Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide that, following its release from axon terminals at the median eminence, stimulates the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland. GnRH can also reach the central nervous system (CNS), as GnRH neurones in the hypothalamus can have axons that extend into other regions of the CNS including the limbic system (Silverman et al., 1987). In addition, GnRH can cross the blood-brain barrier, from the median eminence, into the third ventricle cerebrospinal fluid, albeit with low efficiency (Caraty and Skinner, 2008). GnRH receptor expression has been demonstrated at sites within the CNS (Jennes et al., 1997, Albertson et al., 2009, Schang et al., 2011) and a range of peripheral tissues (Hapgood et al., 2005, Skinner et al., 2009). Thus, when GnRH analogs are used therapeutically in human and veterinary medicine, it is also important to consider the effects at these non-reproductive sites.
As GnRH agonists (GnRHa) result in continued receptor stimulation, as opposed to ultradian cyclic changes, their administration initially results in an increase in LH and FSH secretion (‘flare-effect’), followed by the down-regulation of GnRH receptor expression in the pituitary gland and suppression of reproductive axis function (Garner, 1994, Chen and Eugster, 2015). GnRHa is typically prescribed when the suppression of the reproductive axis is required, such as steroid-sensitive conditions like prostate cancer, uterine fibroids and endometriosis (Garner, 1994). In children and adolescents, GnRHa can be prescribed for treatment of central precocious puberty (CPP) (Chen and Eugster, 2015) and gender dysphoria (GD) (Hembree et al., 2009) to temporarily halt reproductive development.
Carel et al. (2009) emphasized the need for investigation of the potential psychological effects associated with peripubertal GnRHa-treatment in CPP. Similarly, the potential effects of GnRHa-treatment on cognition during this important developmental period are not well characterized. Wojniusz et al. (2016) recently demonstrated that peripubertal GnRHa increases emotional reactivity (i.e. emotional and behavioral responses to a fearful situation) in girls with CPP, whereas resting heart rate decreased and this effect was more pronounced with longer durations of GnRHa-treatment. Studies, using an ovine model, have also demonstrated that peripubertal GnRHa-treated rams display increased risk-taking behavior (Wojniusz et al., 2011), altered emotional reactivity (Evans et al., 2012) and reduced long-term spatial reference memory (Hough et al., 2016). Physiological changes within the limbic system have also been reported in this ovine model, as peripubertal GnRHa-treatment alters amygdala volume (Nuruddin et al., 2013a) and the expression of hippocampal genes that are involved in endocrine signaling and synaptic plasticity (Nuruddin et al., 2013b). With this growing body of evidence that peripubertal GnRHa-treatment may affect development of cognitive function, there is now a requirement to investigate whether these effects are reversible when GnRHa-treatment is discontinued.