Gene-Environment Interactions, Not Neonatal Growth Hormone Deficiency, Time Puberty in Female Rhesus Monkeys1

Abstract

The factors that influence the timing of puberty and the onset of adult fertility are poorly understood. While focus on the juvenile period has provided insights into how growth-related cues affect pubertal timing, growth velocity during infancy that is sustained into the juvenile period may be important. On the other hand, social factors, specifically exposure to psychosocial stressors, can delay sexual maturation, possibly by altering growth velocities during development. Using female rhesus monkeys, the present study used a prospective analysis to determine how neonatal growth hormone (GH) inhibition with a sandostatin analog or suppression of the pituitary-gonadal axis with a GnRH analog affected growth and sexual maturation. A separate retrospective analysis was done assessing the effects of social dominance status during development on pubertal timing. Because a specific polymorphism in the gene encoding the serotonin (5HT) reuptake transporter increases vulnerability to psychosocial stressors, females were also genotyped and were then classified as socially dominant, having both alleles for the long promoter variant or having at least one allele for the short promoter variant, or as socially subordinate, having the long variant or having the short variant. Neonatal treatments were not balanced for social status or genotype, so analyses were performed separately. Although the neonatal treatments reduced GH secretion postnatally and through the juvenile period, neither growth nor sexual maturation was affected. In contrast, the retrospective analysis showed sexual maturation was delayed significantly in subordinate females carrying at least one allele of the short promoter variant in the gene encoding the 5HT reuptake transporter, and this delay was associated with reduced GH and leptin secretion during the juvenile phase but not with differences in growth velocities from birth. These data suggest that decreased neonatal GH secretion does not adversely affect sexual maturation, but that polymorphisms in the gene encoding the 5HT transporter modulate the adverse consequences of social subordination on the timing of puberty in female rhesus monkeys.

Nonhuman Primate Research Contributions to Understanding Genetic and Environmental Influences on Phenotypic Outcomes across Development

“…First, in pubertal females, Wilson and Kinkead (2008) report a later age at first ovulation and longer pubertal tempo in subordinate females with the short allele. In adult females, Hoffman et al (2007) report fewer ovulatory cycles in females with the short allele.…”

Social Subordination and Polymorphisms in the Gene Encoding the Serotonin Transporter Enhance Estradiol Inhibition of Luteinizing Hormone Secretion in Female Rhesus Monkeys1

“…Although studies of the contribution of SLC6A4 polymorphisms to a reproductive phenotype have produced equivocal results [14,29], it is possible that the SLC6A4 shortpromoter-length genotype may predispose females to stressinduced reproductive compromise. Indeed, we have shown previously that subordinate female rhesus monkeys with the svariant SLC6A4 genotype are more likely to have delayed puberty [9]. Whether polymorphisms in the gene encoding SLC6A4 influence effects of social subordination on the regulation of reproduction in adult females is not known.…”

“…Continuous harassment characteristic of subordination is associated with enlarged adrenal glands in cynomolgus macaque females [2], hypercortisolemia due to diminished glucocorticoid-negative feedback [3][4][5], and increased sensitivity to ACTH [6] in both rhesus and cynomolgus macaque females. Importantly, puberty is delayed in subordinate rhesus females [7][8][9], and the incidence of short luteal phase cycles and periods of anovulation increase in both species of macaques [2,10,11] in subordinate compared with dominant females. Consequently, the overall reproductive fitness of subordinate females is reduced relative to more dominant animals [12].…”

Bone growth in juvenile rhesus monkeys is influenced by 5HTTLPR polymorphisms and interactions between 5HTTLPR polymorphisms and fluoxetine

“…Animals with the LL genotype slowed their linear growth and had more advanced skeletal maturity suggesting faster pubertal progression. Faster pubertal maturation associated with LL genotype was also suggested in a study of female monkeys [44]. The endpoint in that study was age at first ovulation, and earlier puberty was accompanied by higher nocturnal serum GH.…”