کورتیزول در دوران جنینی و مواجهه هورمون تستوسترون و واکنش پذیری ترس در مراحل ابتدایی

Abstract Fetal programming is emerging as a major conceptual model for understanding developmental origins of health and disease, including behavioral outcomes. As part of a larger study of prenatal stress and child development, we examined the association between prenatal hormone exposure and fear reactivity, a temperament dimension that is a predictor of long-term behavioral adjustment. Amniotic fluid was collected from a sample of women undergoing clinically indicated amniocentesis for later analysis of cortisol and testosterone. Children with normal birth outcomes were recalled for follow-up assessment at 17 months, at which time we administered an observational assessment of temperament (lab-TAB; n = 108). Information on pregnancy and obstetric outcome was included as covariates. Results indicated that there was a significant association between prenatal testosterone and observed fear reactivity in boys (r(53) = 0.34, p = 0.01); no significant effect was found in girls (r(54) = − 0.07, ns); the effect remained when obstetric, psychosocial, and parental anxiety were controlled for. There was not a significant association between fetal cortisol exposure and fear reactivity. The prediction from in utero testosterone exposure to fear reactivity in boys extends prior research on prenatal testosterone and may represent an association with a general predisposition to greater arousal and reactivity.

Results Sample characteristics are provided in Table 1. Preliminary analyses indicated one expected sex difference: amniotic fluid testosterone was higher in males than females (untransformed means were, for males, n = 53; 0.80 (SD = 0.40); for females, n = 54; 0.24 (SD = 0.19); F(1,105) = 86.55, p < 0.001), although there was overlap in the range of levels between the sexes. There were no difference in amniotic fluid cortisol according to child sex (F(1,106) = 1.06,p = 0.31), neither was the fear reactivity or the joy/please temperament measure associated with child sex (p's > 0.3). For those children on whom we had temperament data, amniotic fluid testosterone and cortisol were positively correlated (r(107) = 0.36, p < 0.01; in females, r(54) = 0.46, p < 0.01, and in males, r(53) = 0.30, p < 0.05). In the range of gestational age in this sample, gestational age was weakly positively associated with amniotic fluid cortisol (r(108) = 0.17, p = 0.08) but not with amniotic fluid testosterone (r(107) = − 0.07). Additional bivariate analyses indicated that gestational age at amniocentesis, time of collection of amniotic fluid, parity, ethnicity, method of delivery, birth weight, and prescription drug use during pregnancy were not significantly related to fear reactivity, neither were these variables was associated with amniotic fluid testosterone. Table 1. Sample descriptive data. Mean (SD), range Maternal age at amniocentesis 36.95 (3.85), 28–45 Time of collection at amniocentesis (24 h) 9:05 am–1:15 pm Child sex, n (%) Female 54 (50.5) Male 53 (49.5) Racial background, n (%) White Caucasian 87 (81.3) Asian/Subcontinent 7 (6.5) Asian Far-Eastern 1 (0.9) Black 10 (9.3) Middle Eastern 2 (1.9) Smoking in pregnancy, n (%) 0 per day 95 (88.8) 1–2/day 10 (9.4) > 2/day 2 (1.8) Child age at follow-up (months) 16.71 (1.48), 14.37–19.97 Gestational age at amniocentesis (weeks) 17.19 (2.86), 15–32 Gestational age at birth (weeks) 39.51 (1.12), 37–42 Birth weight (g) 3499.70 (473.94), 2574–6000 Parity, n (%) Nulliparous 43 (40.2) 1 previous child 41 (38.3) 2 previous children 17 (15.9) 3 previous children 6 (5.6) Alcohol use in pregnancy, n (%) 0 U/week 72 (67.3) 1–2 U/week 30 (28.0) > 2 U/week 5 (4.7) Method of delivery, n (%) Vaginal delivery 58 (54.2) Assisted vaginal 12 (11.2) Elective caesarean 14 (13.1) Emergency caesarean 14 (13.1) Unrecorded 9 (8.4) Note. n's range from 101 to 108. Table options Amniotic fluid cortisol and testosterone and infant fear reactivity Amniotic fluid cortisol was not significantly associated with fear reactivity, either in the whole sample (r(108) = 0.10) or in boys and girls assessed separately. In contrast, amniotic fluid testosterone was significantly associated with fear reactivity in males (r(53) = 0.34, p = 0.01; Fig. 1) but not in females (r(54) = − 0.07, ns; Fig. 2). The association was not significant when boys and girls were combined (r(107) = 0.07, ns). The significant association in males and the greater association in males than females were confirmed in the subsample for whom prenatal testosterone was assayed by HPLC/mass spectrometry: the correlation between amniotic fluid testosterone and fear reactivity in boys was r(24) = 0.62 p = 0.001, and in girls r(16) = 0.26, ns. Correlation between amniotic fluid testosterone (ln) and infant composite ... Fig. 1. Correlation between amniotic fluid testosterone (ln) and infant composite Lab-TAB fear reactivity score at 17 months in males: (r(53) = 0.34, p = 0.01). Figure options Correlation between amniotic fluid testosterone (ln) and infant composite ... Fig. 2. Correlation between amniotic fluid testosterone (ln) and infant composite Lab-TAB fear reactivity score at 17 months in females: (r(54) = − 0.07, ns). Figure options The final regression model (using radioimmunoassay data) is presented in Table 2, which includes a formal test of the child sex × amniotic fluid testosterone interaction. Results show that the link between prenatal testosterone and fearfulness in males remained significant when multiple covariates were included in the model (the significant main effect for sex that indicated higher scores for females was only evident only when the interaction was included in the model). Table 2. Prediction of observed fear reactivity from prenatal testosterone. B (SE) Beta Maternal age 0.05 (0.07) 0.07 Child sex (1 = female, 2 = male) − 3.81 (1.37) − 0.67⁎⁎ Smoking during pregnancy − 0.53 (0.46) − 0.11 Alcohol use during pregnancy 0.16 (0.17) 0.10 Postnatal state anxiety 0.04 (0.03) 0.13 Amniotic fluid testosterone (ln) − 11.43 (6.89) − 1.00 Amniotic fluid testosterone (ln) × child sex 8.19 (3.80) 1.60⁎ Note. n = 103; ⁎p < 0.05; ⁎⁎p < 0.01. Table options Supplementary analyses (not shown) indicated that the findings were unchanged when prenatal cortisol was included. Additional supplementary analyses (not shown) indicated that the prediction of fear reactivity from amniotic fluid testosterone in boys did not differ according to gestational age; neither did eliminating the few cases in which amniotic fluid was obtained after 30 weeks gestation alter the findings. We also considered the possibility that potential outliers may have had undue influence on the findings. Results indicate that this was not the case: dropping the case with the highest prenatal testosterone and fear reactivity values diminished the effect slightly but it remained small/moderate in magnitude; using the arguably more sensitive liquid chromatography/mass spectrometer approach, the effect is diminished slightly but remained moderate/large in magnitude. That is, the effect sizes are comparable with and without this case according to both assays. Dropping the highest scoring female on prenatal testosterone had minimal effect on the association in females. Observed joy/pleasure was not significantly associated with amniotic fluid cortisol or testosterone. Analyses to test the mediational model linking prenatal stress and fear reactivity We previously reported that stressful life events in pregnancy predicted observed fear reactivity (Bergman et al., 2007). The availability of amniotic fluid data in the current study allowed us to test the mediational model that prenatal hormone exposure mediated the link between prenatal stress and observed fear reactivity in the child. There was no evidence for this mediation hypothesis for cortisol given the lack of association between prenatal cortisol exposure and fear reactivity noted above. On the other hand, it was possible that prenatal testosterone mediated the significant association between prenatal life event stress and fear reactivity in boys. Several analyses, however, indicated that this was not the case. For instance, there was not a significant correlation between amniotic fluid testosterone and prenatal stress (r(124) = − 0.05, ns; in males only, r(53) = − 0.03). Neither was prenatal testosterone significantly associated with prenatally assessed maternal state anxiety (r(124) = − 0.01). In addition, for boys, a regression model indicated that both prenatal testosterone and prenatal life event stress were independently associated with fear reactivity (for prenatal testosterone, B = 5.34, SE = 1.83; beta = 0.38, p < 0.01; for prenatal stress, B = 0.66, SE = 0.24; beta = 0.36, p < 0.01); the magnitude of one was little affected by the inclusion of the other in the model. Further supplementary analyses (not shown) indicated that the findings for prenatal testosterone and prenatal stress were unchanged after including prenatal cortisol, prenatal anxiety, postnatal stress, and the interaction between prenatal stress and prenatal testosterone.