EFEK KONTRASEPSI 3.pdf

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Clinical Study Hormonal Contraceptive Use and the Prevalence of Endometriotic Lesions at Different Regions withinthe Peritoneal Cavity

Brett D. McKinnon, Dominic Bertschi, Juilette Wanner,

Nick A. Bersinger, and Michael D. Mueller

Department of Obstetrics and Gynecology, Inselspital, Berne University Hospital, University of Berne,

Effingerstrasse , Berne, Switzerland

Correspondence should be addressed to Brett D. McKinnon; [email protected]

Received April ; Revised August ; Accepted November ; Published January

Academic Editor: Rumiana Koynova

Copyright © Brett D. McKinnon et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Endometriosis is an estrogen-dependent disease that can lead to chronic pain and subertility. Endometriotic lesions oundin different locations are heterogeneous and may represent a collection o related but distinct conditions. Whether there isa relationship between hormonal contraceptive (HC) use and endometriosis is still controversial. Te purpose o this study

was to determine whether HC use affected the prevalence o endometriotic lesions differently based on lesion location. Datawas retrospectively collected rom patients presenting to the Berne University Women’s Hospital between and or laparoscopic investigation. Women with histologically proven endometriosis were included in the study and patients weregrouped according to lesion location and HC use. Te results o the study indicate that HC users are signicantly less likely tohave endometriotic lesions on the ovaries, although in contrast, no difference was observed in the incidence o lesions in therectovaginal septum (RVS) or peritoneal region. In addition, women using HC who were diagnosed with endometriotic lesions onthe peritoneum were signicantly younger than women with lesions in other locations. In conclusion, women with endometriosiswho are currently using HC are less likely to have ovarian endometriotic lesions than in alternate locations.

1. Introduction

Endometriosis is an estrogen-dependent disease dened by the presence, growth, and invasion o endometrial epithelial

and stromal cells outside the uterine cavity that can lead tochronic pelvic pain anda reduced ecundity. It is an extremely prevalent condition with up to % o reproductive agewomen suffering rom the disease [] with an even higherincidence amongst inertile women [] and adolescent girlswith chronic pelvic pain []. Current rst line treatmentinvolves the induction o a hypoestrogenic state through theuse o hormonal contraceptives (HC) or gonadotropin releas-ing hormone agonists (GnRHa). I unsuccessul the endo-metriotic lesions must be removed surgically.

Although the exact aetiology o endometriosis is notyet clear, certain actors such as liestyle, nutrition, geneticpolymorphisms, and environmental pollutants [–] are

known to increase the potential or lesions development.Given the estrogen dependence o the disease HC use has alsobeen investigated. Currently, however, the link between HCuse and endometriosis is still debated as conicting reports

have shown both a reduced [, ], and increased risk [, ]as well as no association at all [–].

It is possible that the effects o HC use in endometriosisdevelopment are not yet clear because the inherent hetero-geneity o endometriotic lesions that develop at differentregions has not yet been sufficiently accounted or in thesestudies. Ectopic endometrial lesions can develop in multiplelocations throughout the body with some examples evenrecorded in the lungs [] and brain []. Predominantly,however, endometriotic lesions are ound within the peri-toneal cavity and can be broadly separated into three mainregions: the rectovaginal septum (RVS), the peritoneum,and the ovaries. Biochemical and histological data show

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014, Article ID 590950, 6 pageshttp://dx.doi.org/10.1155/2014/590950


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BioMed Research International

signicant differences between lesions that develop at differ-ent locations leading to suggestions that lesions rom theselocations may have distinct pathophysiologies and should beclassed as separate entities []. Moreover, lesions can occurin either one or more o these regions, and it is not yetclear whether multiple lesions are established separately, or

their growth is acilitated by the accompanying inammatory reaction.Endometriosis is a disease o reproductive age women

and a signicant portion o this population use HC or bothertility control and the treatment o pathological condi-tions. Te heterogeneity o endometriotic lesions suggestsendometriosis could be considered a collection o related, butindependent diseases, and thus, a thorough understandingo the effects o hormonal treatments and whether they aredependent on the specic presentation o the endometrioticlesion is vital. We have thereore perormed a retrospectiveanalysis o data collectedrom women presenting to ourclinicto determine the prevalence o endometriotic lesions andwhether this is signicantly affected by HC use.

2. Materials and Methods

.. Patient Data. A cross sectional study was perormedwith data collected retrospectively rom women presenting tothe Bern University Women’s Hospital during – orlaparoscopic investigation o chronic pelvic pain or idiopathicinertility. Institutional ethics review board approval wasobtained and women were included in the study i they provided inormed consent and had a lesion removed duringsurgery that was histologically conrmed as endometriosis.All surgery was perormed during the prolierative phase andthe patient was staged according to the revised AmericanFertility Society Score (rAFS) []. Te lesion locationswere noted by the surgeon during the operation and weresubsequently grouped into one o three possible regions; theRVS, ovarian, or peritoneum, as described previously [].Medical records were searched or relevant data.

During the study period we received inormed con-sent rom a total o women, o which had tissueexcised during surgery and at least one lesion subsequently conrmed as endometriosis via histological examination. Aurther women reported GnRHa use prior to surgery andwere excluded rom the study, resulting in a total o women. Te age range o women included in the study was– years with a mean o 32.56 ± 0.46 (Mean ± SEM).

o determine the prevalence o endometriotic lesions atthe different locations, both with and without HC use, twoseparate groupings o women were made. Te initial analysiswas perormed by dividing all women into one o two groupsbased on the presence or absence o a lesion in the denedregion. Tereore, i a woman had a lesion on the ovaries,irrespective o whether additional lesions were identied atother locations, they were grouped as ovarian. I no lesionwas present on the ovary the women were grouped as non-ovarian. Tis was repeated or both the peritoneal and RVSregions.

Grouping the women based on the exact region orcombination o regions that endometriotic lesions were

ound allowed urther analyses with more stringently denedgroups. Based on this criteria, seven groups in total werepossible, three o which represent single locations: (i) ovarian,(ii) RVS, or (iii) peritoneal, and our groups that representedcombined regions: (i) peritoneal and ovarian, (ii) peritonealand RVS, (iii) ovarian and RVS, or (iv) all three locations.

Hormonal treatment was determined by the sel-reporting o women prior to surgery. HC use was split intoeither current or non-use. Current use was dened as useprior to and within the three months leading up to surgery,and non-use was dened as no use or a minimum o threemonths prior to surgery. Contraceptive use included alltreatments used to prevent birth including oral (combinedand gestagen only) and vaginal progesterone.

.. Statistical Analysis. Mean age was compared betweentwo groups with a Student’s -test and between three groupswith a one-way analysis o variance (ANOVA) test with a

post-hoc Bonerroni’s multiple comparison between groups.

A Fisher’s exact test was used to compare the number o women grouped by the presence or absence o endometrioticlesions within each region and the comparison betweensingle and multiple lesions. A Chi-squared test was usedto analyse the difference in prevalence between the threedistinct regions (peritoneal, RVS, and ovarian). All statisticaltests were perormed with GraphPad Prism or Mac OSXand the results were considered signicant i the value wasbelow ..

3. Results

.. Te Incidence of Endometriotic Lesions at Different Loca-tions and the Age of Patients. In o the women (/;.%) an endometriotic lesion was ound in only one o the three dened regions, while patients (/; .%)had endometriotic lesions in more than one (multiple) o the dened regions. Te most common single region was theperitoneum with lesions ound in (/; .%) women.Te RVS (/; .%) and ovarian (/; .%) regionhad a similar incidence with each. Te most commoncombination o multiple regions was the peritoneum andovaries with (/; .%) occurrences, ollowed by acombination o all three regions with (/; .%) cases.A combination o lesions in the peritoneum and RVS wasound in (/; .%) women andthe combination o RVSand ovarian lesions was uncommon with only (/; .%)

cases observed in the total study population (able ).O the women included in this study (/,

.%) were non-HC users, whereas (/, .%)were HC users. Te mean age o the HC users (30.66 ±0.66) was signicantly younger ( = 0.0001) than womenwho were non-HC users (34.14 ± 0.60). When ages werecompared between the absence vs. presence groups there wasa signicant difference ( = 0.0003) in the peritoneal groupwith HC users (29.49 ± 0.79, = 49) younger than non-HCusers (33.43 ± 0.70, = 61). A similar difference was alsoobserved in the ovarian group, as HC users (31.41 ± 1.15, =32) were signicantly younger ( = 0.0218) than non-HCusers (34.09 ± 0.72, = 57). In the single lesion groups, the


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: Te incidence and mean age o patients with endometriotic lesions at dened locations in both the current HC use or non-HC usegroups.

(%) Age

All No HC HC

All women

Age . ±

. . ±

. . ±

. .

Absence versus presence

Peritoneal . ± . ( = 110) . ± . ( = 61) . ± . ( = 49) .

RVS . ± . ( = 58) . ± . ( = 30) . ± . ( = 28) .

Ovarian . ± . ( = 89) . ± . ( = 57) . ± . ( = 32) .

value 0.09712 0.70332 0.07712

Single region / (.) . ± . ( = 81)

Peritoneal / (.) . ± . ( = 37) . ± . ( = 14) . ± . ( = 23) .

RVS / (.) . ± . ( = 22) . ± . ( = 11) . ± . ( = 11) .

Ovarian / (.) . ± . ( = 22) . ± . ( = 16) . ± . ( = 6) .

Single location ( value) 0.00582 0.49322 0.04342

Multiple regions / (.) . ± . ( = 80)

Peritoneal and ovarian / (.) . ± . ( = 42) . ± . ( = 27) . ± . ( = 15) .

Peritoneal and RVS / (.) . ± . ( = 14) . ± . ( = 6) . ± . ( = 8) .

RVS and ovarian / (.) . ± . ( = 3) — . ± . ( = 3) —

Peritoneal, ovarian, & RVS / (.) . ± . ( = 21) . ± . ( = 14) . ± . ( = 7) .

Multiple location ( value) 0.93332 0.73892 0.78732

Single versus multiple ( value) 0.84621

1Comparison o the mean age between HC users and non-HC users, as well as between the single and the multiple regions, was perormed by a Student’s -test. Comparison o the mean age between women with lesions in different locations, as well as or both the single and multiple regions, was perormed by aone-way ANOVA test with a post-hoc Bonerroni’s multiple comparison test.

women with peritoneal lesions that were HC users (27.91 ±1.20, = 23) were signicantly younger ( = 0.0114) com-pared to non-HC users (33.36 ± 1.71, = 14) (able ).

When comparing ages across lesion locations there wasno signicant difference ( = 0.0971) between the ages o women based on presence o a lesion at the dened region. I the samples were split by HC and non-HC use, again, therewas no signicant difference between the age o the womenbased on the presence o a lesion. When only women witha lesion in a single location were taken into account a one-way ANOVA test conrmed a signicant difference betweenthe mean ages ( = 0.0058). A post-hoc Bonerroni’s Multiplecomparison test indicated thatwomen with peritoneal lesionswere signicantly younger (29.97± 1.07, = 37) than women

with lesions in either the RVS (34.40 ± 1.20, = 22; < 0.05)or the ovaries (34.73 ± 1.30, = 22; > 0.05). Whenthese women were urther split based on HC use a one-way ANOVA test indicated a signicant difference existedbetween the HC users ( = 0.0434) but not in the non-HCusers ( = 0.4932) (able ).

.. Hormonal Contraceptive Use and the Region SpecicPrevalence of Endometriotic Lesions. O the entire study population, .% (/) o the women were currently non-HC users compared to .% (/) who were current HCusers. O the women with endometriotic lesions in a singleregion, (/; .%) were non-HC users, whereas

(/; .%) were current HC users. O the women with

endometriotic lesions in multiple regions (/; .%)were non-HC users compared to (/; .%) who werecurrent HC users. Te difference between the prevalence o lesions in either single or multiple locations based on currentHC use was not signicant ( = 0.3435) (able ).

When grouped via the simple presence or absence o endometriotic lesions the most common location was theperitoneal region with cases (/; .%). Ovarianlesions were detected in cases (/; .%) and RVSlesions in (/; .%) cases. In the study group, therewas a signicantly lower probability (OR = ., % CI.–., = 0.0167) o having an endometriotic lesionpresent (/; .%) on the ovary compared to it being

clear o a lesion (/; .%) i the women were current HCusers. In contrast, no signicant effect o current HC use wasobserved on the incidence o endometriotic lesions in eitherthe peritoneum or the RVS (able ).

o conrm an association between the reduced preva-lence o ovarian endometriotic lesions and HC use weselected women with lesions in a single region only andused a Chi-squared test to analyse the distribution amongstthese locations between current HC users and non-HC users.In these women, the incidence o ovarian endometrioticlesions, compared to the peritoneum and the RVS, was alsosignicantly lower ( = 0.0347) with current HC use(able ).


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: Hormonal contraceptives and the presence o endometriotic lesions in dened regions.

Single region, (%) Multiple region, (%) OR (% CI) value

Single versus multiple regions

All

No hormone (.) (.)

HC (.) (.) . (.–.) .Absence, (%) Presence, (%) OR (% CI) value

Ovarian

All

No hormone (.) (.)

HC (.) (.) . (.–.) .

Peritoneal

All

No hormone (.) (.)

HC (.) (.) . (.–.) .

RVS

All

No hormone (.) (.)HC (.) (.) . (.–.) .

A Fisher’s exact test was used to determine i the incidence o endometriotic lesions in particular locations was signicantly different under HC use.

: Prevalence o women with endometriotic lesions in single regions only with and without hormonal contraceptive use.

Ovarian, (%) Peritoneal, (%) RVS, (%) value

Single location cases

No hormone (%) (.) (.) (.).

HC (%) (.) (.) (.)

A Chi-squared test was used to determine whether the incidence o endometriotic lesions in different locations was signicantly different under HC use.

4. Conclusion

Te relationship between HC use and endometriosis isstill controversial. We proposed that the heterogeneity o endometriotic lesions that are ound in different regionsmight contribute to the disparity in results previously reported. Tis study reports that current HC users are lesslikely to have endometriotic lesions on the ovaries, whereasin contrast, no difference was observed in the incidence o lesions in either the RVS or peritoneal regions. Te resultsthereore suggest that HC use may affect endometrioticlesions at separate locations differently and may be indicativeo distinct pathophysiologies or lesions that develop at

separate locations. Although this study only represents asmall sample set it also suggests a potentially protective effecto HC use on the development o ovarian endometrioticlesion, which should be investigated urther.

Previous evidence indicates that signicant biochemicaland anatomical differences exist between lesions at differentlocations and that it is possible that lesions ound in theperitoneal cavity, the ovaries, and in the RVS all have adistinct pathophysiologies []. HC use has been suggestedto inuence the incidence o endometriosis []; howeverwhether it affects all lesions equally has not been assessed andthus may offerurtherevidence or distinct pathophysiologiesbased on the location o the lesions or underlying tissue.

Tis study was thereore designed to assess the relationshipbetween endometriosis and HC use while accounting or theheterogeneity that may exist between endometriotic lesionsthat develop in separate regions. A particular strength o this study is that we have identied the location o every lesion removed rom the patients and as such have beenable to perorm a dual analysis with two distinct patientgroupings. Firstly, an analysis was perormed based simply on the presence or absence o a lesion at the dened location.Secondly, a smaller but more stringent grouping was madethat included only women with lesions in a single region.By using the larger cohort o women based simply on thepresenceor absence o a lesion, we hadlarger samplenumbers

in each group and thereore more statistical power. Teresults o this analysis show it was signicantly less likely orwomen who have endometriosis and are using HC to have alesion on the ovaries than either the peritoneal cavity or theRVS. Subsequently, by studying women with lesions connedto a single region only we have analysed a smaller butmore distinct subgroup that may help to eliminate potentialconounding actors introduced when women have morethan one affected region. Most importantly, the results o thisanalysis conrmed those o the larger cohort.

Previously, only a limited number o studies on HC useand endometriosis have taken into account the location o the lesions, or when they have done so this aspect was not


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a primary ocus as a potential source o heterogeneity. Tesestudies have also used different methods o grouping patientsand as such have also reported disparate results. One study by Chapron et al. () examined both the location o thelesion as well as the primary reason or HC prescription.Tis study ound that past, but not current HC use, was

requently associated with the development o deep inltrat-ing endometriosis (DIE) [], particularly when prescribedor severe primary dysmenorrhea, but ound no relation-ship with HC use and endometriomas. Contrary to ourstudy, this report grouped women based on the most seriouslesion identied, rather than their presence or absence.Supercial peritoneal endometriosis was considered the leastsevere, ollowed by endometrioma andnally DIEas themostsevere. Tereore, based on these groupings, a number o women with endometriomas may have also been included inthe DIE group, or women with peritoneal lesions may havebeen included in both the endometrioma andDIE group. Tisrepresents a signicant difference rom the groupings per-ormed in ourstudy andcouldexplain the variation in results.Another study that ocused primarily on environmental risk actors ound a lower but nonsignicant previous use o HCwith women whohad either peritonealor DIE. Tis study didnot report on ovarian endometriosis [].

It must also be noted that in this study we have only analysed women with histologically conrmed endometrio-sis. We have not analysed the incidence o endometriosis inthe population, but rather the incidence o endometriosis atdened regions in a population o women with endometrio-sis. By perorming the analysis in this way we have eliminateda non-endometriosis group that is notoriously difficult toestablish as a homogenous sample and have ocused on theincidence o endometriosis at different locations in a group o women known to be susceptible to endometriosis. WhetherHC use has a similar effect on women that are not originally susceptible to endometriosis is not addressed in this study.

As with all studies some inherent weakness andlimitationare also present and thus should be discussed. Firstly, themean age o the current HC users was signicantly youngerthan those who were non-HC users. A urther analysis o the mean ages shows that women with lesions in both theperitoneal cavity andthe ovaries, but notthe RVS, are also sig-nicantly younger in the current HC users group comparedto the non-HC users, although in the single lesion group thisdifference exists only in the peritoneal samples and not theovarian or RVS samples. Tis difference between the age o

the current HC users and non-HC users is not surprisingas the primary reason or HC use (contraception) will bemorecommon amongst younger women. Tese demographicdifferences in the use o HC will thereore always make thisdifficult to resolve in such studies.

Tis difference in age between the current HC users andnon-HC users also raises the possibility that the lower inci-dence o ovarian endometriotic lesions observed in womenusing HC may be due to their younger age. Previous studieshave ound that the incidenceo endometriosisincreases withincreasing age, with one study showing a peak between and [] and another showing a peak between and [], although both suggest that a difference o at least years

is required to achieve a signicant difference. While there isa statistically signicant difference between the ages o thetwo groups in our study, the entire difference is less then years which is unlikely to be sufficient to alter incidenceo the disease, particularly as a delay in the diagnosis romthe original inception o the lesion can be up to years

[]. In addition, although the age difference was statistically signicant with both the peritoneal and ovarian groups weonly observed a differencein the incidenceo lesions based oncurrent HC use in the ovarian group and not the peritonealgroup. In act, the incidence o ovarian endometriosis incurrent HC users was still much lower than that observedin peritoneal lesions even though the mean age o womenwith peritoneal lesions was signicantly lower than that o women with ovarian lesions. Te role o age in the incidenceo endometriotic lesions at differentlocations should be takeninto account when designing urther studies to analyse theeffect o HC use on lesions rom different locations.

Previous studies have also suggested that the inuence o HC use on the incidence o endometriotic lesions depends onwhether the usage is still current. Women currently takingHC have a reduced incidence o endometriosis, whereaswomen who had stopped taking HC or over months havean increased incidence [, ]. Past users were also shownto have an increased incidence o DIE, but not other typeso endometriosis []. A meta-analysis o studies alsoconcluded that there was an increased incidencein past users,but a decreased incidence in current users []. As previousstudies have shown that the duration o HC use is not relatedto disease status [], but rather whether or not use is current,we ocused only on current use and whether it inuences theincidence o endometriotic lesions at different locations. Weused a three-month period to establish current use, as thisis a period commonly needed or a stable menstrual cycle tobe reestablished afer hormonal control. Although we usedthis three-month cut-off we do not suggest that abstinencerom HC or three months is sufficient to allow the growth o endometriosis. It is most likely that non-HC users have nottaken HC or a period much longer than this. Unortunately,we did not have a large enough sample size to analyse theimpact o the duration o use.

Multiple theories have been proposed to explain theaetiology o endometriosis [] and although retrogrademenstruation is the most widely accepted it cannot explainthe occurrence o all lesions, particularly those that occurin the absence o a unctioning endometrium [, ],

supporting the possibility o multiple aetiologies. Itis possiblethat the results o this study are a reection o the inherentdifferences that exist in lesions that develop at differentanatomical locations and that these lesions may have variableaetiologies potentially inuenced by HC use. Tis is notsurprising given the variability o the underlying tissue whereendometriotic lesions can be ound.

Te results o thisstudy thereore showed that endometri-otic lesions are less likely to be ound on the ovaries thanin other locations in current HC users. Tese results suggesta potential protective effect o HC use that differs based onthe anatomical locations most susceptible to the disease. Itis important to note that the results do not suggest that HC


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use protects against endometriosis, but rather only that it may affect development at separate locations differently. It mustbe remembered, however, that no causality can be drawnrom this study, and urther work should be perormed tounderstand exactly what the link is between HC use and thedevelopment o location specic endometriotic lesions.

Conflict of Interests

Te authors declare that there is no conict o interestsregarding the publication o this paper.

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