The role of the endogenous opioid system in polycystic ovary syndrome Aimee D. Eyvazzadeh, M.D., M.P.H., Kathryn P. Pennington, M.D., Rodica Pop-Busui, M.D., Ph.D., MaryFran Sowers, Ph.D., Jon-Kar Zubieta, M.D., Ph.D., Yolanda R. Smith, M.D., M.S.  Fertility and Sterility  Volume 92, Issue 1, Pages 1-12 (July 2009) DOI: 10.1016/j.fertnstert.2009.05.012 Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Centrally mediated and peripherally mediated effects of the opioid system. Fertility and Sterility 2009 92, 1-12DOI: (10.1016/j.fertnstert.2009.05.012) Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Hypothalamic production of β-endorphin. Pre-proopiomelanocortin (POMC) generates several peptides, including γ-MSH, adrenocorticotropic hormone (ACTH), which is cleaved to produce corticotropin-like intermediate lobe peptide (CLIP) and α-melanocyte-stimulating hormone (α-MSH), as well as β-lipotropin (β-LPH), which is cleaved to produce γ-LPH, β-MSH, and β-endorphin. Fertility and Sterility 2009 92, 1-12DOI: (10.1016/j.fertnstert.2009.05.012) Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions

Figure 3 Three-dimensional PET image of μ-opioid receptor distribution in the human brain. The μ-opioid receptor availability was quantified with positron emission tomography and the μ-opioid receptor selective radiotracer [11C] carfentanil. High receptor concentrations are shown in limbic and paralimbic “cognitive–emotional” associative regions, such as the cingulate and frontal cortex, as well as in the insular cortex, basal ganglia, amygdala, thalamus, and hypothalamus. The concentration of receptors is depicted by a pseudocolor scale ranging from blue (lowest), green, yellow, to red (highest) gradations. Fertility and Sterility 2009 92, 1-12DOI: (10.1016/j.fertnstert.2009.05.012) Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions

Figure 4 The opioid system and PCOS. Opioids increase the secretion of LH in response to GnRH. Opioids can also inhibit the clearance of insulin by the liver and stimulate production of insulin by the pancreas, both contributing to the hyperinsulinemia that can be observed in PCOS. Insulin and LH synergize to lead to excess androgen production by the ovaries. Insulin also inhibits production of sex hormone-binding globulin, leading to increased free androgens. Hyperandrogenism predisposes toward central adiposity and insulin resistance, as free fatty acids inhibit the uptake of glucose into muscle cells. Thus, the opioid system, hyperinsulinemia, and hyperandrogenism appear to be all involved in the metabolic and reproductive disturbances seen in PCOS. Fertility and Sterility 2009 92, 1-12DOI: (10.1016/j.fertnstert.2009.05.012) Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions