Adipose tissue and reproduction in women Henry Bohler, M.D., Sriprakash Mokshagundam, M.D., Stephen J. Winters, M.D.  Fertility and Sterility  Volume 94, Issue 3, Pages 795-825 (August 2010) DOI: 10.1016/j.fertnstert.2009.03.079 Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Hormone regulation of TG metabolism. Fat mass is regulated by the processes of lipogenesis and lipolysis which are controlled primarily by lipoprotein lipase (LPL) and hormone sensitive lipase (HSL), respectively. LPL is released to the capillary endothelium where it hydrolyzes TGs in very low density lipoproteins and chylomicrons. FFA are re-esterified with glycerol-3-phosphate to form TG in the adipocyte. HSL, so named because of its responsiveness to catecholamines and insulin, hydrolyzes adipose tissue TGs into FFA and glycerol. Androgens increase LPL and decrease HSL activity. Estrogens decrease LPL and increase HSL activity. ∗Actions are fat depot-specific. (See text) ANP = atrial natriuretic peptide; TG = triglyceride; LPL = lipoprotein lipase; FFA = free fatty acids; HSL = hormone sensitive lipase. Modified and used with permission from Frayn KN, Karpe F, Fielding BA, Macdonald IA, Coppack SW. Integrative physiology of human adipose tissue. Int J Obes Relat Metab Disord 2003;27:875–88. Fertility and Sterility 2010 94, 795-825DOI: (10.1016/j.fertnstert.2009.03.079) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Adipokines that promote or inhibit glucose uptake. Adipocytes secrete proteins with variable effects on glucose homeostasis. Adipocyte-derived proteins with antihyperglycemic action include leptin, adiponectin, omentin and visfatin. Other factors tend to raise blood glucose, including resistin, TNF-α and RBP4. TNF-α and human resistin are probably secreted by cells other than adipocytes within the fat pad. TNF-α = tumor necrosis factor; IL, interleukin; RBP = retinol binding protein. Modified and used with permission from Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006;444:847–53. Fertility and Sterility 2010 94, 795-825DOI: (10.1016/j.fertnstert.2009.03.079) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 3 Leptin effects on the reproductive axis. When fat stores are adequate, leptin stimulates GnRH release. This action is most likely indirect through other neurohormones, including kisspeptin, neuropeptide-y, and pro-opiomelanocortin. Leptin and its receptor are also found in the pituitary. Whether estrogen has a physiologic role in releasing leptin from fat stores is unclear. Receptors for leptin have been localized in the ovary and endometrium implying additional direct actions on these tissues. GnRH = gonadotropin releasing hormone; LH = luteinizing hormone; FSH = follicle stimulation hormone; KISS = kisspeptin; POMC = pro-opiomelanocortin; NPY = neuropeptide-Y. Fertility and Sterility 2010 94, 795-825DOI: (10.1016/j.fertnstert.2009.03.079) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 4 Computerized tomography showing cross-sectional abdominal areas at the umbilicus level in two women demonstrating variation in fat distribution despite similar BMIs. A. 49-yr-old female with a BMI of 23; B. 40-yr-old female with a BMI of 24. VAT = visceral adipose tissue; SAT = subcutaneous adipose tissue. From Wajchenberg B. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:697–738. Fertility and Sterility 2010 94, 795-825DOI: (10.1016/j.fertnstert.2009.03.079) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 5 Cortisol metabolism may be tissue-specific in obesity and polycystic ovary syndrome. In these conditions, hepatic 11β-HSD1 activity is reduced in the liver resulting in a decrease in the regeneration of cortisol; however, adipocyte 11β-HSD1 activity is increased (Fig. 6). 5α-R activity is increased in the liver and skin resulting in an increase in 5α-reduced cortisol metabolites and dihydrotestosterone production from testosterone (not shown). Inreased production of cortisol in visceral fat because of increased 11βHSD activity may contribute to insulin reistance and low SHBG. HSD = hydroxysteroid dehydrogenase. Fertility and Sterility 2010 94, 795-825DOI: (10.1016/j.fertnstert.2009.03.079) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 6 Possible role of VAT and SAT in the pathophysiology of polycystic ovary syndrome. An increase in central obesity and VAT may result from elevated serum androgens and local cortisol production, the latter caused by increased 11ß-HSD1 activity in adipocytes. 5α-R activity is also dysregulated and contributes to increased cortisol clearance. The negative feedback of cortisol may be decreased resulting in a compensatory increase in ACTH in an effort to maintain normal cortisol levels, while increasing adrenal androgen production. FFA in the liver and skeletal muscle contribute to insulin resistance and hyperinsulinemia, as does altered adipokine levels. Insulin acts as a co-gonadotropin, amplifying the effect of LH to induce androgen production from the ovary leading to anovulation. Leptin may play a role in the increase in LH secretion although other factors and obesity dampen this effect. VAT = visceral adipose tissue; SAT = subcutaneous adipose tissue; FFA = free fatty acid; HSD = hydroxysteroid dehydrogenase; E = cortisone; F = cortisol; R = reductase; SHBG = sex hormone binding globulin; ACTH = adrenocorticotropic hormone; LH = luteinizing hormone; GnRH = gonadotropin releasing hormone;TNF = tumor necrosis factor; IL = interleukin; PAI = plasminogen activator inhibitor. Fertility and Sterility 2010 94, 795-825DOI: (10.1016/j.fertnstert.2009.03.079) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions