Prenatal Steroid Exposure Research Articles

Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder.

Polycystic ovary syndrome, a fertility disorder affecting approximately 7% of women, is characterized by elevated androgens, disrupted reproductive cycles, and high luteinizing hormone, the latter reflecting increased gonadotropin-releasing hormone (GnRH) release. In animal models, a similar reproductive endocrine phenotype occurs after prenatal androgen exposure. To study the effects of in utero androgen exposure directly on GnRH neurons, the central regulators of fertility, we prenatally androgenized (PNA) transgenic mice that express GFP in these cells. Pregnant females were injected with dihydrotestosterone, and their female offspring were studied as adults. PNA mice had irregular estrous cycles and elevated testosterone and luteinizing hormone levels, suggesting altered hypothalamo-pituitary-gonadal axis function. GnRH neurons receive a major input from gamma-aminobutyric acid (GABA)ergic neurons, and GABA type A receptor activation may play a role in their regulation by steroids. We tested whether PNA alters GABAergic drive to GnRH neurons by comparing frequency and size of GABAergic postsynaptic currents in GnRH neurons from PNA and control females. Both postsynaptic current frequency and size were increased in PNA mice; these effects were reversed by in vivo treatment with the androgen receptor antagonist flutamide, suggesting that androgens mediated these effects. Changes in postsynaptic current frequency and size were action potential-independent, suggesting the possibility that PNA increased connectivity between GABAergic and GnRH neurons. The ability of prenatal steroid exposure to initiate changes that alter functional inputs to GnRH neurons in adults has important implications for understanding the regulation of normal reproduction as well as the hypothalamic abnormalities of fertility disorders.

Second to fourth digit ratio, body mass index, waist-to-hip ratio, and waist-to-chest ratio: their relationships in heterosexual men and women

Background: Prenatal sex steroids have been broadly discussed in terms of their possible effect on brain differentiation, whereas pubertal/adult sex hormones are thought to be the main regulators of sexually dimorphic physical features in males and females. Assessing prenatal steroid exposure has previously been difficult but evidence now suggests that finger length ratio may provide a ‘window’ into prenatal hormone exposure. The length of the second digit (the index finger) relative to the length of the fourth digit (the ring finger) is sexually dimorphic as males have a lower second to fourth digit ratio (2D:4D). The sexual dimorphism is determined as early as the 14th week of fetal life, and remains unchanged at puberty. There is evidence that sex differences in 2D:4D arise from in utero concentrations of sex steroids, with a low 2D:4D (male typical ratio) being positively related to prenatal testosterone, while a high 2D:4D (female typical ratio) is positively associated with prenatal oestrogen.Aim: The studied aimed to determine whether, and to what extent, adult sexually dimorphic physical traits, which are largely determined at puberty, relate to traits that are largely determined in utero. This work examined the relationship between three sexually dimorphic traits—body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-chest ratio (WCR)—and digit ratio.Participants and methods: BMI, WHR and WCR were assessed in 30 heterosexual male and 50 heterosexual female participants by recording their body height, weight, and measuring their waist, hip and chest circumference. Digit lengths of the second and fourth fingers were measured from photocopies of the ventral surface of the hand and by actual finger measurements.Results: Digit ratio was found to be significantly lower in men than in women. Significant negative correlations were found between female’s left and right hand 2D:4D, waist and hip circumference, and WCR. In males, BMI was found to be positively related to digit ratio but remained significant only for left hand 2D:4D. Generally, the relationships were stronger for females than for males. Although not all relationships were found to be significant, they were in accord with our predictions.Conclusion: In addition to an activational effect of sex hormones at puberty, the present data suggest an early organizational effect of sex hormones through the association between indices of female body shape, male BMI, and human finger length patterns.

Sexual Orientation and Psychoanalysis: Sexual Science and Clinical Practice

Sexual Orientation and Psychoanalysis: Sexual Science and Clinical Practice

The incidence of necrotizing enterocolitis after introducing standardized feeding schedules for infants between 1250 and 2500 grams and less than 35 weeks of gestation.

To evaluate the incidence of necrotizing enterocolitis (NEC) after implementing standardized feeding schedules. This was a cohort study, which retrospectively reviewed the incidence of NEC for a 3-year period before implementing feeding schedules and prospectively evaluated the incidence of NEC for a 3-year period after implementing feeding schedules in infants with birth weights between 1250 and 2500 g and <35 weeks' gestation. The feeding schedules were comprised of 3 parts. First, no group was fed within the first 24 hours of life. Feeds were started between 24 to 72 hours of life based on birth weight. Second, the initial feed was full-strength breast milk or half-strength formula. Half-strength formula was changed to full-strength formula on the fourth day for all groups. Third, the daily feeding volume increase was no greater than 20 mL/kg for all groups. In the 477 infants before the feeding schedules, there were 23 (4.8%) cases of definite NEC defined as pneumatosis on abdominal film or NEC confirmed at the time of surgery, and in the 466 infants after the feeding schedules, there were 5 (1.1%) cases of NEC. Before the feeding schedules, those who developed NEC started feeds sooner 1.5 +/- 1.5 (+/- standard deviation [SD]) days versus 3.0 +/-.7 (+/-SD) days, reached full feeds sooner 4.0 +/- 1.8 (+/- SD) days versus 9.8 +/-.5 (+/-SD) days and were more likely to have been started on formula than those who developed NEC after implementing the feeding schedules. The mean time for NEC to occur after the feeding schedules increased from 5.9 +/- 4.1 (+/-SD) days to 19.4 +/- 16.3 (+/- SD) days, although not statistically significant. The number of mothers who received prenatal steroids increased after the feeding schedules. The number of infants with NEC, however, significantly decreased whether their mothers were pretreated with steroids. The risk of NEC was reduced 84% after the introduction of feeding schedules as determined by multiple logistic regression analysis and adjusting for confounding by birth weight, white race, prenatal steroid exposure, day of life of first feed, day of life to reach full feeds, and breast milk. The incidence of NEC was significantly decreased after the implementation of standardized feeding schedules, which was independent of birth weight, prenatal steroid exposure, breast milk, day of life of first feed, and the number of days to reach full feeds.

Neonatal outcome in growth-restricted versus appropriately grown preterm infants.

The objective of this paper is to examine whether growth-restricted preterm infants have a different neonatal outcome than appropriately grown preterm infants. All consecutive, singleton preterm deliveries between 27-35 weeks' gestation were included over a 4-year period. Infants with congenital anomalies and infants of diabetic mothers were excluded. Infants were categorized as small-for-gestational-age (SGA) when birth weight was at or below the 10th percentile, and appropriate-for-gestational-age (AGA) when between the 11th and 90th percentiles. Outcome variables included: neonatal death, respiratory distress syndrome (RDS), sepsis, intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Neonatal morbidity and mortality were examined by univariate and stepwise multivariate logistic regression analyses. Factors controlled for during the analysis included: maternal age; gestational age; mode of delivery; presence of preeclampsia, HELLP syndrome, prolonged premature rupture of membranes (PROM), placental abruption, placenta previa, prenatal steroid exposure, infant gender, and low Apgar score. Seventy-six infants were included in the SGA group and 209 in the AGA group. SGA infants had a higher mortality rate (p = 0.003). They also had more culture-proven sepsis episodes (p = 0.001). No differences were found with respect to the other outcomes. The results were similar when analyzed separately for the group of infants born at or below 32 weeks' gestation. Growth-restricted preterm infants were found to have both higher mortality and infection rates compared with AGA preterm infants. Growth restriction in the preterm neonate was not found to protect against other neonatal outcomes associated with prematurity. When considering elective preterm delivery for this high-risk group of pregnancies, the increased risks in the neonatal period should be taken into account.

Isolated lateral ventricular asymmetry in very low-birth-weight infants: a left-sided lesion?

We prospectively performed serial cranial ultrasonography to determine the incidence of asymmetry of the lateral ventricles in very low-birth-weight (VLBW) infants (500-1500 g) who did not have evidence of other intracranial pathology. Of the 490 babies scanned, 354 were free of other pathology and 41 (11.6%) had isolated ventricular asymmetry. In 10 infants, the asymmetry was seen on the initial scan and in 31, it developed subsequently. In 19 infants, the ventricular asymmetry resolved and in 22 infants it persisted until hospital discharge. In no case was progressive enlargement of the ventricles noted. There was a striking tendency of the larger ventricle to be on the left side (33 L>R, 8 R>L). Compared with a control group of babies matched for birth weight and gestational age who had persistently negative scans, there were no differences in Apgar scores, cesarean section rate, gender distribution, prenatal steroid exposure, or complications of prematurity except for an increased incidence of respiratory distress syndrome requiring surfactant in the group with ventricular asymmetry (63% vs. 29%, p = 0.04). Ventricular asymmetry is common in VLBW infants, but whether it is an incidental finding or represents subtle brain injury is unknown.

Postnatal lung function after prenatal steroid treatment in sheep: effect of gender.

The effect of fetal gender on postnatal lung function and response to prenatal steroid exposure were examined retrospectively in a group of 115 preterm lambs. Fetuses received a single intramuscular injection of 0.5 mg/kg betamethasone alone or in conjunction with L-thyroxine 48 h before delivery at 128-d gestational age. Control animals received an equivalent volume of saline. After delivery, respiratory mechanics and blood gas parameters were recorded for 40 min. Deflation pressure volume curves were constructed in excised lungs. Right upper lobes from a randomly selected subgroup of control animals were examined morphometrically. Control (saline-treated) females were able to be ventilated at lower ventilatory pressures with equivalent tidal volumes and more efficient gas exchange. There were no gender differences in compliance, conductance, or excised lung volumes for saline-treated animals. More efficient gas exchange in females could not be explained by thinner alveolar septa or greater alveolar surface area. After hormone treatment, both males and females exhibited significant improvements in respiratory mechanics, gas exchange, and an increase in alveolar surfactant concentration. However, female exhibited a significantly greater improvement than males for compliance, conductance, excised lung volume, and arterial oxygen partial pressure. These data provide a comprehensive description of gender differences in postnatal lung function and response to steroid treatment in preterm animals, and support clinical findings of sexual dimorphism.

Prenatal androgens time neuroendocrine puberty in the sheep: effect of testosterone dose.

In sheep, prenatal exposure to androgens during a critical period for sexual differentiation of the brain (30-90 days of gestation; 145 days is term) can advance the timing of puberty in females and prevent the preovulatory LH surge. The present study tests the hypothesis that in sheep, the timing of neuroendocrine sexual maturation is related to the amount of prenatal steroid exposure. In addition, we determined if different steroid requirements exist for sexual differentiation of the tonic and surge modes of gonadotropin secretion. Testosterone was administered weekly to three groups of pregnant ewes from days 30-90 of gestation at doses of 200, 80, or 32 mg/week. The resulting androgenized female lambs together with control males and females (n = 5-7/group) were gonadectomized at 3 weeks of age, and gonadal steroids were replaced with a SILASTIC brand estradiol-filled capsule. LH concentrations were measured from biweekly blood samples. Sustained increases in circulating LH were considered to reflect the initiation of neuroendocrine puberty. In male lambs, LH secretion started to increase at 8.3 +/- 0.9 weeks of age (mean +/- SEM). The two highest doses of prenatal androgen advanced the onset of neuroendocrine sexual maturation in females. In the 200 mg androgenized females, the pubertal LH rise (10.2 +/- 2.0 weeks) began about the same time as in males. In the 80 mg treatment group, LH concentrations increased at 16.2 +/- 1.5 weeks, which was later than in males, but well before that in normal females (27.1 +/- 0.7 weeks). For females treated with the lowest dose of androgen (32 mg), the pubertal LH increase (24.6 +/- 1.9 weeks) began about the same time as in normal females. To test the function of the LH surge system, LH was measured every 2 h for 60 h after an acute increase in circulating estradiol was produced by implanting additional estrogen capsules. All control females produced a surge in response to acute estradiol stimulation. LH surges did not occur in males, 200 mg androgenized females, or 80 mg androgenized females. Of six females from the 32 mg treatment group, two produced LH surges in response to the stimulatory feedback action of estradiol. We conclude that the greater the amount of prenatal testosterone, the earlier the initiation of the pubertal LH rise. Moreover, the finding that low doses of testosterone (32 mg/week) are capable of abolishing the LH surge without significantly advancing the timing of puberty supports our hypothesis that different steroid requirements exist for sexual differentiation of tonic and surge modes of LH secretion.

Cord prealbumin values in newborn infants: Effect of prenatal steroids, pulmonary maturity, and size for dates

We assessed cord prealbumin concentrations in 214 appropriate for gestational age newborn infants, 21 small for gestational age infants, and 27 large for gestational age infants to establish normal values and to assess the effect of intrauterine growth, prenatal steroids, and pulmonary maturity on prealbumin levels. Cord prealbumin values were significantly correlated with increasing gestational age (r = 0.33; P less than 0.001) and birth weight (r = 0.40, P less than 0.001) in the AGA neonates. Neonates born before 37 weeks gestation had significantly lower prealbumin levels than those born at term (P less than 0.001). The SGA infants had significantly lower levels than age-matched AGA controls (P less than 0.01), and LGA infants had significantly higher levels than age-matched AGA controls (P less than 0.001). In preterm infants, those with exposure to prenatal steroids (betamethasone or premature rupture of membranes) had significantly higher prealbumin values than control infants of comparable age and weight (P less than 0.001). Infants without respiratory distress syndrome had higher levels than those of comparable age and weight with hyaline membrane disease (P less than 0.05). This study demonstrates that a correlation of gestational age and birth weight exists with cord prealbumin levels, and that the large variability at each gestational age may be accounted for in part by appropriateness of size for dates, prenatal steroid exposure, and pulmonary maturity.

Prenatal effects of sex hormones on human male behavior: medroxyprogesterone acetate (MPA)

(1) Results of clinical research on the effects of prenatal sex hormone exposure in man on sex-dimorphic behavior are compatible with the androgen organization hypothesis. (2) Results of similar studies on the effects of prenatal progestogens in males suggest a demasculinizing effect which, however, could not be separated from the confounding effects of maternal disease states. (3) A new study on the effects of prenatal hormone exposure in man is outlined. (4) Preliminary results of this study on a subsample of 13 boys and their matched controls show only insignificant effects of prenatal MPA-exposure on sex-dimorphic behavior as assessed by interview.