Timing of Prenatal Androgen Exposure: Anatomical and Endocrine Effects on Juvenile Male and Female Rhesus Monkeys

Abstract

Prenatal androgen shapes genital differentiation. In humans, genital anatomy determines sex of rearing and subsequent behavioral development. Rhesus monkey genital anatomy and neuroendocrine function are sexually differentiated, and behavioral development occurs in a complex social environment. We investigated prenatal hormonal influences on sexual differentiation by suppressing or increasing androgens in male and female rhesus monkeys. Pregnant multiparous female rhesus monkeys received 35-40 days of testosterone enanthate (TE) treatment, androgen antagonist (flutamide, FL) treatment, or vehicle starting on gestation day (GD) 35 or 40 (early) or GD 110 or 115 (late). Exogenous androgen increased neonatal LH secretion in females when given early and altered female genital differentiation when administered either early or late. TE treatment, early or late in gestation, had no measurable effects on male genital differentiation or neuroendocrine function. Early FL treatment, however, radically altered male genital differentiation, producing in two cases males with a urethral opening separate from the glans. In females, early FL treatment produced detectable alterations in genitalia consistent with a reduced exposure to prenatal androgen, suggesting that female rhesus monkeys are naturally exposed prenatally to meaningful levels of T. Late FL treatment reduced male penis size and increased neonatal T secretion, but had no effect in females. This is the first study to block endogenous prenatal testosterone in rhesus monkeys, thereby altering sexual differentiation. These findings illustrate the complexity of prenatal influences on anatomical and neuroendocrine development. The relationship between the anatomical changes reported here and sex differences in behavior is currently under investigation.

Exposure to naturally circulating androgens during foetal life incurs direct reproductive costs in female spotted hyenas, but is prerequisite for male mating

“…Thus, experimental female infants still lacked an external vagina and displayed a penile clitoris. Although such prenatal treatment did not produce the typical 'feminization' seen in other mammalian species (Neri 1977;Thornton et al 1991;Imperato-McGinley et al 1992;Herman et al 2000), there were significant 'feminizing' effects on external genital morphology provided that 'femininity' is defined in terms of the normal sex differences between male and female spotted hyenas .…”

Cognitive performance in rhesus monkeys varies by sex and prenatal androgen exposure

“…All subjects have been studied throughout infancy, the juvenile period, and puberty, and subtle but significant effects of the treatments have been seen in their morphology and endocrinology (Herman et al, 2000), developmental timing (Herman et al, 2006), vocal communication (Tomaszycki et al, 2001, and social behavior (Herman et al, 2003;Wallen, 2005).…”

“…Treatments produced six experimental and two control groups of subjects as shown in Table 1. Androgen-treated male offspring were not included in this study as a result of subject loss over the 8 years of this extended study.All subjects have been studied throughout infancy, the juvenile period, and puberty, and subtle but significant effects of the treatments have been seen in their morphology and endocrinology (Herman et al, 2000), developmental timing (Herman et al, 2006), vocal communication (Tomaszycki et al, 2001, and social behavior (Herman et al, 2003;Wallen, 2005).For all habituation, training, and testing, subjects were temporarily removed from their social groups using procedures to which all subjects were already fully accustomed. All females tested in the first three months of testing performed trials with their infant offspring present on their ventrum.…”

Sex differences in juvenile rhesus macaque (Macaca mulatta) agonistic screams: Life history differences and effects of prenatal androgens

“…Only when the data were later analyzed were subjects assigned to their sex and treatment groups. With the exception of some early flutamide treated males, prenatal treatments were not discernable from genital anatomy (Herman, Jones, Mann, & Wallen, 2000).…”

“…One possibility is that flutamide indirectly resulted in a heightened exposure to androgens, due to the suppression of negative feedback on the HPG axis (Giusti et al, 1995;Viguier-Martinez, Hochereau de Reviers, Barenton, & Perreau, 1983). Indeed, prenatal treatment with flutamide caused a significant increase in maternal androgen levels (Herman et al, 2000), and if flutamide does not cross into the brain in high enough concentrations this elevated androgen could effectively increase neural androgen exposure even in the face of anti-androgen treatment. Our finding that both late androgen and late flutamide treatment masculinized scream production in females is consistent with an androgen producing this effect.…”