CB1 and CB2 receptors present on gonadotropin-releasing neurons in the hypothalamus and disrupt normal pulsate release of gonadotropin, thus decreasing LH release from the pituitary. They can do this directly, but also by inhibiting excitatory GABAergic neurons upstream from GnRH neurons. Feedback modulation of CB1 receptors appears to be instigated by both testosterone and estrogen, with low testosterone possibly decreasing CB1 expression, while higher estrogen levels had a similar effect. CB1 receptors are present in Leydig cells, interstitial testosterone-producing cells, and Sertoli cells, and both CB1 and CB2 receptors are necessary for sperm development. Both receptors are also present in the ovaries and are necessary for development of oocytes also well as the surrounding follicle. Appropriate AEA tone as regulated by expression of FAAH is important for fertilization and transit of the egg, and alterations in CB1 levels in the fallopian tubes have been linked to ectopic pregnancy. Endocannabinoid tone may also play a role in preeclampsia and preterm labor. PCOS is a common infertility syndrome that also involves metabolic changes. Similar to metabolic diseases, polymorphisms in CB1 gene demonstrate evidence of ECS excess, leading to elevated androgens. CB1 and CB2 are also expressed and highly controlled throughout early embryo development and necessary in preparing the embryo for implantation. During neurogenesis, CB1 receptor expression is low during the first 14 weeks of proliferation and migration and then increases around 24 weeks during synaptogenesis, although both CB1 and CB2 have been found to play a role in proliferation. In late-stage development, CB1 has been shown to be involved in the generation of deep layer cortical neurons and influenced connectivity to corticospinal motor neurons. CB1 knockout mice develop autism-like behaviors. Breast milk also has high concentrations of endocannabinoids, which can be altered by diet with subsequent changes in fetal development.