterine bleeding in neonates has been described in detail in the German literature of the 1970s. Based on this phenomenon, the hypothesis can be formulated that, in rare cases, the estrogenic effect of maternal steroids, or the prepubertal estrogen secretion, might be sufficient to stimulate angiogenesis in endometrial cell clusters that may have attached themselves onto the peritoneum right after birth.
A first study of 153 newborns found visible vaginal bleeding in 5.3% of the cases and occult bleeding, as shown by hemoglobin positive reaction, in 61.3%. Uterine bleeding usually began between days 4-7 of life and lasted a mean 3.2 days. A similar study of 350 newborn girls revealed uterine bleeding during the week after birth in 25.4%, mostly demonstrable only by chemical micromethods, but also macroscopically visible in 3.3%. Histological and cytological controls confirmed these observations indicating that, as a rule, no menstrual withdrawal bleeding, but degenerative, regressional changes of endometrium occur leading to bleeding by diapedesis. Stem cells derived from the endometrium can today be obtained from women’s menstrual blood ; they display stem cell markers and can differentiate into various cell types. They quickly regenerate after menstruation and secrete many growth factors displaying recurrent angiogenesis. Further studies should clarify whether premenarcheal and even adolescent endometriosis may originate from stem cells of retrograde neonatal uterine bleeding.
Adult endometriosis
Current knowledge of endometriosis is largely based on the inspection of endometriotic lesions in the abdominal cavity in women with infertility or pelvic pain. However, in recent years the picture has been expanded by molecular investigations of the eutopic endometrium and high-definition imaging of the uterus.
The lesions
Appearance of peritoneal endometriosis in the adult includes, in addition to peritoneal endometriosis, adenomyotic lesions or deep endometriosis and ovarian endometriomas ( Table ). Deep endometriosis can be described as progressive endometriosis with smooth-muscle metaplasia. Clinicopathological studies indicate that, in contrast with superficial lesions, deep endometriosis is strongly associated with pelvic pain. For many years the ovarian endometrioma has not been recognized as a form of endometriosis, until Hughesdon showed that, in contrast with luteal cysts, the ovarian endometrioma is in most cases a pseudocyst formed by invagination adherent to the posterior side of the parametrium as confirmed by ovarioscopy.
Menstrual preconditioning
A younger age seems to confer an increased risk of adverse pregnancy outcomes as manifested by lower birth weight, premature delivery, and small for gestational age that is independent of the major confounding sociodemographic factors. This observation is consistent with the menstruation preconditioning hypothesis, which explains the decrease in the risk of adverse pregnancy outcome after adolescence and, in the absence of pregnancy, an increased risk of endometriosis. The number of peritoneal areas involved in endometriosis seems to increase in adolescence until the early twenties.
Compared with our primate relatives, menstruation in human beings is not only extraordinarily heavy, but placentation is also exceptionally deep, with trophoblast invading not only the decidual endometrium but also the inner third of the myometrium, the uterine junctional zone (JZ) and its spiral arteries. According to the menstrual preconditioning hypothesis, cyclic endometrial remodeling and menstruation precondition the human uterus for pregnancy by creating tolerance to the injurious effects of a subsequent more severe insult. The mechanisms underpinning preconditioning include reactive oxygen production, activation of redox-sensitive signaling pathways, expression of angiogenic factors such as VEGF, and resistance to apoptosis. These factors are highly regulated in the endometrium in response to hormonal signaling and perturbed in the presence of endometriosis. In this sense, endometriosis could be considered a disease creating an exaggerated endometrial preconditioning, which not only confers protection against the hyperinflammation and oxidative stress associated with pregnancy, but also endows endometrial cells with the mechanisms to survive in unfavorable ectopic locations.
Endometrial dysfunction
Patients with severe endometriosis have been found to have defects in endometrial receptivity including aberrant integrin expression, suggesting decreased cycle fecundability. Both eutopic endometrial tissues and endometriotic implants from patients with endometriosis are biochemically different from that of disease-free women and show both changes at the molecular level and heterogeneous responses. Endometriosis is also associated with relative 17beta-hydroxysteroid dehydrogenase type II deficiency and these molecular aberrations indicate that local estrogen production sustains ectopic implants. Endometriosis disrupts coordinated progesterone response throughout the reproductive tract, including the endometrium, leading to a condition of progesterone resistance. In conclusion, molecular phenotyping of the endometrium is changing the disease paradigm, from being foremost an estrogen-dependent disease to a disorder characterized primarily by progesterone resistance.
Aromatase expression in eutopic endometrial tissues from patients with endometriosis may be related to the ability of fragments of endometrium reaching the peritoneal cavity to survive and implant. VEGF, being an estrogen-responsive angiogenic factor, may be important for both physiological and pathological angiogenesis of human endometrium, since it is elevated in women with endometriosis ; VEGF content was found to be higher in the eutopic glandular epithelium of women with endometriosis during the late secretory phase, possibly suggesting a tendency to implant.
Investigation of the transcriptome of eutopic endometrium across the menstrual cycle comparing severe vs mild forms showed that differences in transcriptomic signatures and signaling pathways may result in poorly programmed endometrium during the cycle that may contribute to lower implantation and pregnancy rates in women with severe vs mild endometriosis.
A recent study investigated the types of nerve fibers in endometrium and myometrium in women with endometriosis and showed an increased nerve fiber density in both ; in addition, small nerve fibers (the so-called polyclonal rabbit anti-protein gene product 9.5-immunoactive nerve fibers) were identified in the basal and functional layers of the endometrium in women with endometriosis, suggesting that they may play an important role in the mechanisms of pain generation. A prospective study investigated the role of neurotrophins (NT) in eutopic endometrium from patients with endometriosis and refuted the assumed neurotrophic properties of eutopic endometrium of patients with endometriosis. The presence of nerve growth factor, NT-4/5, and brain-derived neurotrophic factor messenger RNAs has now been confirmed and the hypothesis has been proposed that local production of NT induces sensory innervation of the endometrium of women with endometriosis.
In conclusion, it is increasingly evident that the evaluation of eutopic endometrium in patients with endometriosis is an important line of investigation of the pathophysiology of the disease.
Myometrial JZ hyperplasia
The myometrial JZ, first identified by magnetic resonance (MR) imaging, represents the inner portion of the myometrium and has several specific functions in human reproduction, such as facilitating gamete transport, and plays a critical role in the achievement of deep placentation.
The MR studies of Kunz et al revealed the presence of anomalies of the JZ in women with endometriosis. This process is already ongoing in young women who also have endometriosis, as compared with healthy control subjects; however, the difference only reached statistical significance in women 30 years and older. Starting from an age of 35 years, both groups of women demonstrated a parallel and sharp increase of the diameter of the JZ suggesting a common phenomenon with the age-related pathophysiological continuum of adenomyosis. However, the relationship between myometrial JZ hyperplasia and adenomyosis defined by the presence of endometrial glands in the outer myometrium is unknown. Both endometriosis and adenomyosis have been linked in case of severe endometriosis, a fact that could explain the recurrence or persistence of pain after extensive surgery for endometriosis. Today, this makes it mandatory in cases of severe endometriosis, or endometriosis with severe pain, to evaluate the possible concomitant presence of adenomyosis through a careful evaluation of the myometrial JZ by imaging techniques.
Pregnancy and endometriosis
Whether pregnancy can influence the further course of endometriosis is not really known. At the same time, we know that, although improvement and worsening of primary dysmenorrhea are equally likely for all women, improvement is more likely in women who bear children.
More information exists on how endometriosis can influence pregnancy outcomes, since recent studies indicate that endometriosis and adenomyosis may be associated with an increased risk of obstetrical syndromes including late miscarriage, preterm birth, fetal growth restriction, and obstetrical hemorrhage. These syndromes are known to be associated with defective transformation of the myometrial JZ spiral arteries and, in cases of underlying hypertensive disease, obstructive lesions of the myometrial spiral arteries. A recent cross-sectional study found that women with endometriosis have more subclinical atherosclerosis compared with the general population, and, hence, are not only at higher risk for future cardiovascular disorders, but also placental bed arteriopathy. An overlap of molecules and mechanisms may explain the fact that preterm birth is a common complication in pregnant patients with endometriosis.
Postmenopausal endometriosis
A history of endometriosis-associated infertility is strongly associated with an early onset of menopause that persists after multivariate adjustment. When a woman with endometriosis reaches menopause symptoms usually disappear, although hormonal replacement therapy (HRT) is indicated especially in case of premature or early menopause. Use of HRT in these women raises 3 major concerns: return of pain symptoms; need for surgery; and a possible, although definitely rare, malignant transformation of residual endometriosis.
It has been suggested that that unopposed estrogen carries a higher risk than combined preparations. A position statement by the European Menopause and Andropause Society concluded that “it may be safer to give either continuous combined estrogen-progestogen therapies or tibolone in both hysterectomized and nonhysterectomized women as the risk of recurrence may be reduced.”
Frequency of endometriosis in menopause
Reports of significant endometriosis after menopause began to appear some 50 years ago in women without or with HRT. In an early series of postmenopausal symptomatic patients the presence of endometriosis was found in 2.2% of them at a mean distance from menopause of 7.3 years. There was a frequent association between ovarian endometriosis and ovarian carcinoma and an increased estrogen activity. In this series, only 1 patient had received estrogen therapy.
A recent review found 32 case reports on postmenopausal endometriosis, confirming that the most common location is the ovary ( Table ). The risk of malignant transformation seems at around 1%, and these patients have an increased risk of ovarian cancer, and, possibly, other malignancies. The following year, 3 additional cases were found in women with no history of HRT. A recent examination of the clinical records of 72 postmenopausal women with endometriosis who underwent surgery over a period of 12 years found 11 patients (15.3%) with a history of endometriosis and 5 patients who had previously undergone surgery for this reason. Only 2 women were using HRT at the time of surgery. This study confirmed that the ovary is the most frequent location of postmenopausal endometriosis, with 35% showing different grades of metaplasia, hyperplasia, atypia, and endometrioid carcinoma arising in endometriosis. It has been guessed that endometriosis may affect between 2-4% of postmenopausal women.
Localization of postmenopausal endometriosis
As already mentioned, the most frequent localization of endometriosis diagnosed in postmenopause is the ovary. Frequently affected is also the urinary tract, with the first report of ureteral obstruction caused by postmenopausal endometriosis dating from 1973. Since then a total of 5 cases of postmenopausal ureteral endometriosis have been reported, followed by 4 cases of vesical invasion and 1 of de novo renal and diaphragmatic endometriosis in a woman taking HRT. Other sites can be affected, such as the skin ; the intestines ; the sigmoid ; the rectum (in this case, 22 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy, an invasive endometrioid adenocarcinoma was found showing histological progression from endometriosis to complex hyperplasia with cytological atypia, and carcinoma) ; the inferior vena cava (in this case a woman who had been previously hysterectomized with bilateral salpingo-oophorectomy for endometriosis developed a periaortic mass with ureteral obstruction–the mass was resected surgically and histopathology confirmed invasion of the inferior vena cava) ; and the vagina.
Relationship with hormonal therapy
Following the first case of postmenopausal relapse caused by estrogen treatment 14 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis treated with radiotherapy, several additional cases have been reported (mostly following hysterectomy and bilateral oophorectomy), with a number of localizations including the ureter with high-grade obstruction ; the ovary ; the broad ligament ; and the vesicouterine pouch (with a malignant degeneration).
Proof of a causal relationship between recurrence of endometriosis in postmenopause and HRT was provided by a prospective randomized trial of 115 women receiving HRT and 57 control subjects. The study found no recurrence among control women vs a 3.5% rate (4 of 115) in women who received HRT, with 2 cases requiring abdominal surgery.
It is well known that, whereas tamoxifen has an antiestrogenic effect on breast tissues, it action on the endometrium is estrogenic. Therefore, it should not be a surprise that an association has been found between tamoxifen treatment and the development of endometriosis in postmenopause. The first such case was published in 1991. The woman had taken the drug for 7 years and at age 69 years developed an endometrioma. This association has been confirmed and even a case of endometriosis with an ovarian endometrioid carcinoma has been published.
Nature and mechanism of induction of endometriosis in postmenopause
Reappearance of endometriosis even years after menopause in women using HRT can be easily explained with the trophic effect of estrogens. More complex is the case of endometriosis arising years after menopause in the absence of exogenous hormones. It has been postulated that in some cases surgery may increase adrenal androgen production and their conversion into estrogen in fat tissues may reactivate endometrial foci. In the already mentioned series, 70% of the patients were obese giving rise to the suspicion that in these women there was an extraglandular estrogen formation.
A review of the topic led to the conclusion that the classic paradigm whereby estrogen dependence is considered central to development and progression of endometriosis must be revised, since the main issue is whether endometriosis should be considered a progressive disease, in which case its presence in postmenopausal women would not contradict the theory of retrograde menstruation. If, on the other hand, endometriotic lesions can arise de novo in postmenopausal women, then an alternative processes must be in place. It is unlikely that one single theory can account for all postmenopausal lesions that have been described. It has been suggested that in untreated postmenopausal women endometriosis may arise from coelomic metaplasia.
A comparative study of 21 cases of postmenopausal endometriosis investigated the ectopic as well the eutopic endometrium, analyzing estrogen receptor (ER), progesterone receptor (PR), and Ki-67 nuclear antigen. Histologically, endometriotic foci contained both epithelial and stromal components mostly lacking atrophic features in contrast to the corresponding eutopic endometrium. The endometriotic lesions and the corresponding endometrium exhibited immunoreactivity for ER in both the glands and stroma. The stromal cells of endometriotic lesions revealed positive PR staining, whereas those of the eutopic endometrium were either negative or weakly positive for PR, but the epithelial components of both were positive for PR. The positivity of Ki-67 antigen tended to be higher in the stroma of the postmenopausal endometriosis than in the eutopic endometrial stroma. Thus, endometriotic lesions appear to remain biologically active, with proliferative activity as well as retained hormonal responsiveness, even in the low-estrogen milieu of the postmenopausal age.
A review of 100 cases of endometriosis plus all cases occurring in women aged ≥50 years was carried out to compare premenopausal and postmenopausal endometriosis. Cases were divided into ages <50, 50-59, and ≥60 years and analyzed for extent of disease, proportions of epithelium and stroma, and amount of hemorrhage. Immunohistochemistry for ER, PR, and CD10 was performed and analyzed on all cases. Less disease was found in older women when cases occurring in the cervix and in scars were excluded ( P = .0191). Also, there was a statistical difference in the amount of hemorrhage with older women showing less hemorrhage. Thus, although endometriosis can occur in postmenopausal women it is less common, is present in smaller volumes, and is less active.
Conclusions
From reviewing observations gathered over almost a century, it appears that the endometriosis can affect the entire life cycle of a woman. Around the time of menarche the disease begins with angiogenesis of peritoneal implants, in adult life becomes predominantly an adenomyotic lesion, and after the menopause exposes a woman to obstructive lesions and ovarian malignancy. The impact of the uterus in subjects with endometriosis is not restricted to menstrual regurgitation, and possibly neonatal bleeding, but is part of the disorder as manifested by the development of adenomyosis. Endometriosis reflects how the uterus evolves as determined by menstruation and pregnancy. The regression of peritoneal endometriosis in adolescents is particularly interesting and supports the concept of uterine preconditioning during the early adult stage of reproductive life. In the absence of pregnancy endometriosis can be worsened in its severity with the involvement of the myometrial JZ. In adult women, endometriosis is characterized by an increased risk of JZ hyperplasia and of adenomyosis. Early studies suggested that changes in the myometrial JZ are associated with an increased risk of major obstetrical syndromes, in particular preterm birth and fetal growth retardation. The question may arise whether the changes in the myometrial JZ can be reversed by aromatase inhibitors or gonadotropin-releasing hormone agonists with a decrease in the risk of impaired pregnancy outcome. It can be stated that proper management of the complex reproductive pathology associated with endometriosis at various stages of life requires the combined investigation by laparoscopy and appropriate imaging of the uterus by MR imaging or 3-dimensional transvaginal sonography to diagnose both the extrauterine and the uterine disorders associated with the condition.
One final point needs to be stressed: is there one disease called “endometriosis” or do different forms (neonatal, premenarcheal, adolescent, adult, postmenopausal) as well as different localizations (superficial, peritoneal, deep, nonperitoneal) have different origins and therefore should they be considered as separate entities? There is no clear answer to this question. There is some evidence that at least some forms are separate entities, but conclusive evidence is still missing.
Under the circumstances, a conclusion seems inevitable: given the small nature of many of the studies presented, no final answer will be forthcoming without well-designed, controlled, large, multicenter studies and these may be extremely difficult to conduct.
The authors report no conflict of interest.
Results
Premenarcheal and adolescent endometriosis
Premenarcheal endometriosis occurs in the normal young girl before menarche and needs to be distinguished from a congenital obstructive form that appears after menarche and is caused by complete outflow obstruction in the menstruating young girl.
Marsh and Laufer carefully documented a classic form of endometriosis in 5 premenarcheal girls aged between 8.5-13 years and with breast development from Tanner I-III having chronic pelvic pain for >6 months. In none of them could an obstructive abnormality of the reproductive tract be suspected. At laparoscopy, all 5 girls had clear and red lesions of peritoneal endometriosis. On biopsy the lesions included stroma (but no endometrial-like glands), vascular proliferation, hemosiderin deposits, macrophage proliferation, inflammation, ciliated epithelium, and/or adhesions ( Table ). In all of them the clinical situation improved substantially after surgical removal of the lesions. Because of a relapse of pelvic pain not responsive to hormonal therapy, in 2 girls–6 and 8 years later–a second-look laparoscopy was performed and the presence of endometriosis with glandular structures and stroma was confirmed by biopsy. Recently, more cases have been described of peritoneal endometriosis in a 9-year-old premenarcheal girl with cyclic pelvic pain since her 8th year of life and ovarian endometrioma in an 11-year-old premenarcheal girl and an 18-year-old woman.
