{"paper_id":"5a989da8-fa6a-41ee-b337-4ac555b1adef","body_text":"1 \n 1 \n 2 \n 3 \n 4 \nEndometriosis risk is associated with shorter anogenital distance by meta-analysis 5 \n 6 \n 7 \n 8 \n 9 \n 10 \n 11 \n 12 \nBernard J. Crespi 13 \nDepartment of Biological Sciences 14 \nSimon Fraser University 15 \nBurnaby, British Columbia, Canada V5A 1S6 16 \n 17 \n 18 \n 19 \n 20 \n 21 \n 22 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n 2 \nAbstract 23 \nBackground: Anogenital distance is a well-validated marker of prenatal testosterone, with 24 \nshorter distances indicating lower levels during early gestation. A suite of studies has linked 25 \nanogenital distance with risk of endometriosis, but the findings are variable, leading to 26 \nuncertainty in interpretation. The relationship of anogenital distance with endometriosis is 27 \nespecially important because lower testosterone has been associated with endometriosis in 28 \nrecent Mendelian Randomization studies, which implies causality in the association, with direct 29 \nimplications for future research and treatment. 30 \nMethods: A systematic review and meta-analysis was conducted on the association of 31 \nendometriosis with anogenital distance. Three databases were queried in the identification 32 \nphase, and a random-effects meta-analysis was applied to the data in studies that met the 33 \ninclusion criteria. 34 \nResults: Shorter anogenital distance AF, measured from the anus to the posterior fourchette, 35 \nwas significantly associated with higher risk of endometriosis in the meta-analysis. By contrast, 36 \nthere was no such association for anogenital distance AC, measured from the anus to the 37 \nclitoral surface. Both analyses demonstrated significant heterogeneity across studies. Too few 38 \nstudies were available for robust investigation of publication bias. 39 \nConclusions: The association of short anogenital distance with endometriosis risk provides 40 \nsupport for the hypothesis that endometriosis represents, in part, a disorder mediated by 41 \nrelatively low testosterone levels in early prenatal development. This conclusions has notable 42 \nimplications for understanding the causes and treatment of endometriosis. 43 \nKeywords: endometriosis, prenatal testosterone, anogenital distance, meta-analysis 44 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 3 \nBackground 45 \nEndometriosis, which has been reported in about 5-10% of reproductive-aged women, is 46 \ncharacterized by endometrial tissue establishing outside of the uterus, most often in the 47 \novaries, peritoneum, or rectovaginal region [1]. This 'ectopic' endometrial tissue undergoes 48 \nmenstrual cycle changes similar to those of normally situated, 'eutopic' endometrium, 49 \nproliferating under the influence of estradiol. Endometriosis often causes severe pelvic pain, as 50 \nwell as reduced fertility in many patients. Management typically involves various means to 51 \nreduce the effects of estrogenic stimuli that promote endometrial tissue proliferation, and 52 \nsurgery to remove endometriotic tissue [2,3].  53 \n  54 \nEndometriosis risk is mediated by many genes each of small effect [4], exhibiting a heritability 55 \nof approximately 0.50 [5,6]. GWA (genome wide association) studies have identified a set of 56 \nsingle nucleotide polymorphisms (SNPs) that account for a small proportion of this heritability, 57 \nand that includes SNPs in genes with demonstrated roles in early sexual development (WNT4, 58 \nHOXC6), steroid hormone signalling (ESR1, GREB1, KDR), overall growth (IGF1), HPO axis 59 \nfunction (FSHB), among other phenotypes [4]. Endometriosis risk is also mediated by 60 \nenvironmental steroid effects, as exemplified by links of the disorder with the synthetic 61 \nestrogen diethylstilbestrol, via influences during prenatal development [7,8].  62 \n  63 \nA series of studies has tested for associations of endometriosis with anogenital distance (AGD), 64 \nwhich represents an indicator of levels of prenatal testosterone in early fetal development 65 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 4 \n(reviews in [9,10]). Anogenital distance, which is measured from the anus to landmarks on the 66 \ngenitalia, is substantially longer on average in males than in females among humans and other 67 \nmammals, due to variation between the sexes in levels of prenatal testosterone that control 68 \ngrowth of the perineal region. AGD also varies substantially within each sex, as indicated by 69 \nobservational studies and extensive experimentation with non-human animals, as well as 70 \nstudies of humans naturally subject to altered levels of testosterone [11–14]. Female mammals 71 \nthat develop under relatively low levels of prenatal testosterone thus tend to develop relatively 72 \nshort AGDs, and high levels result in longer AGDs [15].  73 \n  74 \nAnogenital distance in women with endometriosis was initially studied in the context of 75 \ndeveloping new biomarkers for this disorder [16]. More recently, AGD has been analyzed in the 76 \ncontext of the developmental basis of endometriosis, whereby relatively low prenatal 77 \ntestosterone differentially programs the developing hypothalmic-pituitary-ovarian (HPO) axis in 78 \nsuch a way as to increase risk in later life [17,18]. This paradigm provides a novel conceptual 79 \nand empirical framework for understanding and studying endometriosis, in a comparable way 80 \nto analyses of the well-established role of relatively high prenatal testosterone in risk for 81 \ndevelopment of polycystic ovary syndrome [17].  82 \n 83 \nA suite of studies of anogenital distance in women with endometriosis, compared to controls, 84 \nhas been published to date. These studies all include the two main measures of AGD: AGD-AF 85 \n(from the anus to the posterior fourchette), and AGD-AC (from the anus to the clitoral surface), 86 \nand the results are heterogeneous both across studies and between these two measures of 87 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 5 \nAGD. The purpose of this analysis is to conduct the first meta-analysis of AGD in relation to risk 88 \nof endometriosis, to ascertain the strength of evidence overall, and to help guide future work. 89 \n  90 \nMethods 91 \nThree databases were searched systematically on 23 November 2023. First, Web of Science was 92 \nsearched using the search terms 'anogenital distance endometriosis' in the 'All fields' search 93 \nbox, which returned a total of 33 entries. Second, PubMed was searched using the search terms 94 \n'anogenital distance endometriosis', which generated 21 returns. Third, Google Scholar, a more 95 \nbroadly inclusive search engine, was also searched using the terms 'anogenital distance 96 \nendometriosis', for any date, and with sorting by relevance. For this latter database, the first 97 \n100 citations were included in the initial screening. The returned articles were searched to 98 \ndetermine if they met the search criteria (data on AGD from women with endometriosis, and 99 \nfrom controls), and the other criteria for inclusion (unique data set not used in published work 100 \npreviously, and conduct of measurements for both AGD-AF and AGD-AC). A PRISMA diagram 101 \ndepicts the search and inclusion processes (Figure 1). 102 \n 103 \nA random-effects model meta-analysis was conducted using the program Meta MAR [19]. The 104 \nmain goal of the meta-analysis was to increase statistical power to test for differences in AGD-105 \nAF, AGD-AC, or both, between women with endometriosis and controls. A random-effects 106 \nmodel was used so that the results can be applied beyond the included studies, and given that 107 \nwomen with different forms and severities of endometriosis may be subject to different 108 \nmagnitudes of effects on AGD (see e.g., [20]).  109 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 6 \n 110 \nFor the study [21] that included measurements of AGD-AF and AGD-AC from women with two 111 \ndifferent forms of endometriosis (ovarian and deep-infiltrating) separately but not together, 112 \nthe authors provided a copy of their data set, which allowed calculation and use of the data for 113 \nall women with endometriosis combined. 114 \n 115 \nResults 116 \nA total of six studies met the inclusion criteria (Figure 1), comprising a total of 883 subjects 117 \noverall, and were subject to meta-analyses for AGD-AF and AGD-AC. The random-effects meta-118 \nanalysis demonstrated a significant difference between women with endometriosis and 119 \ncontrols for AGD-AF (SMD=-0.77, p = 0.026, Figure 2). By contrast, the meta-analysis indicated 120 \nno significant difference for AGD-AC (SMD=-0.29, p = 0.166, Figure 2). Both analyses 121 \ndemonstrated significant heterogeneity between studies (AGD-AF, Cochran's Q = 47.4, P < 122 \n0.001; AGD-AC, Cochran's Q = 30.8, p < 0.001). There was an insufficient number of studies 123 \navailable for robust interpretation of funnel plots in the context of testing for publication bias. 124 \n 125 \nDiscussion 126 \nThe primary finding of this study is that meta-analysis provides support for the hypothesis that 127 \nAGD-AF is significantly shorter among women with endometriosis than among controls. By 128 \ncontrast, the comparison for AGD-AC was non-significant. The results for AGD-AF indicate that 129 \nendometriosis shows a robustly replicated association with this measure of prenatal 130 \ntestosterone, such that low levels of this hormone in early prenatal development represent a 131 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 7 \nrisk factor, even if the predictive value of AGD-AF as a biomarker for diagnosis of endometriosis 132 \nis limited [16,22]. These findings are of importance given that: (1) two studies have recently 133 \ndemonstrated that genetically predicted lower serum testosterone is significantly associated 134 \nwith higher risk of endometriosis [23,24], and (2) shorter anogenital distance (AGD-AF) has 135 \nbeen linked with lower serum teststerone in healthy women of reproductive age [25]. 136 \n 137 \nThe meta-analyses indicated significant heterogeneity among studies, for both AGD-AF and 138 \nAGD-AC. Some of this variation is likely due to the populations analyzed; for example, the 139 \nstudies differed in the proportions of women with different forms of endometriosis (deep-140 \ninfiltrating, ovarian, or peritoneal), in the body mass index (BMI) of participants, and in other 141 \nvariables. For example, nine of the 43 women with endometriosis in one sample [26] exhibited 142 \nhyperandrogenism (and eight reported acne, and two showed hirsutism), which is characteristic 143 \nof polycystic overy syndrome (PCOS), and may be related to the lack of difference in AGD-AF 144 \nbetween women with endometriosis and controls in this study.  145 \n 146 \nThe differences in results reported here between AGD-AF and AGD-AC should be considered in 147 \nthe context of the AGD-AF distance being a subset of the AGD-AC distance, such that AGD-AC is 148 \nequal to the sum of AGD-AF plus the distance between the posterior fourchette to the clitoral 149 \nsurface. As such, AGD-AF and AGD-AC are related as part-whole, and are positively correlated 150 \nwith one another, with correlation coefficients of between 0.33 and 0.60 (mean=0.48, N =7) 151 \n[16,26–31]. Given that the overall average distance of AGD-AF is about one-third that of the 152 \noverall average distance of AGD-AC, a substantial proportion of the mean difference between 153 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 8 \nwomen with endometriosis and controls in AGD-AC can thus be attributed to the differences in 154 \nAGD-AF. As such, for the results reported here, AGD-AF can be considered as the metric that 155 \ndiffers significantly between women with endometriosis compared to controls, with any 156 \ndifferences in AGD-AC (in some individual studies) being attributable at least in part to its 157 \nvariation. These inferences are demonstrated most clearly in the results from Mendiola et al. 158 \n[16] and Buggio et al. [21], where the distance AGD-AF is 50–100% of that for AGD-AC, such 159 \nthat the former accounts for the bulk of the variation in the latter.  160 \n 161 \nThe biological significance of AGD-AF, compared to AGD-AC, is supported by the observations 162 \nthat: (1) the approximately two-fold difference between females and males for distance of the 163 \nperineum (measured from the anus to the genitalia: posterior fourchette in females or base of 164 \nscrotum in males), and corresponding to AGD-AF, is proportionally much larger than the sex 165 \ndifference in AGD-AC (measured in males from the anus to the anterior base of penis) (e.g., 166 \n[32]); (2) among rodents, the longer AGD in males than females, which is known from 167 \nexperiments to be due to higher prenatal testosterone in males, corresponds to AGD-AF among 168 \nhumans; (3) AGD-AF, but not AGD-AC, is positively correlated with levels of serum testosterone 169 \nin young women without endometriosis or PCOS [25,28]; and (4) AGD-AF is a better predictor of 170 \nendometriosis than is AGD-AC in studies that use AUC (Area Under receiver operating 171 \nCharacteristic curve) analyses [27,33].  172 \n  173 \nSignificantly shorter AGDs (for AGD-AF, AGD-AC, or both) have also been associated with four 174 \ncorrelates of endometriosis: premature ovarian insufficiency [34,35], dysmenorrhea [36,37], 175 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 9 \nreduced responses to ovarian stimulation in IVF [29,38], and relatively regular menstrual cycles 176 \n[39]. These findings support the hypothesis of causal links between lower prenatal testosterone 177 \nand higher risk of endometriosis, as does evidence suggesting that women with endometriosis 178 \nexhibit a higher level of sexual difference from males than do healthy women for a suite of 179 \nsexually dimorphic traits [40]. Most broadly, these results provide evidence that endometriosis 180 \nrepresents, in part, a reproductive disorder mediated by early development whereby relatively 181 \nlow testosterone affects the expression of many sexually dimorphic and sex limited traits [18].  182 \nThis hypothesis is convergently supported by recent Mendelian Randomzation studies showing 183 \nthat lower genetically predicted testosterone is linked with higher risk of endometriosis, such 184 \nthat the relationship between the two shows evidence of causality [23,24]. Future studies that 185 \ninvestigate effects of low prenatal testosterone in women, in the context of other correlates of 186 \nendometriosis (such as early menarche and higher pain sensitivity), should provide further 187 \ninsights into the causes of this disorder. Studies testing for shorter AGDs in daughters of women 188 \nwith endometriosis, compared to controls, would also represent useful tests for effects of low 189 \nprenatal testosterone in endometriosis risk. 190 \n 191 \nThe main limitations of this study include the relatively small number of studies conducted thus 192 \nfar on AGD in relation to endometriosis, the low sample sizes of some of the studies, their 193 \nrestriction thus far mainly to women of European descent, and the heterogeneity among 194 \nstudies in the clinical characteristics of the particpants. These limitations should be addressed 195 \nwith larger studies of more-diverse participants, and analyses of the genetic basis of AGD and 196 \nits relationship to endometriosis risk factors. 197 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 10 \n  198 \nIn contrast to these studies of endometriosis and its correlates, analyses of PCOS provide 199 \nevidence for longer AGDs in women with this disorder. Thus, in three data sets, women with 200 \nPCOS showed significantly longer AGDs compared to controls [27,28] or to women with 201 \nendometriosis [26], and in a fourth study, the difference between women with PCOS and 202 \ncontrols was marginally non-significant (p=0.08 for AGD-AF, 0.17 for AGD-AC) [41]. Women with 203 \nPCOS also show evidence of bearing daughters with longer AGDs, compared to controls, from 204 \nthree studies [42–44], whereas a fourth study showed no significant differences [45].  205 \n 206 \nLonger AGDs in women with PCOS, and in their daughters, may be related in part to their higher 207 \nbody mass indices (BMIs) (women with PCOS had significantly higher BMIs than did controls in 208 \nmost studies of AGD [26,27,41,46]), given that: (1) BMI is higher among women with PCOS than 209 \nin controls (e.g., [47]); (2) BMI is positively correlated with AGD among women [16,26,29,31, 210 \n33]; (3) maternal obesity is associated with longer AGD among daughters [48,49]; (4) AGD is 211 \npositively correlated with serum testosterone [25,28]; and (5) BMI is positively associated with 212 \nlevels of testosterone, which represent a key correlate of PCOS [50]. Additional studies are 213 \nneeded of AGD in women with PCOS, and in daughters of women with PCOS, in the context of 214 \nmaternal BMI and testosterone, for sufficient data to be available for meta-analysis of AGD in 215 \nthis disorder. 216 \n 217 \n 218 \n 219 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 11 \nConclusions 220 \nThis meta-analysis provides evidence that risk of endometriosis is mediated by lower anogenital 221 \ndistance (specifically, AGD-AF), which suggests that lower testosterone in prenatal 222 \ndevelopment increases risk of this disorder. Further studies are needed on AGD-AF in relation 223 \nto the correlates and potential causes of endometriosis.  224 \n 225 \nAbbreviations: 226 \nAGD: anogenital distance 227 \nAGD-AC: anogenital distance, anus to clitoral surfac 228 \nAGD-AF: anogenital distance, anus to posterior fourchette 229 \nBMI: body mass index 230 \nGWA: genome-wide-association 231 \nPCOS: polycystic ovary syndrome 232 \nSNP: single nucleotide polymorphism 233 \n 234 \n  235 \nDeclarations: 236 \nEthics approval and consent to participate: Not applicable 237 \nConsent for publication: Not applicable 238 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 12 \nAvailability of data and materials: The data (means, standard deviations, and sample sizes) 239 \nused in the meta-analysis were taken from the respective studies that were included in the 240 \nsystematic review, and are shown in Figure 1. 241 \nCompeting interests: The author declares that they have no competing interests. 242 \nApprovals: The author has seen and approved the manuscript. 243 \nFunding: This work was funded by Discovery Grant 2018-04208 from the Canadian Natural 244 \nSciences and Engineering Research Council. 245 \nAuthors' contributions: BC conducted all of the research and manuscript preparation. 246 \nAcknowledgements: I am grategul to L. 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Associations 383 \nof maternal anthropometrics with newborn anogenital distance and the 2:4 digit ratio. 384 \nHum Reprod. 2022;37:2154-66. 385 \n49. Halici-Ozturk F, Yetiskin FD, Gurlek B, Ocal FD, Yakut K, Engin-Ustun Y, et al. Longer 386 \nanogenital distance in female fetus of diabetic and obese pregnant women. Taiwanese J 387 \nObstetr Gynecol. 2023;62:530-6. 388 \n50. Diamanti-Kandarakis E, Bergiele A. The influence of obesity on hyperandrogenism and 389 \ninfertility in the female. Obesity Rev. 2001;2:231-8. 390 \n 391 \n  392 \n 393 \n 394 \n 395 \n 396 \n 397 \n 398 \n 399 \n 400 \n 401 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 20 \n 402 \nFigures   403 \n 404 \nFigure 1. PRISMA diagram showing identification, screening, and inclusion process for the meta-405 \nanalysis. 406 \n 407 \n 408 \n 409 \n 410 \n 411 \n 412 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint \n\n 21 \nFigure 2. Main results of meta-analyses for (a) AGD-AF and (b) AGD-AF. 413 \n 414 \n 415 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300901doi: medRxiv preprint","source_license":"CC0","license_restricted":false}