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

Abstract

Psychosocial factors, particularly social stress, may compromise reproduction. However, some individuals may be more susceptible to socially induced infertility. The present study used group-housed, adult, ovariectomized rhesus monkeys to test the hypothesis that exposure to psychosocial stress, imposed by social subordination, would enhance estradiol (E2)-negative feedback inhibition of LH. Because polymorphisms in the gene encoding the serotonin transporter (SLC6A4) may contribute to individual differences in response to adverse environments, we determined whether subordinate females with the short-promoter-length allele (s-variant) would show greater suppression of LH. Subordinate females, particularly those with the s-variant SLC6A4 genotype, received significantly higher rates of noncontact aggression from more dominant cage mates and had consistently lower body weights. Serum LH was not influenced by social status in the absence of E2. In contrast, subordinate females were hypersensitive to E2-negative feedback inhibition of LH. Furthermore, serum LH in subordinate females with s-variant SLC6A4 genotype was maximally suppressed by Day 4 of treatment, whereas nadir concentrations were not reached until later in treatment in other females. Finally, pharmacological elevation of serum cortisol potentiated E2-negative feedback inhibition in all females. The current data suggest that infertility induced by psychosocial stressors may be mediated by hypersensitivity to E2-negative feedback and that polymorphisms in the SLC6A4 gene may contribute to differences in reproductive compromise in response to chronic stress.

Social status modifies estradiol activation of sociosexual behavior in female rhesus monkeys

“…The effects of stress on LHPG axis function have been shown at the hypothalamic-pituitary level, whereby chronic stress amplifies LHPG axis sensitivity to E2 negative-feedback, resulting in the suppression of pituitary LH secretion (Michopoulos et al, 2009). The mechanism by which this interaction takes place is still unknown.…”

“…An individual resident male was introduced into each group approximately three years following group formation. Since social group formation, females participated in several protocols in which they received replacement therapy with physiological concentrations of gonadal steroids (Collura et al, 2009; Michopoulos et al, 2009; Michopoulos et al, 2011; Michopoulos and Wilson, 2011). All females had at least three months of E2-washout between the completion of any previous study and the beginning of the current study.…”

“…In response to a stressor, the LHPA axis mounts a systemic response to increase adrenal glucocorticoid secretion, and under conditions of chronic stress, a sustained LHPA axis response can lead to subsequent hypo- or hypercortisolemia and a dysregulation of glucocorticoid negative feedback (Chrousos, 2009; Chrousos and Gold, 1992). Consequently, chronic exposure to stress or stress hormones can potentiate E2 negative-feedback inhibition of LHPG axis function (Ronnekleiv et al, 2010) and result in reduced hypothalamic release of gonadotropin releasing hormone (GnRH) (Oakley et al, 2009), pituitary release of luteinizing hormone (LH) (Berga and Loucks, 2007; Chrousos et al, 1998; Michopoulos et al, 2009), or impair normal ovarian function and subsequent ovulation (Adams et al, 1985). The mechanism for this inhibition, however, is unclear, as administration of exogenous glucocorticoids do not consistently interfere with reproductive physiology in women (Saketos et al, 1993; Samuels et al, 1994) or monkeys (Lovejoy and Wallen, 1990).…”

Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research

“…Gonadal steroid hormones and the HPA axis modulate neurotransmitter and neuropeptide systems (146), influence amygdala activity (147, 148), and influence inflammatory responses (93). HPA activity, via cortisol and CRH, alters sensitivity to gonadal hormones (149). Inflammation alters HPA activity and has adverse effects on cardiovascular function (150).…”

On Deep History and Pyschotropy

“…These are not particularly new ideas. Primatologists have a reasonably detailed understanding of how dominant individuals in primate groups influence the levels of neurotransmitters in subordinate members of the group (see Michopoulos et al 2009) for an interesting example) and hence alter their behavioral tendencies. Nor is it difficult to draw parallels with the impact of public bodily dismemberment of one sort or another for traitors in medieval Europe for example.…”