{"paper_id":"fa7f8735-a2a3-498f-91e4-72d29d8a90f2","body_text":"Several lifestyle factors affect human reproductive performance (1). Exposure to endocrine-disrupting chemicals in fetal life can be concerning because the sexual organs are formed in this period, which is the foundation of reproductive health in adulthood (2, 3). Reproductive disorders and anogenital problems can be debilitating and negatively impact people's quality of life (4, 5). In the past decades, reproductive disorders and anogenital problems have increased dramatically (6-8).\nDiagnostic procedures may generally be associated with health-related complications (9, 10). Some other methods result in high financial costs and time for the individuals and delay the “golden time” for diagnosis and treatment of the disease (11). Therefore, a noninvasive indicator that predicts and diagnoses the disease earlier seems important.\nHormonal dysfunction during fetal life can cause anogenital problems in adulthood (12-14). As a result, we can use anogenital distance (AGD) as a proxy for hormonal dysfunction in the past to determine whether or not a hormonally disruptive action occurred during fetal growth (15, 16). AGD is a noninvasive and easily measurable anthropometric measurement, the distance between the anus and the genital tubercle (17-20). It is considered the amount of distance between the anterior clitoral surface to the upper verge of the anus (AGD \n AC \n ) and distance between posterior fourchette to the upper verge of the anus in women (AGD \n AF \n ) (21). It is indicated the amount of distance between cephalad insertion of the penis to the center of the anus (AGD \n AP \n ) and distance between posterior base of the scrotum to the center of the anus in male (AGD \n AS \n ) (22).\nAGD has been used as an indicator of fetal androgen dysfunction and as an adverse outcome in adulthood (23). AGD is a broad marker that retrospectively describes fetal androgen disruption and potentially adult reproductive disorders (24). Intrauterine hormonal changes can affect AGD (25, 26). Thus, AGD is a biomarker of prenatal hormonal exposure at birth and can also reflect reproductive health in adulthood (12, 27). In men, correlations have been found between the length of AGD and semen quality, testicular volume, hypospadias, and cryptorchidism (28-31). Also, in women, AGD is a potential determinant of some female gynecologic and reproductive disorders, such as polycystic ovary syndrome (PCOS), endometriosis, and pelvic organ prolapse (POP) (31-33). AGD can also determine the gender of the fetus in the first trimester of pregnancy (11).\nThere are large numbers of studies supporting the ability of AGD as a tool for disorder prediction. Thus, in this study, we have systematically summarized the available evidence related to assessing the association of AGD in the diagnosis and prediction of different health conditions.\n\nThe current systematic review was performed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement (34). The electronic databases, including Medline via PubMed, Scopus, and ISI Web of Knowledge up to July 30, 2021 were systematically searched. The following keywords were used: “anogenital distance\" OR “anogenital index\" OR “ano genital distance\" OR “ano genital index\". Boolean Operators (AND, OR) were used in search strategy. Also, we review the reference of all included paper for any related articles. No any language limitation considered in the search strategy.\nThe below criteria were used for selecting studies.\nInclusion criteria:\n1. All quantitative research evaluated the association of AGD in diagnosing or prognosis of any disorder or disease.\n2. Studies that have a proper definition of AGD.\n3. All observational and comparative studies such as cross-sectional, case-control, and cohort studies.\nExclusion criteria:\n1. All studies that are not the original studies such as letter, editorial.\n2. Studies conducted on animals.\n3. Laboratory and in vivo studies.\nFor removing the duplicate references and managing retrieved evidences we used EndNote software.\nAs presented in the PRISMA flowchart, we retrieved 1194 unique references after removing the duplicates. In total, 1542 articles were duplicated in basic search, found, and removed by the EndNote software. Another 958 were excluded after the title and abstract review. The full texts of the remaining 241 articles were retrieved and critically evaluated. This systematic review comprised 47 publications after the screening procedure (Figure 1).\n2 independent reviewers (MK and PZ) reviewed the full text of publications identified by the literature search for their possible relevance or screened the titles and abstracts for inclusion in the review.\nIf there was a dispute, it was settled by consulting with a third reviewer (SK). The data was abstracted separately by 2 reviewers (ZH and MD). The following information was retrieved from all eligible papers: first author's name, year of publication, study location, age group, participant characteristics, study design, type of outcome, type of AGD, and key findings. According to high heterogeneity between included studies quantitative meta-analysis was not performed.\nThe Newcastle-Ottawa Scale was used for assessing the quality of included studies (35). The Newcastle-Ottawa Scale score have 9 score and 3 main criteria. Each investigation was assessed based on 3 main criteria: 1) appropriate study population selection, 2) comparability of study groups, and 3) determination of the desired exposure (in cohort studies) or result (in case-control studies).\nEach publication was evaluated independently by 2 reviewers. Disagreements were worked out via conversation until a consensus was reached. Studies with a score of 7 or more out of 9 were considered to be of high quality. Table I displays the results of each study's quality evaluation.\nClassification of the result according to each category of outcomes\nPapers search and review flowchart for selection of primary study.\nThe present study was approved by Shahroud University of Medical Sciences Ethical Committee, Shahroud, Iran (Code: IR.SHMU.REC.1398.140).\n\nIn this systematic review, we studied the association of AGD as a surrogate for diagnosing different diseases. Different outcomes have been studied, including endometriosis, prostate cancer, PCOS, POP, hypospadias, and cryptorchidism, fertility and semen parameters, maternal and birth outcomes, and ovarian and gynecological disorders related to pregnancy. The results of the included research are summarized in table I. We classified the results according to each outcome category.\nOverall, a negative association was observed between AGD, endometriosis, and hypospadias, and a positive association between AGD and prostate cancer, PCOS, male fetal gender, and fertility parameters.\nThe methodological quality of the included articles according to NOS is provided in the supplementary file. Also, the overall NOS scores for the included studies are shown in table I. As shown, 22 high-quality and 12 medium-quality studies were included.\nThis is the first systematic review to assess the association of AGD as a non-invasive alternative to diagnostic and prognostic diseases requiring clinical intervention.\nWe did a comprehensive, systematic search of the literature to find studies that investigated the association of AGD as a non-invasive alternative to diagnostic and prognostic diseases. Important procedures, including searching, data extraction, and quality assessment, were also carried out independently by 2 experts.\nUsing quantitative indicators such as AGD to determine the prognosis and early diagnosis of diseases in the future may be of great help in therapeutic interventions and the treatment of individuals in the early stages of the disease.\nThe current evidence showed that a shorter AGD was significantly associated with endometriosis. Few studies exist about AGD in women. Previous studies have shown that AGD was longer in women with a higher ovarian follicular number and higher testosterone levels (71), and disorder in the menstrual cycle before pregnancy (57). One study showed a strong relationship between endometriosis and shorter AGD \n AF \n  (21). A case-control study of 114 women with endometriosis and 105 controls revealed that shorter AGD was seen in women with endometriosis (36). A prospective cohort study among 168 women over 18 yr old showed that the diagnosis of endometriosis was negatively associated with both the AGD \n AF \n  and the AGD \n AC \n , and the AGD \n AF \n  had a better predictive value than the AGD \n AC \n  for discriminating the presence of endometriosis (38). Another study suggests that AGD biomarkers may be useful in diagnosing endometriosis in women (37). AGD is a bidirectional marker that is shorter in women with exposure to estrogens, for example, endometriosis, and in women with exposure to antiandrogens, such as phthalates (72). On the other hand, AGD is longer in a woman with relatively high levels of androgens, like PCOS. Therefore, AGD is a biomarker that may be useful in identifying the intrauterine environment from the prenatal period to adulthood (73).\nBased on the included evidence, a correlation was observed between AGD and prostate cancer. One study demonstrated that AGD \n AP \n  was higher in individuals with prostate cancer than in cases of prostatic hyperplasia (42). Another cross-sectional study among 120 prostate cancer patients showed that AGD \n AS \n  was positively associated with the highest Gleason score and D'Amico nomogram (39). A previous study in 60 men with prostate cancer and 52 urological controls in 2 hospitals in Barcelona found that longer AGD in men with normal in-utero sexual development was related with a lower risk of prostate cancer (41). The results of 2 studies conducted on adult men showed that disconnection of androgen-mediated pathways in utero was related with the risk of prostate cancer (40). Therefore, having a longer AGD \n AS \n  mention a higher chance of having higher testosterone in adult and, finally, a great risk of suffering a more strict form of prostate cancer (74).\nStudies included in our systematic review showed that AGD measurements were longer in the PCOS group (31, 45). A case-control study of 156 PCOS cases and 180 reproductively healthy women showed that AGD was longer in individuals with PCOS than in the control group (31). A cohort study reported that AGD was more prevalent in newborn daughters of women with PCOS compared with a control group with no PCOS. This study suggested AGD may be a potential marker of the downstream risk of PCOS (44). The evidence confirm earlier study that identified during PCOS, women fetuses may expose higher T levels and suggest that AGD may supply postnatal `read-out' of their prior intrauterine hormonal environment (75).\nA cross-sectional study among healthy young women found that AGD was positively associated with the number of ovarian follicles. This relationship was confirmed in women with PCOS, suggesting that high prenatal testosterone levels and follicular growth in PCOS, may have common fetal origins (67). Indeed, androgen exposure in utero increased follicular recruitment in females (76).\nResults from a descriptive study applying a retrospective list review of 128 patients aged 12-20, showed that androgen exposure in utero increased serum anti-Müllerian hormone, a marker for PCOS (77). Previous studies revealed that intrauterine androgen exposure increases the length of AGD (78, 79). Therefore, exposures to intrauterine and postnatal androgens are associated with PCOS and may also affect the length of AGD. Finally, AGD may have clinical utility when measuring human fetal androgen levels during pregnancy (43).\nAccording to evidences included in the study, significant differences were observed between POP individuals and the controls for AGD \n AC \n  and AGD \n AF \n . In that study, women with POP had longer AGD \n AC \n  (46). A case-control study among 58 patients showed differences between the AGD \n AF \n  (which is shorter in cases of prolapse), AGD \n AC \n  distances, and length of genital hiatus (which is longer in cases) (29). As a result, AGD is presently utilized to quantify the volume of vaginal region hiatus in women with POP since it is less expensive and has a more accessible approach than other methods (80, 81). Hence, AGD may be a more accessible marker for clinical use in calculating the amount of the genital region hiatus in prolapses.\nBased on the study included in the current systematic review, AGD is a novel biomarker that may play a role in determining fetal sex. Few studies exist about fetal AGD and the differences between females and males. A previous cross-sectional study found that measuring AGD in the first trimester of pregnancy is a novel method for determining fetal sex. In that study, AGD was greater in male fetuses than in female fetuses (49). A previous study of 111 cases with a singleton pregnancy between 11 and 13 wk and 6 days found that when ultrasound detected AGD 4.8 mm, the likelihood of the pregnancy being female increased (11). Some evidence reported that AGD was significantly shorter in females than in males (48, 49). Previous study fetal gender was recognize by ultrasound in 310 singleton pregnancies at 11-14 wk of gestation, explain that a cut-off of 4.8 mm was determined to predict male ( \n ≥ \n  4.8 mm) or female ( \n < \n  4.8 mm) fetuses (47). These results are in agreement with those of the Fowler study (48) although the cut-off value in this study (47), was 4.8 mm as opposed to 5 mm. This 4.8 mm cut-off demonstrated a high accuracy of AGD in specify male from female fetuses, resulting in sex determination in 87% of the males and 89% of the females. The results of a previous study in 87 term neonates (38  \n ≥ \n  wk) showed that AGD was twice as common in male infants (average 22 mm) as in female infants (average 11 mm) (82).\nThe results of the current systematic review reported a positive relationship between AGD, hypospadias, and cryptorchidism (50). The findings of the studies included in our study revealed that, when compared to the general population, shorter AGD were statistically significant in fetuses with hypospadias (30). Results of a systematic review and meta-analysis showed that AGD was shorter in boys with hypospadias and cryptorchidism (83). In a large cohort study of boys of pre-pubertal age, AGD was significantly shorter in boys with hypospadias compared to boys with normal genitalia in the healthy control group (52). Another study among boys  \n < \n  2 yr of age diagnosed with cryptorchidism or isolated hypospadias and recruited from clinics at Cambridge University hospital showed that boys with hypospadias or cryptorchidism had significantly lower AGD and penile length than the healthy control group (53). 2 previous studies have shown the relationship between shortened AGD and cryptorchidism. Also, the latter study reported reduced AGD in boys with hypospadias (51, 84). One study among 52 fetuses suggested that, in the prenatal examination and counseling of male external genital abnormalities, AGD may be used as a supplemental objective sonographic measure (30).\nThe present study shows that the majority of the studies demonstrated that AGD was related to semen parameters and fertility in men (60). A study among Spanish children aged between 9 and 11 yr, reported that longer AGD was positively associated with increased testicular volume (28). One study among 473 men showed that AGD was related to semen parameters. In that study, longer AGD was related with great sperm concentration, total sperm count, and total motile sperm count (54).\nA cross-sectional study among infertile men aged between 25 and 38 yr detected a positive relationship between AGD \n AS \n  and total sperm count, sperm concentration, and total sperm motile count (55). Similar results in another study conducted in the US on male students (56) and infertile men referred to andrology clinics (58) have been reported. However, study results among Caucasian young men from southern Spain reported that AGD was not related to the semen parameter (22), which is in opposite to the above results (56, 58, 59). However, the reasons for the controversial findings to date are not yet clear, but they could according to differences in studied age ranges, residual confounding, or even ethnic factors.\nTo our knowledge, the current reports represent the first presentation of the use of assessing AGD in clinical practice to assist patient care. AGD may prognosis normal male genital growth and sperm generation and could therefore provide a new tool to determine reproductive potential in men. Moreover, it may give the professionals additional prognostic information when counseling azoospermic men. Therefore, the results of this systematic review suggested that AGD can help diagnose reproductive function and infertility in men.\nThe findings of the studies in this systematic review demonstrated the relationship between AGD and gynecological conditions in women (64). A prospective cohort of 300 fertile women showed that, when comparing women with below-average AGD to those with above average AGD, the incidence of encounters owing to gynecological issues was much greater (12). Another cohort study among 119 women suggested measures of AGD as risk factors for episiotomy. That study introduced in the episiotomy group AGD \n AC \n  was significantly shorter (61). Another study measured AGD in pregnant women (85). Better AGD measurements in women could thus be added to routine gynecological assessment and admission in the delivery room, providing critical data in women at risk for later gynecological morbidities (12). Another study among 1154 Indian infants reported that, compared with infants with descended testes, AGD was significantly shorter in infants with undescended testes (63). A prospective, observational study among 150 adult men aged 18-55 yr showed that in the premature ejaculation group, AGD \n AP \n  and AGD \n AS \n  were lower than in the control group (66). Therefore, AGD may be clinically useful as a measure of androgen action during pregnancy (65). Studies have shown that fertility and adult sperm production are related to AGD (56, 58). A cohort study suggested that total motile sperm count and sperm concentration after varicocelectomy were associated with longer AGD in men. However, no relationship was observed between improvements in semen volume or sperm motility and AGD length (62).\nAccording to studies included in the present systematic review, poor ovarian response was associated with shorter AGD \n AC \n  and AGD \n AF \n . In that study, AGD \n AC \n  and AGD \n AF \n  were positive and significant in relation to the total number of oocytes (33). A cross-sectional study reported that AGD \n AF \n  was positively associated with ovarian follicle number (67). Some previous studies suggested that AGD length is associated with female reproductive function (57, 67, 71, 86). More studies reported that AGD was longer in women with PCOS (31), and daughters born of these women had longer AGD (78). So, our results may contribute to the claim for using AGD as a marker of the intrauterine hormonal milieu in epidemiological and clinical research.\nThe studies included in our systematic review found links between AGD and maternal and infant characteristics. A cross-sectional study among 133 Korean infants reported that AGD1-3 in the low-birth-weight group were significantly lower than newborns in the control group with normal birth weight (68). A previous study showed that AGD in males was significantly associated with birth weight and gestational age. In that study, AGD in females was associated with birth weight, gestational age, and length (70). Another study demonstrated that AGD was longer in a male newborn with higher cord serum free triiodothyronine, free thyroxine, thyroid-stimulating hormone, and a lower thyroxine/triiodothyronine ratio. In that study, the association between AGD and thyroid-stimulating hormone was not statistically significant in the female neonate (69). A feasible practice is that T3 enhance skeletal muscle growth by adding the frequency and dimension of muscle fibers between the anus and the genital near the central perineal tendon (87). Another possibility is that the placenta influences fetal thyroid hormones and AGD (88).\n\nUsing quantitative indicators such as AGD to determine the prognosis and early diagnosis of diseases in the future may be of great help in therapeutic interventions and the treatment of cases in the early stages of the disease. Along the way, we should not neglect variables such as age, gender, and stressful life events that may confound the relationship pathway between AGD and disorders.\n\nWe declare that this manuscript is original, has not been previously published or submitted elsewhere for publication, and is not under consideration by another journal.\n\nThe authors declare that there is no conflict of interest.","source_license":"CC0","license_restricted":false}