Roles of Leptin in Reproduction, Pregnancy and Polycystic Ovary Syndrome: Consensus Knowledge and Recent Developments

Schwartz, 2000, Neuroendocrine regulation of reproductive cyclicity, 135 Tena-Sempere, 2003, Gonadotropins and gonadotropin receptors, 225 Pinilla, 2012, Kisspeptins and reproduction: Physiological roles and regulatory mechanisms, Physiol Rev, 92, 1235, 10.1152/physrev.00037.2010 Fink, 2000, Neuroendocrine regulation of pituitary function: General principles, 107 Fernandez-Fernandez, 2006, Novel signals for the integration of energy balance and reproduction, Mol Cell Endocrinol, 254–255, 127, 10.1016/j.mce.2006.04.026 Navarro, 2007, Neuroendocrine factors in the initiation of puberty: The emergent role of kisspeptin, Rev Endocr Metab Disord, 8, 11, 10.1007/s11154-007-9028-2 Casanueva, 1999, Neuroendocrine regulation and actions of leptin, Front Neuroendocrinol, 20, 317, 10.1006/frne.1999.0187 Tena-Sempere, 2008, Ghrelin as a pleiotropic modulator of gonadal function and reproduction, Nat Clin Pract Endocrinol Metab, 4, 666, 10.1038/ncpendmet1003 Elias, 2012, Leptin signaling and circuits in puberty and fertility, Cell Mol Life Sci, 70, 841, 10.1007/s00018-012-1095-1 Castellano, 2010, Kisspeptins: Bridging energy homeostasis and reproduction, Brain Res, 1364, 129, 10.1016/j.brainres.2010.08.057 Acosta-Martinez, 2012, PI3K: An attractive candidate for the central integration of metabolism and reproduction, Front Endocrinol (Lausanne), 2, 110, 10.3389/fendo.2011.00110 Elias, 2012, Leptin action in pubertal development: Recent advances and unanswered questions, Trends Endocrinol Metab, 23, 9, 10.1016/j.tem.2011.09.002 Hill, 2008, Hypothalamic pathways linking energy balance and reproduction, Am J Physiol Endocrinol Metab, 294, E827, 10.1152/ajpendo.00670.2007 Xu, 2012, Cross-talk between metabolism and reproduction: The role of POMC and SF1 neurons, Front Endocrinol (Lausanne), 2, 98, 10.3389/fendo.2011.00098 Tena-Sempere, 2007, Roles of ghrelin and leptin in the control of reproductive function, Neuroendocrinology, 86, 229, 10.1159/000108410 Chou, 2014, 20 YEARS OF LEPTIN: Role of leptin in human reproductive disorders, J Endocrinol, 223, T49, 10.1530/JOE-14-0245 Halaas, 1995, Weight-reducing effects of the plasma protein encoded by the obese gene, Science, 269, 543, 10.1126/science.7624777 Ahima, 2000, Leptin regulation of neuroendocrine systems, Front Neuroendocrinol, 21, 263, 10.1006/frne.2000.0197 Mantzoros, 2011, Leptin in human physiology and pathophysiology, Am J Physiol Endocrinol Metab, 301, E567, 10.1152/ajpendo.00315.2011 Dardeno, 2010, Leptin in human physiology and therapeutics, Front Neuroendocrinol, 31, 377, 10.1016/j.yfrne.2010.06.002 Ahima, 1996, Role of leptin in the neuroendocrine response to fasting, Nature, 382, 250, 10.1038/382250a0 Zhou, 2014, Nutrient restriction induces failure of reproductive function and molecular changes in hypothalamus-pituitary-gonadal axis in postpubertal gilts, Mol Biol Rep, 41, 4733, 10.1007/s11033-014-3344-x True, 2011, Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance, J Neuroendocrinol, 23, 1099, 10.1111/j.1365-2826.2011.02144.x Cheung, 1997, Leptin is a metabolic gate for the onset of puberty in the female rat, Endocrinology, 138, 855, 10.1210/endo.138.2.5054 Farooqi, 2014, 20 YEARS OF LEPTIN: Human disorders of leptin action, J Endocrinol, 223, T63, 10.1530/JOE-14-0480 Roa, 2010, Metabolic control of puberty onset: New players, new mechanisms, Mol Cell Endocrinol, 324, 87, 10.1016/j.mce.2009.12.018 Ahima, 1997, Leptin accelerates the onset of puberty in normal female mice, J Clin Invest, 99, 391, 10.1172/JCI119172 Chehab, 1997, Early onset of reproductive function in normal female mice treated with leptin, Science, 275, 88, 10.1126/science.275.5296.88 Farooqi, 1999, Effects of recombinant leptin therapy in a child with congenital leptin deficiency, N Engl J Med, 341, 879, 10.1056/NEJM199909163411204 Barash, 1996, Leptin is a metabolic signal to the reproductive system, Endocrinology, 137, 3144, 10.1210/endo.137.7.8770941 Castellano, 2009, KiSS-1/kisspeptins and the metabolic control of reproduction: Physiologic roles and putative physiopathological implications, Peptides, 30, 139, 10.1016/j.peptides.2008.06.007 Garcia-Mayor, 1997, Serum leptin levels in normal children: Relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage, J Clin Endocrinol Metab, 82, 2849 Plant, 1997, Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta), Endocrinology, 138, 4505, 10.1210/endo.138.10.5574 Mantzoros, 1997, A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty, J Clin Endocrinol Metab, 82, 1066 Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea, N Engl J Med, 351, 987, 10.1056/NEJMoa040388 Chou, 2011, Leptin is an effective treatment for hypothalamic amenorrhea, Proc Natl Acad Sci U S A, 108, 6585, 10.1073/pnas.1015674108 Chan, 2003, The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men, J Clin Invest, 111, 1409, 10.1172/JCI200317490 Yu, 1997, Role of leptin in hypothalamic-pituitary function, Proc Natl Acad Sci U S A, 94, 1023, 10.1073/pnas.94.3.1023 Watanobe, 2002, Leptin directly acts within the hypothalamus to stimulate gonadotropin-releasing hormone secretion in vivo in rats, J Physiol, 545, 255, 10.1113/jphysiol.2002.023895 Herbison, 2001, New evidence for estrogen receptors in gonadotropin-releasing hormone neurons, Front Neuroendocrinol, 22, 292, 10.1006/frne.2001.0219 Garcia-Galiano, 2012, Sex steroids and the control of the Kiss1 system: Developmental roles and major regulatory actions, J Neuroendocrinol, 24, 22, 10.1111/j.1365-2826.2011.02230.x Quennell, 2009, Leptin indirectly regulates gonadotropin-releasing hormone neuronal function, Endocrinology, 150, 2805, 10.1210/en.2008-1693 Finn, 1998, The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey, Endocrinology, 139, 4652, 10.1210/endo.139.11.6297 Hakansson, 1998, Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus, J Neurosci, 18, 559, 10.1523/JNEUROSCI.18-01-00559.1998 Magni, 1999, Expression of a leptin receptor in immortalized gonadotropin-releasing hormone-secreting neurons, Endocrinology, 140, 1581, 10.1210/endo.140.4.6622 Pralong, 2010, Insulin and NPY pathways and the control of GnRH function and puberty onset, Mol Cell Endocrinol, 324, 82, 10.1016/j.mce.2010.01.037 Navarro, 2012, Neuroendocrine control by kisspeptins: Role in metabolic regulation of fertility, Nat Rev Endocrinol, 8, 40, 10.1038/nrendo.2011.147 Williams, 2012, From neuroanatomy to behavior: Central integration of peripheral signals regulating feeding behavior, Nat Neurosci, 15, 1350, 10.1038/nn.3217 Roa, 2012, Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice, Endocrinology, 153, 5587, 10.1210/en.2012-1470 Huszar, 1997, Targeted disruption of the melanocortin-4 receptor results in obesity in mice, Cell, 88, 131, 10.1016/S0092-8674(00)81865-6 Butler, 2002, The melanocortin receptors: Lessons from knockout models, Neuropeptides, 36, 77, 10.1054/npep.2002.0890 Balthasar, 2004, Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis, Neuron, 42, 983, 10.1016/j.neuron.2004.06.004 Hill, 2010, Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility, Cell Metab, 11, 286, 10.1016/j.cmet.2010.03.002 Wu, 2012, Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility, Proc Natl Acad Sci, 3155, 10.1073/pnas.1120501109 Israel, 2012, Effects of leptin and melanocortin signaling interactions on pubertal development and reproduction, Endocrinology, 2408–2419 Sheffer-Babila, 2013, Agouti-related peptide plays a critical role in leptin's effects on female puberty and reproduction, E1512 Schwartz, 2005, Diabetes, obesity, and the brain, Science, 375, 10.1126/science.1104344 Woods, 2008, Central control of body weight and appetite, J Clin Endocrinol Metab, s37, 10.1210/jc.2008-1630 Erickson, 1996, Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y, Science, 1704, 10.1126/science.274.5293.1704 van de Wall, 2008, Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion, Endocrinology, 1773, 10.1210/en.2007-1132 Canteras, 1992, Projections of the ventral premammillary nucleus, J Comp Neurol, 195, 10.1002/cne.903240205 Leshan, 2009, Direct innervation of GnRH neurons by metabolic- and sexual odorant-sensing leptin receptor neurons in the hypothalamic ventral premammillary nucleus, J Neurosci, 3138, 10.1523/JNEUROSCI.0155-09.2009 Donato, 2011, Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons, J Clin Invest, 121, 355, 10.1172/JCI45106 Zuure, 2013, Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function, J Neurosci, 17874, 10.1523/JNEUROSCI.2278-13.2013 Martin, 2014, Leptin-responsive GABAergic neurons regulate fertility through pathways that result in reduced kisspeptinergic tone, J Neurosci, 6047, 10.1523/JNEUROSCI.3003-13.2014 Bellefontaine, 2014, Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction, J Clin Invest, 124, 2550, 10.1172/JCI65928 Fuente-Martin, 2012, Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes, J Clin Invest, 122, 3900, 10.1172/JCI64102 Oakley, 2009, Kisspeptin signaling in the brain, Endocr Rev, 30, 713, 10.1210/er.2009-0005 d'Anglemont de Tassigny, 2010, The role of kisspeptin signaling in reproduction, Physiology (Bethesda), 25, 207, 10.1152/physiol.00009.2010 Cravo, 2011, Characterization of Kiss1 neurons using transgenic mouse models, Neuroscience, 173, 37, 10.1016/j.neuroscience.2010.11.022 Smith, 2006, KiSS-1 neurones are direct targets for leptin in the ob/ob mouse, J Neuroendocrinol, 18, 298, 10.1111/j.1365-2826.2006.01417.x Backholer, 2010, Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells, Endocrinology, 151, 2233, 10.1210/en.2009-1190 Quennell, 2011, Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice, Endocrinology, 152, 1541, 10.1210/en.2010-1100 Luque, 2007, Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: Analyses using mouse models and a cell line, Endocrinology, 148, 4601, 10.1210/en.2007-0500 Castellano, 2006, Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats, Diabetes, 55, 2602, 10.2337/db05-1584 Morelli, 2008, Sex steroids and leptin regulate the "first Kiss" (KiSS 1/G-protein-coupled receptor 54 system) in human gonadotropin-releasing-hormone-secreting neuroblasts, J Sex Med, 5, 1097, 10.1111/j.1743-6109.2008.00782.x Qiu, 2011, Guinea pig kisspeptin neurons are depolarized by leptin via activation of TRPC channels, Endocrinology, 152, 1503, 10.1210/en.2010-1285 Cota, 2006, Hypothalamic mTOR signaling regulates food intake, Science, 312, 927, 10.1126/science.1124147 Roa, 2009, The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system, Endocrinology, 150, 5016, 10.1210/en.2009-0096 Louis, 2011, Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis, Endocrinology, 152, 2302, 10.1210/en.2011-0096 Hanchate, 2012, Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation, J Neurosci, 32, 932, 10.1523/JNEUROSCI.4765-11.2012 Donato, 2013, Lesions of the ventral premammillary nucleus disrupt the dynamic changes in Kiss1 and GnRH expression characteristic of the proestrus-estrus transition, Neuroscience, 241, 67, 10.1016/j.neuroscience.2013.03.013 Cravo, 2013, Leptin signaling in kiss1 neurons arises after pubertal development, PLoS One, 8, e58698, 10.1371/journal.pone.0058698 Tena-Sempere, 2002, Leptin in male reproduction: The testis paradigm, Mol Cell Endocrinol, 188, 9, 10.1016/S0303-7207(02)00008-4 Spicer, 1997, The adipose obese gene product, leptin: Evidence of a direct inhibitory role in ovarian function, Endocrinology, 138, 3374, 10.1210/endo.138.8.5311 Ghizzoni, 2001, Leptin inhibits steroid biosynthesis by human granulosa-lutein cells, Horm Metab Res, 33, 323, 10.1055/s-2001-15419 Kendall, 2004, Direct in vivo effects of leptin on ovarian steroidogenesis in sheep, Reproduction, 128, 757, 10.1530/rep.1.00256 Swain, 2004, Direct effects of leptin on mouse reproductive function: Regulation of follicular, oocyte, and embryo development, Biol Reprod, 71, 1446, 10.1095/biolreprod.104.033035 Serke, 2012, Leptin-deficient (ob/ob) mouse ovaries show fatty degeneration, enhanced apoptosis and decreased expression of steroidogenic acute regulatory enzyme, Int J Obes (Lond), 36, 1047, 10.1038/ijo.2011.220 Karlsson, 1997, Expression of functional leptin receptors in the human ovary, J Clin Endocrinol Metab, 82, 4144 Duggal, 2002, Expression of the long (OB-RB) and short (OB-RA) forms of the leptin receptor throughout the oestrous cycle in the mature rat ovary, Reproduction, 123, 899, 10.1530/rep.0.1230899 Loffler, 2001, Evidence of leptin expression in normal and polycystic human ovaries, Mol Hum Reprod, 7, 1143, 10.1093/molehr/7.12.1143 Fungfuang, 2013, Serum leptin concentrations, leptin mRNA expression, and food intake during the estrous cycle in rats, Lab Anim Res, 29, 1, 10.5625/lar.2013.29.1.1 Duggal, 2000, The in vivo and in vitro effects of exogenous leptin on ovulation in the rat, Endocrinology, 141, 1971, 10.1210/endo.141.6.7509 Craig, 2004, Leptin enhances oocyte nuclear and cytoplasmic maturation via the mitogen-activated protein kinase pathway, Endocrinology, 145, 5355, 10.1210/en.2004-0783 Joo, 2010, Role of leptin in improvement of oocyte quality by regulation of ovarian angiogenesis, Anim Reprod Sci, 119, 329, 10.1016/j.anireprosci.2010.02.002 Panwar, 2012, Effect of passive immunization against leptin on ovarian follicular development in prepubertal mice, J Reprod Immunol, 96, 19, 10.1016/j.jri.2012.07.004 Attig, 2011, Postnatal leptin is necessary for maturation of numerous organs in newborn rats, Organogenesis, 7, 88, 10.4161/org.7.2.14871 Barkan, 2005, Leptin induces ovulation in GnRH-deficient mice, FASEB J, 19, 133, 10.1096/fj.04-2271fje Tena-Sempere, 2001, Developmental and hormonal regulation of leptin receptor (Ob-R) messenger ribonucleic acid expression in rat testis, Biol Reprod, 64, 634, 10.1095/biolreprod64.2.634 El-Hefnawy, 2000, Expression of the leptin receptor during germ cell development in the mouse testis, Endocrinology, 141, 2624, 10.1210/endo.141.7.7542 Tena-Sempere, 1999, Leptin inhibits testosterone secretion from adult rat testis in vitro, J Endocrinol, 161, 211, 10.1677/joe.0.1610211 Caprio, 1999, Expression of functional leptin receptors in rodent Leydig cells, Endocrinology, 140, 4939, 10.1210/endo.140.11.7088 Caprio, 2001, Leptin in reproduction, Trends Endocrinol Metab, 12, 65, 10.1016/S1043-2760(00)00352-0 Tena-Sempere, 2001, Molecular mechanisms of leptin action in adult rat testis: Potential targets for leptin-induced inhibition of steroidogenesis and pattern of leptin receptor messenger ribonucleic acid expression, J Endocrinol, 170, 413, 10.1677/joe.0.1700413 Landry, 2013, Implications of leptin in neuroendocrine regulation of male reproduction, Reprod Biol, 13, 1, 10.1016/j.repbio.2012.12.001 Aquila, 2005, Leptin secretion by human ejaculated spermatozoa, J Clin Endocrinol Metab, 90, 4753, 10.1210/jc.2004-2233 Bhat, 2006, Influence of a leptin deficiency on testicular morphology, germ cell apoptosis, and expression levels of apoptosis-related genes in the mouse, J Androl, 27, 302, 10.2164/jandrol.05133 Isidori, 1999, Leptin and androgens in male obesity: Evidence for leptin contribution to reduced androgen levels, J Clin Endocrinol Metab, 84, 3673 Zhao, 2014, Leptin level and oxidative stress contribute to obesity-induced low testosterone in murine testicular tissue, Oxid Med Cell Longev, 2014, 190945, 10.1155/2014/190945 Senaris, 1997, Synthesis of leptin in human placenta, Endocrinology, 138, 4501, 10.1210/endo.138.10.5573 Schubring, 1998, Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: Relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels, Horm Res, 50, 276, 10.1159/000023290 Thomas, 2001, Circulating leptin during ovine pregnancy in relation to maternal nutrition, body composition and pregnancy outcome, J Endocrinol, 169, 465, 10.1677/joe.0.1690465 Masuzaki, 1997, Nonadipose tissue production of leptin: Leptin as a novel placenta-derived hormone in humans, Nat Med, 3, 1029, 10.1038/nm0997-1029 Maffei, 1995, Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects, Nat Med, 1, 1155, 10.1038/nm1195-1155 Garcia, 2000, Gestational profile of leptin messenger ribonucleic acid (mRNA) content in the placenta and adipose tissue in the rat, and regulation of the mRNA levels of the leptin receptor subtypes in the hypothalamus during pregnancy and lactation, Biol Reprod, 62, 698, 10.1095/biolreprod62.3.698 Zhao, 2003, Comparative analysis of expression and secretion of placental leptin in mammals, Am J Physiol Regul Integr Comp Physiol, 285, R438, 10.1152/ajpregu.00776.2002 Hoggard, 2001, Leptin secretion to both the maternal and fetal circulation in the ex vivo perfused human term placenta, Placenta, 22, 347, 10.1053/plac.2001.0628 Hoggard, 1997, Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta, Proc Natl Acad Sci U S A, 94, 11073, 10.1073/pnas.94.20.11073 Gavrilova, 1997, Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor, J Biol Chem, 272, 30546, 10.1074/jbc.272.48.30546 Trujillo, 2011, Hyperphagia and central mechanisms for leptin resistance during pregnancy, Endocrinology, 152, 1355, 10.1210/en.2010-0975 Sahu, 2002, Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones, J Neuroendocrinol, 14, 796, 10.1046/j.1365-2826.2002.00840.x Maymo, 2009, Up-regulation of placental leptin by human chorionic gonadotropin, Endocrinology, 150, 304, 10.1210/en.2008-0522 Gambino, 1823, Regulation of leptin expression by 17beta-estradiol in human placental cells involves membrane associated estrogen receptor alpha, Biochim Biophys Acta, 2012, 900 Nagaishi, 2014, Possible crosstalk between leptin and prolactin during pregnancy, Neuroscience, 259, 71, 10.1016/j.neuroscience.2013.11.050 Mounzih, 1997, Leptin treatment rescues the sterility of genetically obese ob/ob males, Endocrinology, 138, 1190, 10.1210/endo.138.3.5024 Malik, 2001, Leptin requirement for conception, implantation, and gestation in the mouse, Endocrinology, 142, 5198, 10.1210/endo.142.12.8535 Ramos, 2005, Leptin serves as an upstream activator of an obligatory signaling cascade in the embryo-implantation process, Endocrinology, 146, 694, 10.1210/en.2004-1186 Brannian, 2001, Baseline non-fasting serum leptin concentration to body mass index ratio is predictive of IVF outcomes, Hum Reprod, 16, 1819, 10.1093/humrep/16.9.1819 Christou, 2001, Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth, J Clin Endocrinol Metab, 86, 935, 10.1210/jcem.86.2.7217 Varvarigou, 1999, Cord blood leptin concentrations in relation to intrauterine growth, Clin Endocrinol (Oxf), 50, 177, 10.1046/j.1365-2265.1999.00630.x Forhead, 2009, The hungry fetus? Role of leptin as a nutritional signal before birth, J Physiol, 587, 1145, 10.1113/jphysiol.2008.167072 Azziz, 2004, The prevalence and features of the polycystic ovary syndrome in an unselected population, J Clin Endocrinol Metab, 2745, 10.1210/jc.2003-032046 Chen, 2013, Adipokines in reproductive function: A link between obesity and polycystic ovary syndrome, J Mol Endocrinol, R21, 10.1530/JME-12-0247 March, 2010, The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria, Hum Reprod, 544, 10.1093/humrep/dep399 Mantzoros, 1997, Leptin concentrations in the polycystic ovary syndrome, J Clin Endocrinol Metab, 82, 1687 Escobar-Morreale, 2007, Abdominal adiposity and the polycystic ovary syndrome, Trends Endocrinol Metab, 18, 266, 10.1016/j.tem.2007.07.003 Kauffman, 2007, Sexual differentiation of Kiss1 gene expression in the brain of the rat, Endocrinology, 148, 1774, 10.1210/en.2006-1540 Castellano, 2011, Early metabolic programming of puberty onset: Impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system, Endocrinology, 152, 3396, 10.1210/en.2010-1415 Sanchez-Garrido, 2014, Obesity-induced hypogonadism in the male: Premature reproductive neuroendocrine senescence and contribution of Kiss1-mediated mechanisms, Endocrinology, 155, 1067, 10.1210/en.2013-1584