This first national descriptive study used an indicator, which comprehensively reflects incident all-type hospitalized cases coded endometriosis in the French territory up to the municipality scale. We observed an increase in the risk of being hospitalized from 2011 to 2017 and spatial heterogeneity with the identification of 20 scattered hotspots in Metropolitan France as well as in 2 overseas departments.
Descriptive results
The annual incidence rate (12.9/10,000 PYs) of all-type hospitalized cases coded endometriosis in France in females aged 10–49 years was of the same order of magnitude as the rates observed in other countries (Italy, Iceland) using similar methods29,30. Moreover, a recent meta-analysis2 estimated the pooled incidence rate of endometriosis based on hospital data to be 13.6/10,000 PYs (95% CI: 10.9; 16.3), which situates the French estimation within the confidence interval and close to the pooled value.
In our study, 68.3% of all-type cases and 83.2% of non-adenomyosis cases were aged 25–49 years, and only 3.6% (8.5% for non-adenomyosis cases) were under 24 years. In young females, this low percentage could reflect underdiagnosis or delayed diagnosis, because histologic evidence may occur after an interval of 5–10 years following the first signs of endometriosis31. Moreover, many cases are fortuitously diagnosed during fertility check-ups, which rarely take place before 25 years of age. This age distribution in France is close to the distribution observed in a recent Italian study (3.6% < 25 years, 76.4% in 25–49 years, and 21% > 50 years) carried out using similar methods in the population of the Friuli Venezia Giulia region from 2011 to 201330. The Italian authors remarked a noticeable percentage of incident cases over 50 years of age for non-adenomyosis cases (11.5%), close to our results (8.3%), even though endometriosis is expected to attenuate after menopause. They suggested that endometriosis deposits could still be potentially active in older patients and be reactivated in the presence of certain hormones30. This hypothesis seems quite relevant regarding the potential link with EDC exposure. Indeed, the developmental hypothesis supposes that reproductive disorders at adult age could result from early (i.e., prenatal, perinatal, or pubertal) exposure to EDCs in specific exposure windows. In males, this hypothesis has been especially developed according to the so-called “testicular dysgenesis syndrome (TDS)”32. The disruption of fetal androgen action with EDCs, specifically in the “masculinization programming window” (MPW), induces a shorter anogenital distance that is supposed to provide a life-long readout of the level of androgen exposure in the MPW33 and is consistently associated in animals and humans with TDS troubles (cryptorchidism, hypospadias, poor sperm quality)34.
In females, the mirror concept of “ovarian dysgenesis syndrome” has been proposed, including a higher risk to develop endometriosis35. Interestingly, endometriosis has recently been associated with a shorter anogenital distance in women36, and this anthropological indicator, measurable using MRI, could be useful for a non-invasive diagnosis of the disease37.
In addition, some authors suggest that endometriosis onset could occur in two steps: an early hormonal-developmental step and a second hormonal step at adult age38,39, or a first initiation step with a second promotion step based on experimental tumor production40. Overall, these hypotheses could contribute to the unexpected proportion of hospitalized endometriosis cases identified after menopause. Another explanation could be the large number of fortuitous diagnoses of endometriosis at the same time as hysterectomies performed for diverse indications in women at an older age.
Temporal trends
Studies on the temporal trends of endometriosis incidence used diverse methods and delivered differing results according to the country as reviewed in a recent study1. Only three studies carried out with hospital data in the general population are available. A Finnish study showed a decrease in incidence from 1987 to 201241. An Icelandic study did not conclude to any trend from 1981 to 200029, and a recent Korean study only showed an incidence increase in young women aged 15–19 and 20–24 years, but not in other age groups42.
In France, the increase in the risk of being hospitalized, observed for both adenomyosis and non-adenomyosis cases, could reflect a real increase in the incidence of endometriosis, consistent with the perception of numerous clinicians. We did not observe an upward trend in females under the age of 25 years, which could reflect the underdiagnosis of this population. The global increase could also relate to the increasing use of non-invasive examinations, like ultrasounds or pelvic MRI during the study period. Pelvic MRI was only recommended by the French Health Authority at the end of the study period43, although clinicians would have anticipated this recommendation, which is supported by the results of the additional analyses (Supplementary Material). In the study period, there was a 69% increase in cases who underwent this examination concurrently with hospitalization, which accounted for around a third of cases. The increasing use of MRI (or ultrasounds) would result in more and more cases treated without hospitalization and could explain the apparent increase of hospitalized incidence at later ages and less at younger ages.
Regarding the secondary indicator, the incidence rate in the whole of France during the study period remained steady. However, the trends differed according to each type (Table 4). The risk did not increase for endometrioma, a type of endometriosis that is not expected to depend on the use of pelvic MRI, but it did increase for intestinal endometriosis, expected to be strongly influenced by pelvic MRI. Therefore, these results also support the role of pelvic MRI. As for the divergent evolution of specific types of endometriosis, experts believe that it could depend on shifting practice patterns such as the more frequent tendency to medically treat endometrioma.
Another factor could also contribute to the global increase in hospitalized endometriosis. Several patient societies (EndoFrance, Endomind, Info-endometriose) have strongly advocated for better detection and care of this disease and provided targeted information, which may have resulted in increased awareness of patients and clinicians regarding the disease during the study period.
These factors are likely interlinked with a possible real increase in endometriosis incidence, which could be confirmed by a longer monitoring period.
Spatiotemporal and spatial trends
The spatiotemporal and spatial heterogeneity of the risk of hospitalized endometriosis that we observed in France during the study period could be related to spatial disparities and different evolutions in terms of detection and hospital care. In half of the 20 hotspots in Metropolitan France, we identified a town where an expert clinic for endometriosis was operational during the study period (Fig. 4). In the overseas departments, we identified an expert clinic in the Reunion Island, where we also observed a high incidence. However, we identified expert clinics in areas with a low or moderate risk of hospitalized endometriosis, especially in Paris (four expert clinics), Lyon (two expert clinics), Rennes, Brest, and Angers. Adjusting the spatial model at the department scale with the density of gynecologists and obstetricians using the available data provided by the shared inventory of health professionals from 2011 to 2016 did not change the geographic distribution (data not shown). Adjusting for incident cases of non-endometriotic ovarian cysts only brought about some changes in several departments in the north where the risk attenuated, even though it stayed above 1 (data not shown).
Taken together, these results indicate that the activity of local expert clinics could only partially explain the spatial and spatiotemporal heterogeneity of the risk of hospitalized endometriosis. The contribution of environmental factors remains possible and plausible, as we argued above.
The results of the exploratory cluster detection performed in Metropolitan France showed a negative relation with the socioeconomic deprivation index. Indeed, a high socioeconomic status (SES) or education level has been associated with a higher frequency of endometriosis44,45, which probably reflects the better detection and patient care of women with high SES. However, this relation was inverted in a recent Swedish study, although the authors partly attribute this inconsistent finding to egalitarian health care in Sweden46.
Among the 40 detected clusters (p < 0.0001) in Metropolitan France, 23 were located in cities or their outskirts where expert clinics have been identified. Hence, even if there were some clues about the high industrial or agricultural activity in several cluster areas, this exploratory analysis did not allow us to further develop the environmental hypotheses.
Limitations
The major limitation of the study is the potential variability of the results due to the local clinical practices and their evolution over time, which complicates the interpretation of our results, especially in the evolving field of endometriosis. We tried to minimize this bias by carrying out additional analyses. In addition, the indicator that we used only targeted the hospitalized cases of endometriosis, and therefore we underestimated the incidence of the disease. In the literature, the incidence estimated by cohorts in the general population is about three times the incidence of hospitalized endometriosis2. We know that coding errors may also occur, although in a monitoring system, this should not bias the results if the errors are steady in time and homogeneous across the territory. Finally, we did not have individual information about specific factors such as BMI, alcohol or tobacco consumption, nutrition, or lifestyle, which could have been important to further develop the analyses. Nevertheless, the indicator used here allows for the comprehensive and long-term monitoring of the whole territory, which was our purpose.
Source: Ecology - nature.com
