Table 1.

Summary of studies on the role of upstream and downstream components of the PI3K signaling pathway in HPG axis function.

Molecule	Description	Experimental approach	Results	References
ERα	Estrogen hormone receptor	Global KO	Infertility: elevated LH and E2, ovarian hemorrhage	Couse and Korach (1999), Mayer et al. (2010)
	Binds the PI3K regulatory subunit p85α	Kisspeptin-cell specific deletion	Advancement of puberty onset in female mice accompanied by elevated LH, abnormal ovulatory activity in the adult
IGF-1R	Receptor tyrosine kinase	GnRH neuron-specific deletion	Delayed pubertal development (VO) with normal fertility	Divall et al. (2010)
		i.c.v. infusion of the IGF-1-R antagonist JB-1 in E2 + P-primed ovx rats	Attenuation of lordosis behavior	Quesada and Etgen (2002), Etgen and Acosta-Martinez (2003)
			Blockade of hormone-induced LH surge
IR	Receptor tyrosine kinase	Neuron-specific deletion	Impaired spermatogenesis and ovarian follicle maturation, reduced LH levels	Bruning et al. (2000)
LepR	Class I type cytokine receptor	Global KO	Infertility: delayed/abnormal puberty, low gonadotropins	Leibel et al. (2001), Ring and Zeltser (2010)
		Hypothalamic deletion	Infertility: absence of offspring
IRS-2	Adaptor protein	Global KO	Infertility: anovulatory ovaries with reduced number of follicles, reduced pituitary size, low levels of LH, prolactin, and sex steroids	Burks et al. (2000)
IRS-4	Adaptor protein	Global KO	Decreased number of litters	Fantin et al. (2000)
mTOR	Ser/thr kinase	i.c.v. infusion of the mTOR signaling inhibitor, rapamycin in prepubertal female rats	Delayed VO, decreased LH and E2 levels, ovarian and uterine atrophy	Roa et al. (2009b)
p85α	Class IA PI3K regulatory subunit	GnRH neuron-specific deletion	Decreased serum LH, T and sperm counts.	Acosta-Martinez et al. (2009)