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Polycystic ovarian syndrome (PCOS) is a common reproductive disorder, characterized by irregular menses, hyperandrogenism, and polycystic ovaries. Patients with PCOS also commonly suffer from infertility, obesity, and insulin resistance [1]. The biochemical changes that are commonly associated with PCOS are elevated luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratios, elevated bioavailable and total testosterone levels, and elevated insulin levels associated with insulin resistance. Historically considered to be a hyperandrogenic disease, PCOS has been treated by focusing on weight reduction and alleviating the symptoms associated with excess androgens when pregnancy was not desired or on the induction of ovulation with the antiestrogen clomiphene citrate when pregnancy was desired. However, effective treatment of PCOS symptoms with insulin-sensitizing agents for the treatment of type II diabetes has resulted in an increasing emphasis on insulin resistance in the pathogenesis of this disease [2]. Currently, the biguanide insulin-sensitizing agent metformin is increasingly used both to alleviate the symptoms of PCOS and to treat the associated infertility. The successful use of this therapy has resulted in a closer examination of the mechanism of action by metformin at targets throughout the hypothalamicpituitary-gonadal axis. In the treatment of type II diabetes, metformin decreases hepatic glucose production and increases glucose consumption in peripheral tissues, resulting in decreased blood glucose levels, decreased insulin release, and decreased fat accumulation [3]. At the cellular level, metformin inhibits the mitochondrial electron-transport chain at complex I to decrease ATP production; the resulting increase in AMP levels activates the AMP-dependent kinase (AMPK; official symbol PRKA). PRKA serves as a regulator of cellular and systemic energy homeostasis [3]. PRKA is a heterotrimeric protein consisting of alpha, beta, and gamma subunits. It can be activated by any cellular stress that increases AMP levels by means of the allosteric binding of AMP to sites in the gamma subunit [4] as well as through phosphorylation of Thr172 in the alpha subunit by serine/threonine kinase 11 (STK11/LKB1), calcium/calmodulin-dependent protein kinase kinase (CAMKK), and most recently, the transforming growth factor-b-activated kinase (TAK1) [4–6]. A number of hormones that regulate energy homeostasis (leptin, ghrelin, adiponectin, and resistin) have also been shown to exhibit tissue-specific stimulation or inhibition of PRKA kinase [4, 7]. Treatment with metformin may improve reproductive health through a combination of effects on multiple organ systems, resulting in increased insulin sensitivity and normalization of insulin, insulin-like growth factor 1, and androgen levels. The study by Tosca et al. [8] provides a novel point of integration between mediators of energy homeostasis and regulation of reproductive function at the level of the pituitary gland. Using both pharmacologic and molecular tools, the authors have presented compelling data to link this energysensing pathway to both activin-mediated and gonadotropinreleasing hormone (GNRH)-mediated regulation of gonadotropin expression [8]. Because PCOS is associated with elevated LH levels, the authors first asked if metformin treatment could alter the secretion of LH and FSH. Using primary rat pituitary cultures, these investigators determined that metformin had no effect on its own but was able to inhibit LH release in response to GNRH. FSH release was inhibited by metformin in response to both GNRH and activin. Because metformin activates PRKA, the authors also examined the expression of the various PRKA subunits in rat pituitaries and primary cultures of rat pituitary cells. They assessed expression of the six PRKA subunits by RT-PCR and Western blot analysis. They used immunofluorescent analysis to assess the expression of the alpha 1 subunit of PRKA and colocalize its expression with protein hormone expression from each of the five cell types in the anterior pituitary gland. This subunit was strongly expressed in gonadotrophs and thyrotrophs but less so in somatotrophs and lactotrophs, and it was undetectable in corticotrophs. An earlier study indicated that corticotrophs primarily express the alpha 2 subunit of the kinase. For a negative control, the authors showed that no staining occurred in Prkaa1 knockout mouse pituitaries. The authors next examined the effect of metformin on PRKAA-activating phosphorylation and a downstream target of PRKA, acetyl-coenzyme A carboxylase. They demonstrate doseand time-dependent changes in phosphorylation of these targets. Using compound C, a specific inhibitor of PRKA activity, they verified the role of PRKA in the inhibition of LH and FSH release by metformin. Similarly, a dominant negative PRKA construct also blocked the ability of metformin to inhibit Fshb mRNA transcription in response to activin A. The role of SMAD2, AKT, mitogen-activated protein kinase (MAPK) 14 (p38), and MAPK3/1 (Erk1/2) in activin A and GNRH signaling was examined as well, and a time course of response for those activators was established. Having validated this model, the authors determined that metformin treatment is Correspondence: FAX: 970 297 1275; e-mail: dawn.duval@colostate.edu

PRKA/AMPK: Integrating Energy Status with Fertility in Pituitary Gonadotrophs