The association between digit ratio (2D:4D) and the first spermatorrhea among Chinese boys

Early Human Development 118 (2018) 48–52

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The association between digit ratio (2D:4D) and the first spermatorrhea among Chinese boys

T

Ting Lia, Lu Wua, Yujie Wangb,1, Rongying Yaoa, Yanqiu Menga, Yifei Zhanga, Zhiqiang Lia, ⁎ Yanni Zhoua, Hui Hana, Lianguo Fua, a b

Department of Child and Adolescent Health of School of Public Health, Bengbu Medical College, Bengbu, China Bengbu Food and Drug Administration, Bengbu, China

A R T I C L E I N F O

A B S T R A C T

Keywords: 2D:4D First spermatorrhea Chinese boys

Background: The second-to-fourth digit ratio (2D:4D) is a marker of prenatal hormone exposure, which is negatively correlated with prenatal androgen and positively correlated with prenatal estrogen. The study was to analyze the association between 2D:4D and the first spermatorrhea to indirectly show the possible role of prenatal hormone during puberty development among boys. Method: The total of 367 boys aged 8–15 years were enrolled by using the stratified cluster sampling method. The variables of index finger (2D), ring finger (4D), height, weight, waist circumference (WC), skinfold thickness, testosterone and estradiol were measured, and the age at the first spermatorrhea was surveyed. Results: The average age at the first spermatorrhea was 12.15 years. The 2D:4D was not related to first spermatorrhea, circulating testosterone in boys (P > 0.05), however, was positively correlated with circulating estradiol (P < 0.05). The direct association (OR value) between 4D, average of index finger and ring finger (AIR) and first spermatorrhea were 2.79 and 2.29, and the mediating effect (OR value) of which were 1.95 and 2.01 by testosterone, accounting for 41.18% and 46.73% of the total effect, respectively. The 2D, MIDRL, lean body mass (LBM) were indirectly related to first spermatorrhea by testosterone, the mediating effects (OR value) were 2.11, 1.71 and 2.41, respectively. Conclusion: The prenatal androgen exposure may be directly and indirectly related to first spermatorrhea. In addition, the high prenatal estrogen exposure may be indirectly associated with first spermatorrhea by testosterone.

1. Introduction Puberty has been an important stage during growth and development [1], the characteristics of which was the rapid growth of body height and weight [2], active endocrine function, secondary sexual characteristics development gradually tending to mature and occurring the first spermatorrhea [3]. In recent years, there is a secular trend of younger age of first spermatorrhea. The study from Song [4] showed that the average age at first spermatorrhea in 2010 Chinese city boys was 14.03, ahead of 0.54 years compared to 1995. Early puberty development has been related to social adaptation of children, and increased the risk of obesity, diabetes, cardiovascular disease, emotional disorders and depression [5,6]. More and more attention has been paid to the early puberty development. Barker suggested that the adverse environment of the uterus could regulate fetal metabolism and tissue structure [7]. The studies have ⁎

1

shown that high prenatal androgen exposure may be closely related to offspring hormone levels [8]. Recabarren [9] found that prenatal testosterone injection resulted in gonad dysplasia of offspring ram. The perinatal testosterone exposure inhibited estrogen receptor of offspring mice [10]. The second-to-fourth digit ratio (2D:4D) which has been a sensitive marker of prenatal hormone exposure, was negatively correlated with prenatal androgen, and positively correlated with prenatal estrogen [11,12]. It has been suggested that 2D: 4D associated with cardiovascular disease, gastric cancer [13] [14], and Manning and Fink's later researches found that the left and right 2D: 4D were all negatively correlated with the girl's menarche age [15]. The scholars speculated that the prenatal androgen might stimulate the growth of 4D, and the prenatal estrogen might stimulate the growth of 2D. The studies from Manning [16,17] showed that the digit ratio (2D:4D) among males was negatively related to circulating androgen, was positively related to

Corresponding author at: Bengbu Medical College, Department of child and adolescent health of school of public health, Bengbu 233000, China. E-mail address: [email protected] (L. Fu). Bengbu Medical College, No. 2600 east sea avenue, Room 207, Bengbu, Anhui, China.

https://doi.org/10.1016/j.earlhumdev.2018.01.016 Received 5 December 2017; Received in revised form 22 January 2018; Accepted 23 January 2018 0378-3782/ © 2018 Elsevier B.V. All rights reserved.

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circulating estrogen, and has been confirmed based on animal experiments [18]. It was known that the circulating androgen and estrogen were closely related to puberty development. However, the correlation between digit ratio (2D:4D) and first spermatorrhea has been rarely reported. The purpose of this study was to analyze the correlation of digit ratio (2D:4D) and first spermatorrhea to indirectly show the possible role of prenatal hormone exposure in pubertal development among boys. 2. Subjects and methods 2.1. Subjects The study recruited 367 boys aged 8–15 years from 2 Nine-year system schools by stratified cluster sampling method, by school and grade stratification, the class as a whole group, including Grade 3 to 6 in elementary schools and Grade 7 to 9 in middle schools. This project was approved by the Medical Ethics Committee of Bengbu Medical College ([2015] No. 003), and the parents had signed informed consent before physical measurement.

Fig. 1. The proportion of boys with first spermatorrhea.

2.2. Measurement The medical staff who had received standardized training, were recruited as investigators. The students were required to wear only light clothes, barefoot and at ease with empty stomach. Body height was measured to the nearest 0.1 cm using mechanical height meter. Body weight was measured to the nearest 0.1 kg using electronic body weightometer. The waist circumference (WC) were measured to the nearest 0.1 cm using Nylon tape. The triceps skinfold thickness (TST), scapular skinfold thickness (SST) and abdominal skinfold thickness (AST) were measured to 0.1 mm using skinfold thickness gauge. The students were required to hold their left hand palms up and keep their fingers straight. The index finger (2D) and the ring finger (4D) were measured to nearest 0.01 cm from a mid-point of the flexure-crease proximal to the palm to the tip of the finger using vernier callipers. In addition, the age at first spermatorrhea was asked by the medical staff. Fasting venous blood (about 3 ml) were collected for each participant. The circulating testosterone and estradiol were assayed using radioimmunoassay method by DFM-96 10 tube radioimmunogamma counter. The circulating testosterone and estradiol kit were provided by the DIA source company.

Fig. 2. The percentile age at first spermatorrhea.

Lg TTE

a

b

2.3. Calculation of derivative variables

2D, 4D, AIR, MIDRL,

BMI = Weight(kg) / Height(m)2. According to the Body density [19] and Brozek formula by gender - age to calculate the Body fat rate (%BF) [20], Total Body Fat (TBF) (kg) = Weight × %BF, Lean Body Mass (LBM) (kg) = Weight − TBF. Average of index finger and ring finger (AIR) = (2D + 4D)/2. Multiplying index of digit ratio and length (MIDRL) = (2D + 4D)/2 × (2D/4D).

Height, LBM

c' first spermatorrhea

Fig. 3. The mediating effect of testosterone in associations between 2D etc. indexes and first spermatorrhea.

2.4. Statistical analysis 3. Results SPSS17.0 software was used for statistical analysis. The quantitative data was described by Mean ± SD and Percentiles. The boys with the first spermatorrhea and non-spermatorrhea were matched by age with ratio of 1:1. t-test was used to compare the differences of digit ratio (2D:4D), 2D, 4D, AIR, MIDRL between the two groups. The partial correlation analysis was used to analyze the correlation between 2D:4D, 2D, 4D, AIR, MIDRL and testosterone, estradiol adjusting age. In addition, 2D, 4D, AIR, MIDRL, height, LBM and testosterone were divided into two grades by percentile 75 (P75) of each age, respectively. The logistic regression models were used to analyze the mediating effect of testosterone in correlation of each index and first spermatorrhea (Fig. 3). P < 0.05 was statistically significant.

As shown in Fig. 1 and Fig. 2, the rate of boys with first spermatorrhea was 12.5% (46/367), and was 66.7% by 14 years old. Average age at the first spermatorrhea was 12.15 years old, P3 (3rd percentile) age was 10.34 years, P97 (97th percentile) age was 13.97 years. As shown in Table 1, The 2D, 4D, AIR, MIDRL, height, LBM and testosterone among boys with first spermatorrhea were significantly higher than those among boys with non-spermatorrhea, respectively (P < 0.01). However, The TST and SST among boys with first spermatorrhea was significantly lower than those among boys with nonspermatorrhea (P < 0.05). There were no significant difference of 2D:4D, weight, BMI, WC, AST, body fat, estradiol between boys with 49

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Table 1 The comparison of 2D:4D and other variables between boys with first spermatorrhea and non- spermatorrhea. Variables

2D (cm) 4D (cm) 2D:4D AIR(cm) MIDRL (cm) Height (cm) Weight (kg) BMI (kg/m2) WC (cm) TST (mm) SST (mm) AST (mm) TBF (kg) LBM (kg) Lg E2 (mmol/ L) Lg TTE (mmol/ L)

Boys with first spermatorrhea (N = 46)

Boys with nonspermatorrhea (N = 46)

t

7.09 ± 0.44 7.31 ± 0.44 0.97 ± 0.04 7.20 ± 0.42 6.98 ± 0.51 168.00 ± 7.24 55.92 ± 10.68 19.70 ± 2.96 69.28 ± 8.61 13.76 ± 5.55 12.22 ± 5.51 15.94 ± 8.46 11.75 ± 5.77 44.17 ± 6.42 1.30 ± 0.38

6.74 ± 0.47 6.99 ± 0.47 0.97 ± 0.04 6.86 ± 0.45 6.63 ± 0.53 159.87 ± 8.85 52.70 ± 11.77 20.55 ± 4.01 70.24 ± 11.67 16.93 ± 7.22 15.53 ± 8.14 18.03 ± 9.61 13.26 ± 7.21 39.44 ± 6.96 1.23 ± 0.34

3.32 3.12 0.54 3.39 3.03 4.44 1.27 −1.06 −0.42 −2.17 −2.11 −0.19 −1.02 3.12 0.86

0.001 0.003 0.591 0.001 0.003 < 0.001 0.210 0.292 0.678 0.033 0.038 0.848 0.311 0.003 0.395

2.59 ± 0.33

2.26 ± 0.50

3.46

0.001

Table 3 The mediating effect of testosterone in associations between 2D etc. indexes and first spermatorrhea.

P

β(SE)

Wald

P

OR(95% CI)

Model 2D

a b c′ ab a b c′ ab a b c′ ab a b c′ ab a b c′ ab a b c′ ab

0.91(0.26) 0.82(0.40) 0.62(0.40) 0.75 0.93(0.26) 0.72(0.41) 1.02(0.40) 0.67 0.93(0.26) 0.75(0.41) 0.83(0.41) 0.70 0.61(0.26) 0.88(0.40) 0.39(0.41) 0.54 1.02(0.26) 0.62(0.42) 1.25(0.41) 0.63 1.00(0.26) 0.88(0.40) 0.32(0.42) 0.88

12.60 4.17 2.36

< 0.001 0.041 0.124

13.35 3.12 6.47

< 0.001 0.077 0.011

12.96 3.33 4.08

< 0.001 0.068 0.043

5.50 4.88 0.90

0.019 0.027 0.344

15.70 2.18 9.13

< 0.001 0.140 0.003

14.74 4.85 0.56

< 0.001 0.028 0.453

2.49(1.50–4.11) 2.27(1.03–5.00) 1.86(0.84–4.11) 2.11 2.54(1.54–4.19) 2.06(0.92–4.59) 2.79(1.27–6.14) 1.95 2.54(1.53–4.22) 2.11(0.95–4.69) 2.29(1.02–5.12) 2.01 1.85(1.11–3.09) 2.41(1.10–5.26) 1.47(0.66–3.29) 1.71 2.77(1.67–4.59) 1.86(0.82–4.21) 3.48(1.55–7.82) 1.88 2.72(1.63–4.54) 2.42(1.10–5.30) 1.37(0.60–3.12) 2.41

Model AIR

Model MIDRL

Model height

Model LBM

between 2D, MIDRL, LBM and first spermatorrhea, however, the indirect effects of testosterone (OR value) was 2.11, 1.71 and 2.41, respectively. The direct and mediating effects between height and first spermatorrhea were 3.48, 1.88, respectively. 4. Discussion The secular tendency of puberty development has gradually become a focus public health issue. The result of the present study showed that average age at first spermatorrhea was 12.15 years old. Song [4] reported that average age at spermatorrhea among Chinese boys was 14.03 years old based on the 2010 CNSSCH data. The survey covering nine cities in china showed that the average age at first spermatorrhea was 14.05 years old [21]. Compared with the above two surveys, the age at first spermatorrhea among sample boys were earlier for 1.88 years and 1.90 years, respectively. The age at the first spermatorrhea was associated with economic and living standards factors. The first spermatorrhea occurred earlier in the developed areas than developing areas [22,23]. The participants of the present study were recruited from middle-income city in China, their living standards was slightly better than the national average standards, which may be one of the reasons for the first spermatorrhea ahead of time. Because of the secular trend of puberty development [4,24,25], another possible reason may be the present survey being carried out later than 2010 CNSSCH. The results showed a positive correlation between 2D:4D and circulating estradiol, which was consistent with Manning's findings [11,12]. But there were no significant associations between 2D:4D and first spermatorrhea, circulating testosterone, which differed from the findings from Manning et al. [26]. Besides, the previous studies reported that 2D:4D was negatively correlated with circulating testosterone in males [16,17]. Manning found that there were significant ethnic differences in 2D:4D [27], such as British and Spanish with high digit ratio, South Africa (Zulu) and Finnish with low digit ratio [28,29], Black children with low digit ratio [27]. The study from Xi [30] showed that 2D:4D in Chinese Han children was lower than others. The finding of the present study may be related to racial differences. In addition, the studies showed that right hand 2D:4D was more sensitive to prenatal androgen exposure than left hand [31], and reported a greater 2D:4D

Table 2 The correlations between 2D:4D, other variables and circulating testosterone and estradiol.

2D:4D 2D 4D AIR MIDRL Height Weight BMI WC TST SST AST TBF LBM

Effect

Model 4D

first spermatorrhea and non-spermatorrhea, respectively (P > 0.05). As shown in Table 2, The 2D:4D was not related to circulating testosterone (P > 0.05), however, positively correlated with circulating estradiol (P < 0.05). 2D, 4D, AIR, MIDRL were positively correlated with circulating testosterone and estradiol, respectively (P < 0.05). Height, weight, LBM were positively related to circulating testosterone (P < 0.001), however, were not statistically related to circulating estradiol (P > 0.05). The BMI, WC, TST, SST, AST and TBF were not significantly correlated with circulating testosterone and estradiol, respectively (P > 0.05). From the above results, we knew that 2D, 4D, AIR, MIDRL, height and LBM were significantly related to the first spermatorrhea and circulating testosterone. In addition, circulating testosterone was also significantly related to the first spermatorrhea. The multiple logistic regression model was used to analyze the mediating effect of testosterone among associations between 2D, 4D, AIR, MIDRL, height, LBM and first spermatorrhea after adjusting age (Table 3). The direct correlations effect (OR value) between 4D, AIR and first spermatorrhea were 2.79 and 2.29, and the mediating effects (OR value) of which were 1.95 and 2.01 by testosterone, accounted for 41.18% and 46.73% of the total effect, respectively. There were no direct correlation effects

Variables

Model

Lg TTE

Lg E2

r

P

r

P

−0.027 0.247 0.267 0.267 0.217 0.420 0.224 0.080 0.100 −0.001 0.020 0.030 0.084 0.329

0.602 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.129 0.056 0.989 0.699 0.573 0.108 < 0.001

0.104 0.171 0.119 0.151 0.177 0.066 0.006 −0.025 −0.015 0.079 0.046 0.046 0.018 −0.010

< 0.05 < 0.05 < 0.05 < 0.05 < 0.05 0.205 0.907 0.629 0.780 0.134 0.376 0.376 0.729 0.852

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digit indexes and first spermatorrhea. Given the Chinese people's habit of using chopsticks and writing with the right hand, the boys' left hand digit length were only measured in the current study. Although the studies have shown that left hand digit ratio was more closely related to some diseases in the Chinese population [33–35]. However, it has been necessary to measure the right hand digit length for validating the results.

sex difference for the right hand, which may be one of the reasons of no association between 2D:4D and first spermatorrhea, circulating testosterone. However, the sex dimorphism of 2D:4D in newborn infants was significant for the left hand, but not for the right [32]. The studies among Chinese population also showed that left hand 2D:4D was more valuable than right hand 2D:4D. Hong et al. [33] found that the association between left hand 2D:4D and breast cancer was stronger than right hand. Qian [34] found that the left hand 2D:4D was related to psychoanalysis. Furthermore, Sindermann [35] found that 2D:4D in both hands of German was related to neuroticism, however only left hand 2D:4D was associated with neuroticism in Chinese population. We supposed that the 2D:4D of left hand was the more valuable than that of right hand, which may be related to Chinese holding chopsticks and writing by right hand. The digit ratio (2D:4D) has been a sensitive marker of prenatal hormone exposure, which was negatively correlated with prenatal androgen exposure, and positively correlated with prenatal estrogen exposure [11,12]. Previous studies have shown that prenatal androgen levels will increase the rate of abortion, the incidence of recurrent spontaneous abortion was significantly higher than the general population, which also suggests that high prenatal androgen exposure may have adverse effects on the health of their offspring. The high level of prenatal androgens during the first trimester leads to damage to the pancreatic islet beta cells in their offspring, the destruction of islet function, insufficient insulin production, or complete loss of insulinproducing function [36,37]. And any stage of fetal growth and development exposed to high levels of androgen environment, exposed female fetus will appear insulin resistance, polycystic ovary and other clinical features in reproductive age [38]. Estrogen levels during pregnancy can also indicate offspring health. Pathologically high prenatal estrogen exposure can result in fetal growth restriction, increasing the risk of low birth weight in offspring [39]. The prenatal androgen exposure might stimulate the growth of 4D, and the prenatal estrogen exposure might stimulate the growth of 2D. In present study, AIR which was the mean of 2D and 4D, may be related to overall prenatal hormone exposure. MIDRL which was the product of AIR and 2D:4D, may be not only related to the overall prenatal hormone exposure, but also related to the higher prenatal androgen exposure. The results of the current study showed that there were the direct association between 4D, AIR and first spermarche, and also the indirectly association by testosterone, and the mediating effect of testosterone accounted for > 40% of the total effect. The 2D and MIDRL were related first spermatorrhea through the indirect effect of testosterone. The finding of the present suggested that the prenatal androgen exposure might directly and indirectly influence on first spermatorrhea, however, the prenatal estrogen exposure might indirectly affect the first spermatorrhea through testosterone. We hypothesized that the association between prenatal hormone exposure and first spermatorrhea might be caused through affecting circulating hormone level and sensitivity among boys. In addition, the present study showed that the relationship between the first spermatorrhea and TBF in boys was not significant, while closely related to LBM. The previous studies showed that the conclusions of association between obesity and puberty development have been not consistent. Tomova et al. [40] believed that the earlier male puberty development was related to obesity. Wang et al. [41] thought that obesity could delay male puberty development. Karpati et al. [42] thought there was no significant correlation between obesity and male puberty development. However, the present study showed that LBM was associated with the first spermatorrhea through the indirect effect of testosterone. It was known that testosterone promoted decomposition of adipose and synthesis of protein, and increases the proportion of lean body weight [43]. So the circulating hormone level reached a certain degree to increase the muscle mass, which might promote boys' first spermatorrhea. The present study was derived from cross-sectional survey. There were several limitations on explaining the causal relationships between

Conflicts of interest None. Foundation item The study was supported by grants from Natural Science Foundation of China (81502823) and Outstanding Young Talent Key program of College and University in Anhui province (gxyqZD2017063). Acknowledgment The authors would like to thank the students who participated in the current study, and thank Yu LIU and Weige JIANG giving assistance to recruit students. References [1] K.A. Brown, D.R. Patel, D. Darmawan, Participation in sports in relation to adolescent growth and development, Trans. Pediatr. 6 (3) (2017 Jul) 150–159 (PubMed PMID: 28795005. Pubmed Central PMCID: 5532200). [2] B. Holtrup, C.D. Church, R. Berry, L. Colman, E. Jeffery, J. Bober, et al., Puberty is an important developmental period for the establishment of adipose tissue mass and metabolic homeostasis, Adipocytes 08 (2017 Aug) 1–10 (PubMed PMID: 28792785). [3] F.C. Wu, D.C. Brown, G.E. Butler, H.F. Stirling, C.J. Kelnar, Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys, J. Clin. Endocrinol. Metab. 76 (1) (1993 Jan) 26–31 (PubMed PMID: 8421096. Epub 1993/01/01. eng). [4] Y. Song, J. Ma, L.B. Li, B. Dong, Z. Wang, A. Agardh, Secular trends for age at spermarche among Chinese boys from 11 ethnic minorities, 1995-2010: a multiple cross-sectional study, BMJ Open 6 (2) (2016 Feb 24) e010518(PubMed PMID: 26911588. Pubmed Central PMCID: 4769404). [5] L. Juszczak, L. Sadler, Adolescent development: setting the stage for influencing health behaviors, Adolesc. Med. 10 (1) (1999 Feb) 1–11 (v. PubMed PMID: 10086162). [6] F.R. Day, C.E. Elks, A. Murray, K.K. Ong, J.R. Perry, Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study, Sci. Rep. 5 (2015 Jun 18) 11208 (PubMed PMID: 26084728. Pubmed Central PMCID: 4471670). [7] D.J. Barker, C. Osmond, Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales, Lancet 1 (8489) (1986 May 10) 1077–1081 (PubMed PMID: 2871345. Epub 1986/05/10. eng). [8] M.R. Caanen, E.A. Kuijper, P.G. Hompes, M.M. Kushnir, A.L. Rockwood, W.A. Meikle, et al., Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome, Eur. J. Endocrinol. 174 (1) (2016 Jan) 25–32 (PubMed PMID: 26586837). [9] S.E. Recabarren, M. Recabarren, D. Sandoval, A. Carrasco, V. Padmanabhan, R. Rey, et al., Puberty arises with testicular alterations and defective AMH expression in rams prenatally exposed to testosterone, Domest. Anim. Endocrinol. 61 (2017 Oct) 100–107 (PubMed PMID: 28783504). [10] W. Xie, M. Ren, L. Li, Y. Zhu, Z. Chu, Z. Zhu, et al., Perinatal testosterone exposure potentiates vascular dysfunction by ERbeta suppression in endothelial progenitor cells, PLoS One 12 (8) (2017) e0182945(PubMed PMID: 28809938. Pubmed Central PMCID: 5557363). [11] J.T. Manning, M. Callow, P.E. Bundred, Finger and toe ratios in humans and mice: implications for the aetiology of diseases influenced by HOX genes, Med. Hypotheses 60 (3) (2003 Mar) 340–343 (PubMed PMID: 12581609. Epub 2003/02/ 13. eng). [12] J.T. Manning, P.E. Bundred, B.F. Flanagan, The ratio of 2nd to 4th digit length: a proxy for transactivation activity of the androgen receptor gene? Med. Hypotheses 59 (3) (2002 Sep) 334–336 (PubMed PMID: 12208164. Epub 2002/09/05. eng). [13] Y. Sheng, W. Qian, L. Wang, Z. Huo, H. Lu, H. Yu, et al., Decreased digit ratio (2D:4D) and gastric cancer in Chinese men, Early Hum. Dev. 103 (2016 Dec) 109–112 (PubMed PMID: 27565127. Epub 2016/08/28. eng). [14] L. Wang, Z. Huo, H. Lu, C. Bai, K. Li, W. Ma, Digit ratio (2D:4D) and coronary artery disease in north Chinese women, Early Hum. Dev. 116 (2017 Nov 24) 64–67 (PubMed PMID: 29179057. Epub 2017/11/28. eng). [15] J.T. Manning, B. Fink, Is low digit ratio linked with late menarche? Evidence from

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