Anthropometric biomarkers for abnormal prenatal reproductive hormone exposure in women with Mayer-Rokitanksy-Küster-Hauser syndrome, polycystic ovary syndrome, and endometriosis


      To study whether markers of prenatal exposure to reproductive hormones are related to Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, polycystic ovary syndrome (PCOS), and endometriosis.


      Case-control study. Comparison of sex hormone-related external genital and digital characteristics in cases and controls.


      University hospital.


      We enrolled 172 women in four groups—women with MKRH, women with PCOS, women with endometriosis, and controls (43 in each group).


      Measurement of two anthropometric biomarkers: anogenital distance and digit ratio.

      Main Outcome Measure(s)

      Anogenital distance was measured from the anus to the anterior clitoral surface (AGDac) and from the anus to the posterior fourchette (AGDaf). For the digit ratio we used a direct, as well as a computer-assisted graphic measurement to measure the length of the second and fourth digit.


      After adjustment for body mass index and age, AGDac was the shortest in endometriosis and the longest in PCOS groups, with a mean difference of 10 mm (95% confidence interval 3.1–16.8). AGDaf but not AGDac measures were found to be significantly larger in the MRKH group, with a mean difference compared with controls of 2.6 mm (95% confidence interval 0.1–5.2). The digit ratio was not significantly different between the groups.


      In this study we did find limited evidence for androgen exposure during the development of MRKH. This is compatible with the hypothesis that the uterovaginal agenesis may have been the result of temporary prenatal exposure to altered gonadal hormone concentrations. For endometriosis and PCOS we confirm previously observed associations for anogenital distance reflecting possible estrogen-based and androgen-based intrauterine origins, respectively.

      Dutch Trial Registration Number

      Biomarcadores antropométricos para la exposición hormonal prenatal anormal en mujeres con síndrome de Mayer-Rokitansky-Küster-Hauser, síndrome de ovarios poliquísticos y endometriosis.


      Estudiar si los marcadores de exposición prenatal a hormonas reproductivas están relacionados con síndrome Mayer-Rokitansky-Küster-Hauser (MRKH), síndrome de ovarios poliquísticos (PCOS), y endometriosis.


      Estudio de casos y controles. Comparación de las características digitales y genitales externos relacionados con hormonas sexuales en casos y controles.


      Hospital universitario.


      Incluimos 172 mujeres en cuatro grupos, con MKRH, con PCOS, con endometriosis y controles (43 por grupo).


      Medición de dos biomarcadores antropométricos: distancia ano-genital y ratio digital.

      Principales medidas de resultado(s)

      Distancia ano-genital fue medida desde el ano hasta la superficie clitorídea anterior (AGDac) y desde el ano a la horquilla vulvar posterior (AGDaf). Para el ratio digital usamos una medición directa, así como una gráfica asistida por ordenador de la longitud del segundo y cuarto dedo.


      La AGDac ajustada por edad e índice de masa corporal fue más corta en el grupo de endometriosis y más larga en el de PCOS, con una diferencia media de 10 mm (Intervalo de confianza al 95% de 3.1 -16.8). La medición de AGDaf pero no la AGDac fue significativamente más larga en el grupo MRKH con una diferencia media comparada con los controles de 2.6 mm (Intervalo de confianza al 95% de 0.1-5.2). El ratio digital no fue significativamente diferente entre grupos.

      Conclusión (es)

      En este estudio encontramos evidencia limitada de la exposición a andrógenos durante el desarrollo de MRKH. Esto es compatible con la hipótesis que la agenesia útero-vaginal puede haber sido el resultado de una exposición prenatal a concentraciones hormonales gonadales alteradas. En caso de la endometriosis y el síndrome de ovario poliquístico confirmamos de forma retrospectiva las asociaciones previamente observadas que la distancia anogenital refleja posibles orígenes intrauterinos secundarios a la exposición de estrógenos y andrógenos.

      Número de registro de ensayos holandés


      Palabras clave

      síndrome Mayer-Rokitansky-Küster-Hauser, distancia ano-genital, relación digital, síndrome de ovarios poliquísticos, endometriosis.

      Key Words

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        • Fontana L.
        • Gentilin B.
        • Fedele L.
        • Gervasini C.
        • Miozzo M.
        Genetics of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome.
        Clin Genet. 2017; 91: 233-246
        • Jain V.G.
        • Goyal V.
        • Chowdhary V.
        • Swarup N.
        • Singh R.J.
        • Singal A.
        • et al.
        Anogenital distance is determined during early gestation in humans.
        Hum Reprod. 2018; 33: 1619-1627
        • Barrett E.S.
        • Hoeger K.M.
        • Sathyanarayana S.
        • Abbott D.H.
        • Redmon J.B.
        • Nguyen R.H.N.
        • et al.
        Anogenital distance in newborn daughters of women with PCOS indicates fetal testosterone exposure.
        J Dev Orig Health Dis. 2018; 9: 307-314
        • Welsh M.
        • Saunders P.T.
        • Fisken M.
        • Scott H.M.
        • Hutchison G.R.
        • Smith L.B.
        • et al.
        Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.
        J Clin Invest. 2008; 118: 1479-1490
        • Dean A.
        • Sharpe R.M.
        Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders.
        J Clin Endocrinol Metab. 2013; 98: 2230-2238
        • Fabregues F.
        • Gonzalez-Foruria I.
        • Penarrubia J.
        • Carmona F.
        Ovarian response is associated with anogenital distance in patients undergoing controlled ovarian stimulation for IVF.
        Hum Reprod. 2018; 33: 1696-1704
        • Eisenberg M.L.
        • Hsieh M.H.
        • Walters R.C.
        • Krasnow R.
        • Lipshultz L.I.
        The relationship between anogenital distance, fatherhood, and fertility in adult men.
        PLoS One. 2011; 6e18973
        • Hsieh M.H.
        • Eisenberg M.L.
        • Hittelman A.B.
        • Wilson J.M.
        • Tasian G.E.
        • Baskin L.S.
        Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance.
        Hum Reprod. 2012; 27: 1577-1580
        • Mendiola J.
        • Stahlhut R.W.
        • Jorgensen N.
        • Liu F.
        • Swan S.H.
        Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York.
        Environ Health Perspect. 2011; 119: 958-963
        • Wu Y.
        • Zhong G.
        • Chen S.
        • Zheng C.
        • Liao D.
        • Xie M.
        PCOS is associated with anogenital distance, a marker of prenatal androgen exposure.
        Hum Reprod. 2017; 32: 937-943
        • Sanchez-Ferrer M.L.
        • Mendiola J.
        • Hernandez-Penalver A.I.
        • Corbalan-Biyang S.
        • Carmona-Barnosi A.
        • Prieto-Sanchez M.T.
        • et al.
        Presence of PCOS is associated with longer anogenital distance in adult Mediterranean women.
        Hum Reprod. 2017; 32: 2315-2323
        • Mendiola J.
        • Sánchez-Ferrer M.L.
        • Jiménez-Velázquez R.
        • Cánovas-López L.
        • Hernández-Peñalver A.I.
        • Corbalán-Biyang S.
        • et al.
        Endometriomas and deep infiltrating endometriosis in adulthood are strongly associated with anogenital distance, a biomarker for prenatal hormonal environment.
        Hum Reprod. 2016; 31: 2377-2383
        • Manning J.T.
        • Scutt D.
        • Wilson J.
        • Lewis-Jones D.I.
        The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen.
        Hum Reprod. 1998; 13: 3000-3004
        • McIntyre M.H.
        The use of digit ratios as markers for perinatal androgen action.
        Reprod Biol Endocrinol. 2006; 4: 10
        • Zheng Z.
        • Cohn M.J.
        Developmental basis of sexually dimorphic digit ratios.
        Proc Natl Acad Sci. 2011; 108: 16289-16294
        • Cattrall F.R.
        • Vollenhoven B.J.
        • Weston G.C.
        Anatomical evidence for in utero androgen exposure in women with PCOS.
        Fertil Steril. 2005; 84: 1689-1692
        • Lujan M.E.
        • Podolski A.J.
        • Chizen D.R.
        • Lehotay D.C.
        • Pierson R.A.
        Digit ratios by computer-assisted analysis confirm lack of anatomical evidence of prenatal androgen exposure in clinical phenotypes of PCOS.
        Reprod Biol Endocrinol. 2010; 8: 156
        • Peters H.E.
        • Johnson B.N.
        • Ehli E.A.
        • Micha D.
        • Verhoeven M.O.
        • Davies G.E.
        • et al.
        Low prevalence of male microchimerism in women with Mayer-Rokitansky-Kuster-Hauser syndrome.
        Hum Reprod. 2019; 34: 1117-1125
        • Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group
        Revised 2003 consensus on diagnostic criteria and long-term health risks related to PCOS.
        Hum Reprod. 2004; 19: 41-47
        • Fink B.
        • Manning J.T.
        Direct versus indirect measurement of digit ratio: new data from Austria and a critical consideration of clarity of report in 2D:4D studies.
        Early Hum Dev. 2018; 127: 28-32
        • Oppelt P.
        • Renner S.P.
        • Kellermann A.
        • Brucker S.
        • Hauser G.A.
        • Ludwig K.S.
        • et al.
        Clinical aspects of Mayer–Rokitansky–Kuester–Hauser syndrome: recommendations for clinical diagnosis and staging.
        Hum Reprod. 2006; 21: 792-797
        • Cook H.
        • Brennan K.
        • Azziz R.
        Reanalyzing the modified Ferriman-Gallwey score: is there a simpler method for assessing the extent of hirsutism?.
        Fertil Steril. 2011; 96: 1266-1270.e1
        • Mendiola J.
        • Sanchez-Ferrer M.L.
        • Jimenez-Velazquez R.
        • Canovas-Lopez L.
        • Hernandez-Penalver A.I.
        • Corbalan-Biyang S.
        • et al.
        Endometriomas and deep infiltrating endometriosis in adulthood are strongly associated with anogenital distance, a biomarker for prenatal hormonal environment.
        Hum Reprod. 2016; 31: 2377-2383
        • Mendiola J.
        • Roca M.
        • Minguez-Alarcon L.
        • Mira-Escolano M.P.
        • Lopez-Espin J.J.
        • Barrett E.S.
        • et al.
        Anogenital distance is related to ovarian follicular number in young Spanish women: a cross-sectional study.
        Environ Health. 2012; 11: 90
        • Sathyanarayana S.
        • Grady R.
        • Redmon J.B.
        • Ivicek K.
        • Barrett E.
        • Janssen S.
        • et al.
        Anogenital distance and penile width measurements in The Infant Development and the Environment Study (TIDES): methods and predictors.
        J Pediatr Urol. 2015; 11: 76.e1-76.e6
        • Philibert P.
        • Biason-Lauber A.
        • Rouzier R.
        • Pienkowski C.
        • Paris F.
        • Konrad D.
        • et al.
        Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities: a French collaborative study.
        J Clin Endocrinol Metab. 2008; 93: 895-900
        • Sultan C.
        • Biason-Lauber A.
        • Philibert P.
        Mayer-Rokitansky-Kuster-Hauser syndrome: recent clinical and genetic findings.
        Gynecol Endocrinol. 2009; 25: 8-11
        • Vannuccini S.
        • Lazzeri L.
        • Orlandini C.
        • Tosti C.
        • Clifton V.L.
        • Petraglia F.
        Potential influence of in utero and early neonatal exposures on the later development of endometriosis.
        Fertil Steril. 2016; 105: 997-1002
        • Simsir C.
        • Kuru Pekcan M.
        • Aksoy R.T.
        • Ecemis T.
        • Coskun B.
        • Hamdemir Kilic S.
        • et al.
        The ratio of anterior anogenital distance to posterior anogenital distance: a novel biomarker for PCOS.
        J Chin Med Assoc. 2019; 10: 782-786
        • Sánchez-Ferrer M.L.
        • Mendiola J.
        • Jiménez-Velázquez R.
        • Cánovas-López L.
        • Corbalán-Biyang S.
        • Hernández-Peñalver A.I.
        • et al.
        Investigation of anogenital distance as a diagnostic tool in endometriosis.
        Reprod Biomed Online. 2017; 34: 375-382
        • Mira-Escolano M.P.
        • Mendiola J.
        • Minguez-Alarcon L.
        • Melgarejo M.
        • Cutillas-Tolin A.
        • Roca M.
        • et al.
        Longer anogenital distance is associated with higher testosterone levels in women: a cross-sectional study.
        BJOG. 2014; 121: 1359-1364
        • Manno 3rd, F.A.
        Measurement of the digit lengths and the anogenital distance in mice.
        Physiol Behav. 2008; 93: 364-368
        • Abbott A.D.
        • Colman R.J.
        • Tiefenthaler R.
        • Dumesic D.A.
        • Abbott D.H.
        Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in PCOS-like monkeys.
        PLoS One. 2012; 7e42372
        • Berenbaum S.A.
        • Bryk K.K.
        • Nowak N.
        • Quigley C.A.
        • Moffat S.
        Fingers as a marker of prenatal androgen exposure.
        Endocrinology. 2009; 150: 5119-5124
        • Barrett E.S.
        • Parlett L.E.
        • Swan S.H.
        Stability of proposed biomarkers of prenatal androgen exposure over the menstrual cycle.
        J Dev Orig Health Dis. 2015; 6: 149-157
        • Thankamony A.
        • Pasterski V.
        • Ong K.K.
        • Acerini C.L.
        • Hughes I.A.
        Anogenital distance as a marker of androgen exposure in humans.
        Andrology. 2016; 4: 616-625
        • Dunselman G.A.
        • Vermeulen N.
        • Becker C.
        • Calhaz-Jorge C.
        • D'Hooghe T.
        • De Bie B.
        • et al.
        ESHRE guideline: management of women with endometriosis.
        Hum Reprod. 2014; 29: 400-412