Effects of Prenatal Leydig Cell Function on the Ratio of the Second to Fourth Digit Lengths in School-Aged Children

Abstract

Prenatal sex hormones can induce abnormalities in the reproductive system and adversely impact on genital development. We investigated whether sex hormones in cord blood influenced the ratio of the second to fourth digit lengths (2D/4D) in school-aged children. Of the 514 children who participated in a prospective cohort study on birth in Sapporo between 2002 and 2005, the following sex hormone levels were measured in 294 stored cord blood samples (135 boys and 159 girls); testosterone (T), estradiol (E), progesterone, LH, FSH, inhibin B, and insulin-like factor 3 (INSL3). A total of 350 children, who were of school age and could be contacted for this survey, were then requested via mail to send black-and-white photocopies of the palms of both the left and right hands. 2D/4D was calculated in 190 children (88 boys and 102 girls) using photocopies and derived from participants with the characteristics of older mothers, a higher annual household income, higher educational level, and fewer smokers among family members. 2D/4D was significantly lower in males than in females (p<0.01). In the 294 stored cord blood samples, T, T/E, LH, FSH, Inhibin B, and INSL3 levels were significantly higher in samples collected from males than those from females. A multivariate regression model revealed that 2D/4D negatively correlated with INSL3 in males and was significantly higher in males with <0.32 ng/mL of INSL3 (p<0.01). No correlations were observed between other hormones and 2D/4D. In conclusion, 2D/4D in school-aged children, which was significantly lower in males than in females, was affected by prenatal Leydig cell function.

The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS

“…3,11,12 Over the past few years, a body of work has arisen supporting a correlation between higher 2D:4D ratios and higher ratios of androgens to estrogens in the prenatal, and immediately postnatal, period (including in samples obtained from amniocenteses), 4,13,14 and specifically with prenatal Leydig cell function. 15 Beyond this period of susceptibility, while bone growth continues to be regulated by many factors including nutrition and hormonal influences, the 2D:4D ratio has been found to change only minimally, 16 appears stable with age, 17 and does not seem to be influenced with later regulatory periods such as puberty 18,19 or by adult testosterone levels. [20][21][22] Mechanistically, given reported anti-inflammatory and neuroprotective effects in animal models, 23,24 a higher androgen to estrogen ratio might have an organizing role in modulating downstream inflammatory responses.…”

Digit ratio (2D:4D) and prenatal/perinatal sex hormones: A response to Manning and Fink (2017)

“…Manning and Fink correctly pointed out that there are two additional studies relating to cord blood. At the time of publishing my Letter, I was unaware of the two papers by Mitsui et al [9,10]. However, I had previously contacted the lead author of Manning and Fink to ask whether he knew of any relevant studies that I had not included but he did not inform me of these.…”

“…This means my statement "no statistically significant effects have yet been reported in male-only samples" is in fact incorrect. The first paper [9] reported on a sample of school-aged children from Japan (135 males, 159 females), and, whilst controlling for covariates, observed a negative correlation between insulin-like factor 3 (INSL3) and mean 2D:4D in males (β = −0.377, p < 0.05). Closer inspection revealed that digit ratios for the left hand (L2D:4D) were significantly correlated with INSL3 (β = −0.414, p = 0.0125) whereas those for the right hand (R2D:4D) were not.…”

Importance of Serum Testicular Protein Hormone Measurement in the Assessment of Disorders of Sex Development

“…Although serum INSL3 is a proven marker of Leydig cell function before and after birth [Mitsui et al, 2015], it has not been assessed in DSD patients with purportedly isolated Leydig cell impairment.…”