Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-28T05:15:12.429Z Has data issue: false hasContentIssue false

Stability of proposed biomarkers of prenatal androgen exposure over the menstrual cycle

Published online by Cambridge University Press:  13 January 2015

E. S. Barrett*
Affiliation:
Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
L. E. Parlett
Affiliation:
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
S. H. Swan
Affiliation:
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
*
*Address for correspondence: E. S. Barrett, PhD, Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 668, Rochester, NY 14642, USA. (Email [email protected])

Abstract

The prenatal hormonal milieu is widely believed to shape health later in life; however, there are considerable methodological challenges associated with measuring the in utero hormonal environment. Two potential biomarkers of prenatal androgen exposure that can be measured postnatally have been proposed: anogenital distance (AGD) and the ratio of the second to fourth digits of the hand (2D:4D). Although both measures are widely used research tools, their use in adult women may be complicated by the dramatic fluctuations in reproductive hormones across the menstrual cycle. To determine whether there is cyclical variation in these biomarkers, we conducted a longitudinal study of 12 naturally cycling, nulliparous adult women. Trained examiners assessed two measures of AGD [anus to clitoris (AGD-AC) and anus to fourchette (AGD-AF)] and 2D:4D in both hands for the duration of three menstrual cycles, taking measurements during the follicular, peri-ovulatory and luteal phases of each cycle. Despite the small sample size, longer (more masculine) AGD was associated with lower (more masculine) digit ratios, as predicted by the literature. Using multi-level linear regression models, we found that AGD and 2D:4D measurements did not differ significantly across cycle phases. AGD-AF and digit ratios in both hands were associated with age at menarche, suggesting a possible common developmental trajectory. These results demonstrate that AGD and 2D:4D are stable across the menstrual cycle. In addition, research is needed to determine how reliably these measures reflect the in utero hormonal milieu.

Type
Original Article
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Birch, RA, Padmanabhan, V, Foster, DL, Unsworth, WP, Robinson, JE. Prenatal programming of reproductive neuroendocrine function: fetal androgen exposure produces progressive disruption of reproductive cycles in sheep. Endocrinology. 2003; 144, 14261434.Google Scholar
2. Sullivan, SD, Moenter, SM. Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci U S A. 2004; 101, 71297134.Google Scholar
3. Witham, EA, Meadows, JD, Shojaei, S, Kauffman, AS, Mellon, PL. Prenatal exposure to low levels of androgen accelerates female puberty onset and reproductive senescence in mice. Endocrinology. 2012; 153, 45224532.CrossRefGoogle ScholarPubMed
4. Goy, RW, McEwen, BS. Sexual Differentiation of the Brain. 1980. MIT Press: Cambridge, MA.Google Scholar
5. Hines, M. Brain Gender. 2004. Oxford University Press: New York.Google Scholar
6. Constantinescu, M, Hines, M. Relating prenatal testosterone exposure to postnatal behavior in typically developing children: methods and findings. Child Dev Perspect. 2012; 6, 407413.CrossRefGoogle Scholar
7. Giusti, RM, Iwamoto, K, Hatch, EE. Diethylstilbestrol revisited: a review of the long-term health effects. Ann Intern Med. 1995; 122, 778788.Google Scholar
8. Hines, M. Psychosexual development in individuals who have female pseudohermaphroditism. Child Adolesc Psychiatr Clin N Am. 2004; 13, 641656, ix.Google Scholar
9. Mueller, SC, Grissom, EM, Dohanich, GP. Assessing gonadal hormone contributions to affective psychopathologies across humans and animal models. Psychoneuroendocrinology. 2014; 46C, 114128.CrossRefGoogle Scholar
10. Kuijper, EA, Ket, JC, Caanen, MR, Lambalk, CB. Reproductive hormone concentrations in pregnancy and neonates: a systematic review. Reprod Biomed online. 2013; 27, 3363.CrossRefGoogle ScholarPubMed
11. Sathyanarayana, S, Beard, L, Zhou, C, Grady, R. Measurement and correlates of ano-genital distance in healthy, newborn infants. Int J Androl. 2010; 33, 317323.Google Scholar
12. McIntyre, MH. The use of digit ratios as markers for perinatal androgen action. Reprod Biol Endocrinol. 2006; 4, 10.Google Scholar
13. Yeh, S, Tsai, MY, Xu, Q, et al. Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci U S A. 2002; 99, 1349813503.Google Scholar
14. Swan, SH, Main, KM, Liu, F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005; 113, 10561061.Google Scholar
15. Suzuki, Y, Yoshinaga, J, Mizumoto, Y, Serizawa, S, Shiraishi, H. Foetal exposure to phthalate esters and anogenital distance in male newborns. Int J Androl. 2012; 35, 236244.Google Scholar
16. Bustamante-Montes, LP, Hernandez-Valero, MA, Flores-Pimentel, D, et al. Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. J Dev Orig Health Dis. 2013; 4, 4.Google Scholar
17. Welsh, M, Saunders, PT, Fisken, M, 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, 14791490.CrossRefGoogle ScholarPubMed
18. Hsieh, MH, Eisenberg, ML, Hittelman, AB, et al. Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hum Reprod. 2012; 27, 15771580.Google Scholar
19. Mendiola, J, Stahlhut, RW, Jorgensen, N, Liu, F, Swan, SH. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ Health Perspect. 2011; 119, 958963.Google Scholar
20. Eisenberg, ML, Shy, M, Walters, RC, Lipshultz, LI. The relationship between anogenital distance and azoospermia in adult men. Int J Androl. 2012; 35, 726730.Google Scholar
21. Eisenberg, ML, Jensen, TK, Walters, RC, Skakkebaek, NE, Lipshultz, LI. The relationship between anogenital distance and reproductive hormone levels in adult men. J Urol. 2012; 187, 594598.Google Scholar
22. Dean, A, Smith, LB, Macpherson, S, Sharpe, RM. The effect of dihydrotestosterone exposure during or prior to the masculinization programming window on reproductive development in male and female rats. Int J Androl. 2012; 35, 330339.CrossRefGoogle ScholarPubMed
23. Callegari, C, Everett, S, Ross, M, Brasel, JA. Anogenital ratio: measure of fetal virilization in premature and full-term newborn infants. J Pediatr. 1987; 111, 240243.Google Scholar
24. Mendiola, J, Roca, M, Minguez-Alarcon, L, et al. Anogenital distance is related to ovarian follicular number in young Spanish women: a cross-sectional study. Environ Health. 2012; 11, 90.Google Scholar
25. Dean, A, Sharpe, RM. Clinical review: 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, 22302238.Google Scholar
26. Peters, M, Mackenzie, K, Bryden, P. Finger length and distal finger extent patterns in humans. Am J Phys Anthropol. 2002; 117, 209217.Google Scholar
27. Auger, J, Le Denmat, D, Berges, R, et al. Environmental levels of oestrogenic and antiandrogenic compounds feminize digit ratios in male rats and their unexposed male progeny. Proc Biol Sci. 2013; 280, 20131532.Google ScholarPubMed
28. Zheng, Z, Cohn, MJ. Developmental basis of sexually dimorphic digit ratios. Proc Natl Acad Sci U S A. 2011; 108, 1628916294.CrossRefGoogle ScholarPubMed
29. Brown, WM, Finn, CJ, Cooke, BM, Breedlove, SM. Differences in finger length ratios between self-identified ‘butch’ and ‘femme’ lesbians. Arch Sex Behav. 2002; 31, 123127.Google Scholar
30. Buck, JJ, Williams, RM, Hughes, IA, Acerini, CL. In-utero androgen exposure and 2nd to 4th digit length ratio-comparisons between healthy controls and females with classical congenital adrenal hyperplasia. Hum Reprod. 2003; 18, 976979.Google Scholar
31. Rivas, MP, Moreira, LM, Santo, LD, et al. New studies of second and fourth digit ratio as a morphogenetic trait in subjects with congenital adrenal hyperplasia. Am J Hum Biol. 2014; 26, 559561.Google Scholar
32. Ciumas, C, Linden Hirschberg, A, Savic, I. High fetal testosterone and sexually dimorphic cerebral networks in females. Cereb Cortex. 2009; 19, 11671174.Google Scholar
33. Okten, A, Kalyoncu, M, Yaris, N. The ratio of second- and fourth-digit lengths and congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Early Hum Dev. 2002; 70, 4754.CrossRefGoogle ScholarPubMed
34. Berenbaum, SA, Bryk, KK, Nowak, N, Quigley, CA, Moffat, S. Fingers as a marker of prenatal androgen exposure. Endocrinology. 2009; 150, 51195124.Google Scholar
35. Manning, JT, Scutt, D, Wilson, J, Lewis-Jones, DI. 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, 30003004.Google Scholar
36. McIntyre, MH, Chapman, JF, Lipson, SF, Ellison, PT. Index-to-ring finger length ratio (2D:4D) predicts levels of salivary estradiol, but not progesterone, over the menstrual cycle. Am J Hum Biol. 2007; 19, 434436.Google Scholar
37. Auger, J, Eustache, F. Second to fourth digit ratios, male genital development and reproductive health: a clinical study among fertile men and testis cancer patients. Int J Androl. 2011; 34(4 Pt 2), e49e58.Google Scholar
38. Lu, H, Huo, ZH, Liu, YJ, Shi, ZY, Zhao, JL. Correlations between digit ratio and infertility in Chinese men. Early Hum Dev. 2012; 88, 865869.Google Scholar
39. Hong, L, Zhan-Bing, M, Zhi-Yun, S, et al. Digit ratio (2D:4D) in Chinese women with breast cancer. Am J Hum Biol. 2014; 26, 562564.Google Scholar
40. Muller, DC, Baglietto, L, Manning, JT, et al. Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study. Br J Cancer. 2012; 107, 16311636.Google Scholar
41. Dusek, A, Bartos, L. Variation in ano-genital distance in spontaneously cycling female mice. Reprod Domest Anim. 2012; 47, 984987.Google Scholar
42. Morotti, E, Battaglia, B, Persico, N, et al. Clitoral changes, sexuality, and body image during the menstrual cycle: a pilot study. The J Sex Med. 2013; 10, 13201327.CrossRefGoogle ScholarPubMed
43. Mayhew, TM, Gillam, L, McDonald, R, Ebling, FJ. Human 2D (index) and 4D (ring) digit lengths: their variation and relationships during the menstrual cycle. J Anat. 2007; 211, 630638.CrossRefGoogle ScholarPubMed
44. Manno, FA 3rd. Measurement of the digit lengths and the anogenital distance in mice. Physiol Behav. 2008; 93, 364368.CrossRefGoogle ScholarPubMed
45. Hurd, PL, Bailey, AA, Gongal, PA, et al. Intrauterine position effects on anogenital distance and digit ratio in male and female mice. Arch Sex Behav. 2008; 37, 918.Google Scholar
46. Goodman, FR, Scambler, PJ. Human HOX gene mutations. Clin Genet. 2001; 59, 111.Google Scholar
47. Barut, C, Tan, U, Dogan, A. Association of height and weight with second to fourth digit ratio (2D:4D) and sex differences. Percept Mot Skills. 2008; 106, 627632.Google Scholar
48. Wallen, K. Does finger fat produce sex differences in second to fourth digit ratios? Endocrinology. 2009; 150, 48194822.Google Scholar
49. Dieudonne, MN, Leneveu, MC, Giudicelli, Y, Pecquery, R. Evidence for functional estrogen receptors alpha and beta in human adipose cells: regional specificities and regulation by estrogens. Am J Physiol Cell Physiol. 2004; 286, C655C661.Google Scholar
50. Laughlin, GA, Barrett-Connor, E, May, S. Sex-specific association of the androgen to oestrogen ratio with adipocytokine levels in older adults: the Rancho Bernardo Study. Clin Endocrinol (Oxf). 2006; 65, 506513.Google Scholar
51. Scutt, D, Manning, JT. Symmetry and ovulation in women. Hum Reprod. 1996; 11, 24772480.Google Scholar
52. Abbott, AD, Colman, RJ, Tiefenthaler, R, Dumesic, DA, Abbott, DH. Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in polycystic ovary syndrome-like monkeys. PloS One. 2012; 7, e42372.Google Scholar
53. Apter, D, Reinila, M, Vihko, R. Some endocrine characteristics of early menarche, a risk factor for breast cancer, are preserved into adulthood. Int J Cancer. 1989; 44, 783787.Google Scholar
54. Wise, LA, Mikkelsen, EM, Rothman, KJ, et al. A prospective cohort study of menstrual characteristics and time to pregnancy. Am J Epidemiol. 2011; 174, 701709.Google Scholar
55. Guldbrandsen, K, Hakonsen, LB, Ernst, A, et al. Age of menarche and time to pregnancy. Hum Reprod. 2014; 29, 20582064.CrossRefGoogle ScholarPubMed
56. Oberg, AS, Villamor, E. Low digit ratio predicts early age at menarche in Colombian schoolgirls. Paediatr Perinat Epidemiol. 2012; 26, 448455.Google Scholar
57. Medland, SE, Zayats, T, Glaser, B, et al. A variant in LIN28B is associated with 2D:4D finger-length ratio, a putative retrospective biomarker of prenatal testosterone exposure. Am J Hum Genet. 2010; 86, 519525.Google Scholar
58. Manning, JT, Fink, B. Is low digit ratio linked with late menarche? Evidence from the BBC internet study. Am J Hum Biol. 2011; 23, 527533.Google Scholar
59. Matchock, RL. Low digit ratio (2D:4D) is associated with delayed menarche. Am J Hum Biol. 2008; 20, 487489.Google Scholar
60. Helle, S. Does second-to-fourth digit length ratio (2D:4D) predict age at menarche in women? Am J Hum Biol. 2010; 22, 418420.Google Scholar
61. Yermachenko, A, Dvornyk, V. Nongenetic determinants of age at menarche: a systematic review. BioMed Res Int. 2014; 2014, 371583.Google Scholar
62. Sathyanarayana, S, Swan, SH, Farin, FM, et al. A pilot study of the association between genetic polymorphisms involved in estrogen signaling and infant male genital phenotypes. Asian J Androl. 2012; 14, 766772.CrossRefGoogle ScholarPubMed
63. Kang, BH, Kim, SY, Park, MS, Yoon, KL, Shim, KS. Estrogen receptor alpha polymorphism in boys with constitutional delay of growth and puberty. Ann Pediatr Endocrinol Metab. 2013; 18, 7175.Google Scholar
64. Ventura, T, Gomes, MC, Pita, A, Neto, MT, Taylor, A. Digit ratio (2D:4D) in newborns: influences of prenatal testosterone and maternal environment. Early Hum Dev. 2013; 89, 107112.Google Scholar
65. Cattrall, FR, Vollenhoven, BJ, Weston, GC. Anatomical evidence for in utero androgen exposure in women with polycystic ovary syndrome. Fertil Steril. 2005; 84, 16891692.Google Scholar
66. van Anders, SM, Vernon, PA, Wilbur, CJ. Finger-length ratios show evidence of prenatal hormone-transfer between opposite-sex twins. Horm Behav. 2006; 49, 315319.CrossRefGoogle ScholarPubMed
67. Putz, DA, Gaulin, SJC, Sporter, RJ, McBurney, DH. Sex hormones and finger length: what does 2D:4D indicate? EvolHum Behav. 2004; 25, 182199.Google Scholar