Metabolic Regulation of Fertility: An Emerging Role for AMP-activated Protein Kinase in the Control of Gonadotropin-releasing Hormone Neuron Function

Roland, Alison Victoria, Department of Pharmacology, University of Virginia
Keller, Susanna, Department of Medicine, Endocrinology and Metabolism, University of Virginia
Shupnik, Margaret, Department of Medicine, Endocrinology and Metabolism, University of Virginia

Gonadotropin-releasing hormone (GnRH) neurons integrate steroidal and metabolic cues to regulate fertility centrally. Abnormalities in GnRH release play a role in polycystic ovary syndrome (PCOS), the leading cause of infertility in women. PCOS is characterized by elevated androgen and luteinizing hormone (LH) levels, oligoor anovulation, and/or ovarian cysts. Increased central stimulation of the reproductive axis due to increased frequency and amplitude of GnRH secretion is thought to play an important pathophysiological role in this disorder. Metabolic abnormalities, including insulin resistance, are also extremely common in PCOS. Because glucose homeostasis is perturbed in PCOS, we examined metabolic characteristics in female mice prenatally androgenized (PNA) with dihydrotestosterone. PNA mice exhibit increased central drive to the reproductive axis and irregular reproductive cycles, similar to PCOS. PNA mice had impaired glucose tolerance, but did not exhibit peripheral insulin resistance and hyperinsulinemia, suggesting that excess prenatal androgen receptor activation may be insufficient to cause the full spectrum of metabolic abnormalities seen in PCOS. Evidence indicates that glucose is critical in regulating reproduction centrally, but the cellular mechanisms are poorly understood. We examined if changes in extracellular glucose could alter the activity of GnRH neurons, and if glucosensing was affected by dihydrotestosterone and/or estradiol. GnRH neurons were sensitive to physiological reductions in extracellular glucose; androgens inhibited glucosensing. Mechanistically, AMPK proved to be important mediator of glucosensing, and AMPK activation inhibited GnRH neurons. ii The inhibitory effect of AMPK activation led us to hypothesize that metformin, an AMPK activator that restores reproductive function in PCOS, might blunt excessive GnRH release through direct central actions. We tested this hypothesis in PNA mice. Metformin restored estrous cyclicity to PNA mice and reduced LH and GnRH neuronal activity. GnRH neurons from metformin-treated mice were stimulated by an AMPK antagonist and relatively insensitive to low glucose, suggesting AMPK was activated centrally by metformin. Together, these studies have provided novel insight into the regulation of GnRH neuronal activity by metabolic and steroidal cues, shown how interactions between these cues might contribute to the PCOS phenotype, and elucidated the mechanisms by which metformin improves reproductive function in women with PCOS.

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PHD (Doctor of Philosophy)
metabolic regulation, fertility, GnRH
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