Alterations in the maternal endocrine, nutritional, and metabolic environment disrupt the developmental trajectory of the fetus, leading to adult diseases. Female offspring of rats, subhuman primates, and sheep treated prenatally with testosterone (T) develop reproductive/metabolic defects during adult life similar to those that occur after intrauterine growth retardation. In the present study we determined whether prenatal T treatment produces growth-retarded offspring. Cottonseed oil or T propionate (100 mg, im) was administered twice weekly to pregnant sheep between 30-90 d gestation (term = 147 d; cottonseed oil, n = 16; prenatal T, n = 32). Newborn weight and body dimensions were measured the day after birth, and postnatal weight gain was monitored for 4 months in all females and in a subset of males. Consistent with its action, prenatal T treatment produced females and males with greater anogenital distances relative to controls. Prenatal T treatment reduced body weights and heights of newborns from both sexes and chest circumference of females. Prenatally T-treated females, but not males, exhibited catch-up growth during 2-4 months of postnatal life. Plasma IGF-binding protein-1 and IGF-binding protein-2, but not IGF-I, levels of prenatally T-treated females were elevated in the first month of life, a period when the prenatally T-treated females were not exhibiting catch-up growth. This is suggestive of reduced IGF availability and potential contribution to growth retardation. These findings support the concept that fetal growth retardation and postnatal catch-up growth, early markers of future adult diseases, can also be programmed by prenatal exposure to excess sex steroids.

Objective Many children with Pervasive Developmental Disorders (PDDs) have serious, functionally-impairing behavioral problems. We tested whether Combined Treatment (COMB) with risperidone and parent training (PT) in behavior management is superior to Medication alone (MED) in improving severe behavioral problems in children with PDDs. Method This 24-week, three-site, randomized, parallel-groups clinical trial enrolled 124 children, aged 4 through 13 years, with PDDs, accompanied by frequent tantrums, self injury, and aggression. Children were randomized 3:2 to COMB (n= 75) or MED (n= 49). Participants received risperidone monotherapy from 0.5 to 3.5 mg/day (with switch to aripiprazole if risperidone was ineffective). Parents in COMB group (N=75; 60.5%) received a mean of 10.9 PT sessions. The primary measure of compliance was the Home Situations Questionnaire (HSQ) score. Results Primary: Intent-to-treat random effects regression showed that COMB was superior to MED on HSQ (p=.006) [effect size at Week 24 (d)= 0.34]. The HSQ score declined from 4.31 (±1.67) to 1.23 (±1.36) for COMB compared with 4.16 (±1.47) to 1.68 (±1.36) for MED. Secondary: Groups did not differ on Clinical Global Impressions–Improvement scores at end-point; compared with MED, COMB showed significant reductions on Aberrant Behavior Checklist Irritability (d=0.48; p= .01), Stereotypic Behavior (d=0.23; p= .04), and Hyperactivity/Noncompliance subscales (d=0.55; p= .04). Final risperidone mean dose for MED was 2.26 mg/day (0.071 mg/kg), compared to 1.98 mg/day for COMB (0.066 mg/kg) (p=.04). Conclusion Medication plus PT resulted in greater reduction of serious maladaptive behavior than medication alone in children with PDDs, with a lower risperidone dose.