Identification of Hypothalamic Sites that Control Puberty Onset and Sexual Maturation.

Abstract

This dissertation seeks to identify hypothalamic neuronal populations that regulate puberty onset and sexual maturation as part of the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis integrates a variety of signals, including the adipose-derived hormone leptin and the gonadal steroid hormone estradiol. These hormones function either as permissive signals (leptin) or stimulatory signals (estradiol) to affect commencement and progression of puberty, as well as to maintain adult fertility.

First, we investigated the role of direct leptin action through its receptor LepRb in neurons expressing Nos1. Based on previous data, we hypothesized that the reproductive axis would be significantly affected by genetic ablation of LepRb from Nos1-expressing neurons. The deletion resulted in only slightly delayed sexual maturation in females and unaffected overall fertility. Additionally, these mice are profoundly obese and have disrupted energy balance. Thus, leptin action on Nos1-expressing neurons is not critical for fertility, but is necessary for proper energy balance.

Second, we determined whether direct estrogen action through estrogen receptor alpha (ER-alpha) on arcuate nucleus (ARC) kisspeptin neurons is required for estrogen negative feedback. In females, loss of ER-alpha from either ARC kisspeptin or all kisspeptin neurons resulted in a similar phenotype of precocious puberty and incomplete sexual maturation. While both conditional knockouts exhibit reduced negative feedback, there is remaining estrogen negative feedback, likely at the level of the pituitary gland. Thus, while ARC kisspeptin neurons may not be the only neuronal population involved in estrogen negative feedback in females, ER-alpha in these neurons is critical for restraint of puberty onset and normal reproductive function.

Finally, we assessed whether ARC kisspeptin neurons were critical for estrogen negative feedback in the male mouse. Surprisingly, we found that negative feedback was more severely affected in male mice lacking ER-alpha in all kisspeptin neurons than in mice lacking ER-alpha specifically in ARC kisspeptin neurons.

Here, we have identified sites of leptin and estrogen action within the hypothalamus whose function is to modulate the reproductive axis. Future work should focus on the mechanism, potentially through modulation of GnRH neuron function, whereby loss of LepRb or ER-alpha affects puberty onset, sexual maturation and fertility.