Table 1.

A brief summary of some of the key studies investigating the role of the RFRP neuropeptide system in the regulation of adaptive reproduction suppression due to different conditions.

Condition	Evidence for RFRP-3 Involvement	Animal Model	Type of Evidence	References
Pre-puberty	RFRP-3 cell number, Rfrp expression, and Rfrp + cFos co-expression decrease during early pubertal transition	Female mice	Correlational	[34,35]
	ICV injection of RFRP-3 delays puberty onset	Female rats	Functional	[36]
	RFRP-3 administration marginally sustains social subordination-induced pubertal delay	Male and female naked mole rats	Functional	[39]
	NPFFR1 (RFRP-3 receptor) knockout has no effect on puberty	Male and female mice	Inconclusive	[41]
	RFRP neuronal activation delays puberty onset	Male mice (no effect in females)	Functional	[31]
Reproductive Senescence	RFRP-3 cell numbers are further downregulated	Female mice	Correlational	[46]
	Loss of the daily variation in the RFRP neuronal activity	Female mice	Correlational	[44]
Seasonal Breeding	Increased RFRP cells in non-breeding season	Female brushtail possums	Correlational	[52]
	Increased RFRP cells in non-breeding season	Male rhesus macaques	Correlational	[51]
	Increased RFRP cells in non-breeding season	Female sheep	Correlational	[53,54]
	Increased RFRP-3 in portal blood in non-breeding season	Female sheep	Correlational	[18]
	Increased RFRP-3 cells in breeding season	Male and female hamsters	Contradictory	[55,56,57,58]
Lactation	Suckling stimulus increases Rfrp expression	Female rats	Correlational	[64]
Psychosocial Stress	Acute and chronic restraint stress increase Rfrp expression, which is prevented by adrenalectomy	Male rats	Correlational	[67]
	Knockdown of hypothalamic RFRP-3 prevents chronic stress-induced embryo resorption	Female rats	Functional	[32]
	Acute restraint stress increased RFRP neuronal activation and concomitantly decreased LH pulsatility	Male mice	Correlational	[69]
	RFRP neuronal silencing or ablation prevents acute restraint stress-induced suppression in LH pulsatility	Female mice (no effect in males)	Functional	[31]
Metabolic Stress	ICV RFRP-3 administration inhibits POMC neurons	Male and female mice	Correlational	[73]
	NPFFR1 (RFRP-3 receptor) knockout prevents decline in LH pulses in response to 12 h food restriction	Male mice	Functional	[41]
	Leptin deficiency does not affect postnatal development of RFRP neuropeptide system	Male and female mice	Inconclusive	[74]
	RFRP-cFos co-expression is increased 8 and 12 days after food deprivation	Female Syrian hamsters	Correlational	[76]
Immune Stress	A septic dose of LPS decreased serum LH and increased both hypothalamic Rfrp and Npffr1 expression	Female rats	Correlational	[80]
	A low dose of LPS decreased serum LH but had no effect on RFRP neuropeptide system	Female rats	Inconclusive	[80]