Hormonal Programming Across the Lifespan

 

 Buy Article Permissions and Reprints

Abstract

Hormones influence countless biological processes across an animal’s lifespan. Many hormone-mediated events occur within developmental sensitive periods, during which hormones have the potential to cause permanent tissue-specific alterations in anatomy and physiology. There are numerous selective critical periods in development with different targets being affected during different periods. This review outlines the proceedings of the Hormonal Programming in Development session at the US-South American Workshop in Neuroendocrinology in August 2011. Here we discuss how gonadal steroid hormones impact various biological processes within the brain and gonads during early development and describe the changes that take place in the aging female ovary. At the cellular level, hormonal targets in the brain include neurons, glia, or vasculature. On a genomic/epigenomic level, transcription factor signaling and epigenetic changes alter the expression of critical hormone receptor genes across development and following ischemic brain insult. In addition, organizational hormone exposure alters epigenetic processes in specific brain nuclei and may be an important mediator of sexual differentiation of the neonatal brain. Brain targets of hormonal programming, such as the paraventricular nucleus of the hypothalamus, may be critical in influencing the development of peripheral targets, such as the ovary. Exposure to excess hormones can cause abnormalities in the ovary during development leading to polycystic ovarian syndrome (PCOS). Exposure to excess androgens during fetal development also has a profound effect on the development of the male reproductive system. In addition, increased activity of the sympathetic nerve and stress during early life have been linked to PCOS symptomology in adulthood. Finally, we describe how age-related decreases in fertility are linked to high levels of nerve growth factor (NGF), which enhances sympathetic nerve activity and alters ovarian function.

• References

• 1 Tsai HW, Grant PA, Rissman EF. Sex differences in histone modifications in the neonatal mouse brain. Epigenetics 2009; 4: 47-53
  CrossrefPubMedGoogle Scholar
• 2 Rhees RW, Shryne JE, Gorski RA. Onset of the hormone-sensitive perinatal period for sexual differentiation of the sexually dimorphic nucleus of the preoptic area in female rats. J Neurobiol 1990; 21: 781-786
  CrossrefPubMedGoogle Scholar
• 3 Arnold AP, Gorski RA. Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci 1984; 7: 413-442
  CrossrefPubMedGoogle Scholar
• 4 Bakker J, De Mees C, Douhard Q, Balthazart J, Gabant P, Szpirer J, Szpirer C. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci 2006; 9: 220-226
  CrossrefPubMedGoogle Scholar
• 5 McEwen BS, Lieberburg I, Chaptal C, Krey LC. Aromatization: important for sexual differentiation of the neonatal rat brain. Horm Behav 1977; 9: 249-263
  CrossrefPubMedGoogle Scholar
• 6 McCarthy MM. Estradiol and the developing brain. Physiol Rev 2008; 88: 91-134
  CrossrefPubMedGoogle Scholar
• 7 Thornton J, Zehr JL, Loose MD. Effects of prenatal androgens on rhesus monkeys: A model system to explore the organizational hypothesis in primates. Horm Behav 2009; 55: 633-644
  CrossrefPubMedGoogle Scholar
• 8 Bonthuis P, Cox K, Searcy B, Kumar P, Tobet S, Rissman E. Of mice and rats: key species variations in the sexual differentiation of brain and behavior. Front Neuroendocrinol 2010; 31: 341-358
  CrossrefPubMedGoogle Scholar
• 9 Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, Chambon P. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 1986; 320: 134-135
  CrossrefPubMedGoogle Scholar
• 10 Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor α and β mRNA in the rat central nervous system. J Comp Neurol 1997; 388: 507-525
  CrossrefPubMedGoogle Scholar
• 11 Österlund MK, Grandien K, Keller E, Hurd YL. The human brain has distinct regional expression patterns of estrogen receptor α mRNA isoforms derived from alternative promoters. J Neurochem 2000; 75: 1390-1397
  PubMedGoogle Scholar
• 12 Prewitt AK, Wilson ME. Changes in estrogen receptor-alpha mRNA in the mouse cortex during development. Brain Res 2007; 1134: 62-69
  CrossrefPubMedGoogle Scholar
• 13 Simerly R, Swanson L, Chang C, Muramatsu M. Distribution of androgen and estrogen receptor mRNA containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 1990; 294: 76-95
  CrossrefPubMedGoogle Scholar
• 14 Sheridan PJ. Estrogen binding in the neonatal neocortex. Brain Res 1979; 178: 201-206
  CrossrefPubMedGoogle Scholar
• 15 Shughrue PJ, Stumpf WE, Maclusky NJ, Zielinski J, Hochberg RB. Developmental changes in estrogen receptors in mouse cerebral cortex between birth and postweaning: Studied by autoradiography with 11β-methoxy-16α-(125I)iodoestradiol. Endocrinology 1990; 126: 1112-1124
  CrossrefPubMedGoogle Scholar
• 16 O’Keefe JA, Li Y, Burgess LH, Handa RJ. Estrogen receptor mRNA alterations in the developing rat hippocampus. Mol Brain Res 1995; 30: 115-124
  CrossrefPubMedGoogle Scholar
• 17 Overman WH. Sex differences in early childhood, adolescence, and adulthood on cognitive tasks that rely on orbital prefrontal cortex. Brain Cogn 2004; 55: 134-147
  CrossrefPubMedGoogle Scholar
• 18 Galea LAM, Uban KA, Epp JR, Brummelte S, Barha CK, Wilson WL, Lieblich SE, Pawluski JL. Endocrine regulation of cognition and neuroplasticity: Our pursuit to unveil the complex interaction between hormones, the brain, and behaviour. Can J Exp Psychol. 2008. 62. 247-260
  Google Scholar
• 19 Welborn BL, Papademetris X, Reis DL, Rajeevan N, Bloise SM, Gray JR. Variation in orbitofrontal cortex volume: relation to sex, emotion regulation and affect. Soc Cog Affec Neurosci 2009; 4: 328-339
  PubMedGoogle Scholar
• 20 Westberry JM, Trout AL, Wilson ME. Epigenetic regulation of estrogen receptor {alpha} gene expression in the mouse cortex during early postnatal development. Endocrinology 2010; 151: 731-740
  CrossrefPubMedGoogle Scholar
• 21 Kurian JR, Bychowski ME, Forbes-Lorman RM, Auger CJ, Auger AP. Mecp2 organizes juvenile social behavior in a sex-specific manner. J Neurosci 2008; 28: 7137-7142
  CrossrefPubMedGoogle Scholar
• 22 Champagne FA, Weaver ICG, Diorio J, Dymov S, Szyf M, Meaney MJ. Maternal care associated with methylation of the estrogen receptor-α1b promoter and estrogen receptor-α expression in the medial preoptic area of female offspring. Endocrinology 2006; 147: 2909-2915
  CrossrefPubMedGoogle Scholar
• 23 Emery DL, Royo NC, Fischer I, Saatman KE, McIntosh TK. Plasticity following injury to the adult central nervous system: is recapitulation of a developmental state worth promoting?. J Neurotrauma 2003; 20: 1271-1292
  CrossrefPubMedGoogle Scholar
• 24 Dubal DB, Rau SW, Shughrue PJ, Zhu H, Yu J, Cashion AB, Suzuki S, Gerhold LM, Bottner MB, Dubal SB. Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERα in estradiol-mediated protection against delayed cell death. Endocrinology 2006; 147: 3076-3084
  CrossrefPubMedGoogle Scholar
• 25 Westberry JM, Prewitt AK, Wilson ME. Epigenetic regulation of the estrogen receptor alpha promoter in the cerebral cortex following ischemia in male and female rats. Neuroscience 2008; 152: 982-989
  CrossrefPubMedGoogle Scholar
• 26 DeFraja C, Conti L, Magrassi L, Govoni S, Cattaneo E. Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain. J Neurosci Res 1998; 54: 320-330
  CrossrefPubMedGoogle Scholar
• 27 Kudwa A, Michopoulos V, Gatewood J, Rissman E. Roles of estrogen receptors α and β in differentiation of mouse sexual behavior. Neuroscience 2006; 138: 921-928
  CrossrefPubMedGoogle Scholar
• 28 Kudwa AE, Bodo C, Gustafsson JÅ, Rissman E. A previously uncharacterized role for estrogen receptor β: Defeminization of male brain and behavior. Proc Natl Acad Sci USA 2005; 102: 4608-4612
  CrossrefPubMedGoogle Scholar
• 29 Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues?. Front Neuroendocrinol 2009; 30: 1-9
  CrossrefPubMedGoogle Scholar
• 30 Majdic G, Tobet S. Cooperation of sex chromosomal genes and endocrine influences for hypothalamic sexual differentiation. Front Neuroendocrinol 2011; 32: 137-145
  CrossrefPubMedGoogle Scholar
• 31 McClellan KM, Stratton MS, Tobet SA. Roles for γ-aminobutyric acid in the development of the paraventricular nucleus of the hypothalamus. J Comp Neurol 2010; 518: 2710-2728
  PubMedGoogle Scholar
• 32 Stratton MS, Searcy BT, Tobet SA. GABA regulates corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus in newborn mice. Physiol Behav 2011; 104: 327-333
  CrossrefPubMedGoogle Scholar
• 33 Tobet S, Fox T. Sex-and hormone-dependent antigen immunoreactivity in developing rat hypothalamus. Proc Natl Acad Sci USA 1989; 86: 382-386
  CrossrefPubMedGoogle Scholar
• 34 Tobet SA, Chickering TW, Hanna I, Crandall JE, Schwarting GA. Can gonadal steroids influence cell position in the developing brain?. Horm Behav 1994; 28: 320-327
  CrossrefPubMedGoogle Scholar
• 35 Henderson RG, Brown AE, Tobet SA. Sex differences in cell migration in the preoptic area/anterior hypothalamus of mice. J Neurobiol 1999; 41: 252-266
  CrossrefPubMedGoogle Scholar
• 36 Knoll JG, Wolfe CA, Tobet SA. Estrogen modulates neuronal movements within the developing preoptic area-anterior hypothalamus. Eur J Neurosci 2007; 26: 1091-1099
  CrossrefPubMedGoogle Scholar
• 37 Scordalakes EM, Shetty SJ, Rissman EF. Roles of estrogen receptor α and androgen receptor in the regulation of neuronal nitric oxide synthase. J Comp Neurol 2002; 453: 336-344
  CrossrefPubMedGoogle Scholar
• 38 Orikasa C, Kondo Y, Hayashi S, McEwen BS, Sakuma Y. Sexually dimorphic expression of estrogen receptor β in the anteroventral periventricular nucleus of the rat preoptic area: implication in luteinizing hormone surge. Proc Natl Acad Sci 2002; 99: 3306-3311
  CrossrefPubMedGoogle Scholar
• 39 Wolfe CA, Van Doren M, Walker HJ, Seney ML, McClellan KM, Tobet SA. Sex differences in the location of immunochemically defined cell populations in the mouse preoptic area/anterior hypothalamus. Dev Brain Res 2005; 157: 34-41
  CrossrefPubMedGoogle Scholar
• 40 Büdefeld T, Grgurevic N, Tobet SA, Majdic G. Sex differences in brain developing in the presence or absence of gonads. Dev Neurobiol 2008; 68: 981-995
  CrossrefPubMedGoogle Scholar
• 41 Stratton M, Budefeld T, Majdic G, Tobet S. Embryonic GABA-B receptor blockade alters adult hypothalamic structure, and anxiety- and depression-like behaviors in mice. Society for Neuroscience Abstract. 2011. Washington, DC, USA:
  Google Scholar
• 42 Finley KH. The capillary bed of the paraventricular and supraoptic nuclei of the hypothalamus. Res Publ Assoc Res Nerv Ment Dis 1938; 18: 94-109
  PubMedGoogle Scholar
• 43 Frahm KA, Schow MJ, Okland TS, Eitel CM, Tobet SA. The vasculature within the paraventricular nucleus of the hypothalamus in mice varies as a function of development, sub-nuclear location, and GABA signaling. Horm Metab Res. 2012 44. advance online publication 5 April 2012. DOI: 10.1055/S-0032-1304624
  PubMedGoogle Scholar
• 44 Dellovade TL, Davis AM, Ferguson C, Sieghart W, Homanics GE, Tobet SA. GABA influences the development of the ventromedial nucleus of the hypothalamus. J Neurobiol 2001; 49: 264-276
  CrossrefPubMedGoogle Scholar
• 45 Tobet S, Hanna I, Schwarting G. Migration of neurons containing gonadotropin releasing hormone (GnRH) in slices from embryonic nasal compartment and forebrain. Dev Brain Res 1996; 97: 287-292
  CrossrefPubMedGoogle Scholar
• 46 Navratil AM, Knoll JG, Whitesell JD, Tobet SA, Clay CM. Neuroendocrine plasticity in the anterior pituitary: gonadotropin-releasing hormone-mediated movement in vitro and in vivo. Endocrinology 2007; 148: 1736-1744
  CrossrefPubMedGoogle Scholar
• 47 Frahm KA, Clay CM, Tobet SA. Characterization of an ovarian slice model in vitro to view ovulation. Soc Study Reproduction Abstract. 2010. Milwaukee, WI, USA:
  Google Scholar
• 48 Pettine W, Jibson M, Chen T, Tobet S, Henry C. Characterization of novel microelectrode geometries for detection of neurotransmitters. Sensors J, IEEE 2011; PP (99): 1-1
  PubMedGoogle Scholar
• 49 Lynn NS, Tobet S, Henry CS, Dandy DS. Mapping spatio-temporal molecular distributions using a microfluidic array. Anal Chem 2011; 84: 1360-1366
  PubMedGoogle Scholar
• 50 McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG, Murray EK, Nugent BM, Schwarz JM, Wilson ME. The epigenetics of sex differences in the brain. J Neurosci 2009; 29: 12815-12823
  CrossrefPubMedGoogle Scholar
• 51 Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006; 31: 89-97
  CrossrefPubMedGoogle Scholar
• 52 Cooper DN, Krawczak M. Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes. Hum Genet 1989; 83: 181-188
  CrossrefPubMedGoogle Scholar
• 53 Bird AP, Wolffe AP. Methylation-induced repression – belts, braces, and chromatin. Cell 1999; 99: 451-454
  CrossrefPubMedGoogle Scholar
• 54 Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. Epigenetic programming by maternal behavior. Nat Neurosci 2004; 7: 847-854
  CrossrefPubMedGoogle Scholar
• 55 Renthal W, Nestler EJ. Epigenetic mechanisms in drug addiction. Trends Mol Med 2008; 14: 341-350
  CrossrefPubMedGoogle Scholar
• 56 Miller CA, Campbell SL, Sweatt JD. DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiol Learn Mem 2008; 89: 599-603
  CrossrefPubMedGoogle Scholar
• 57 Day JJ, Sweatt JD. Epigenetic mechanisms in cognition. Neuron 2011; 70: 813-829
  CrossrefPubMedGoogle Scholar
• 58 Guo JU, Ma DK, Mo H, Ball MP, Jang MH, Bonaguidi MA, Balazer JA, Eaves HL, Xie B, Ford E. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci 2011; 14: 1345-1351
  CrossrefPubMedGoogle Scholar
• 59 Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev 1993; 3: 226-231
  CrossrefPubMedGoogle Scholar
• 60 He F, Ge W, Martinowich K, Becker-Catania S, Coskun V, Zhu W, Wu H, Castro D, Guillemot F, Fan G. A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 2005; 8: 616-625
  CrossrefPubMedGoogle Scholar
• 61 Wilson ME. Methylation of the ER promoter as a regulator of brain region specific hormone sensitivity. Society for Neuroscience Abstract. 2009. Chicago, IL, USA:
  Google Scholar
• 62 Schwarz JM, Nugent BM, McCarthy MM. Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span. Endocrinology 2010; 151: 4871-4881
  CrossrefPubMedGoogle Scholar
• 63 Konkle A, McCarthy MM. Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology 2011; 152: 223-235
  CrossrefPubMedGoogle Scholar
• 64 Ahmed EI, Zehr JL, Schulz KM, Lorenz BH, DonCarlos LL, Sisk CL. Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions. Nat Neurosci 2008; 11: 995-997
  CrossrefPubMedGoogle Scholar
• 65 Métivier R, Gallais R, Tiffoche C, Le Péron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G. Cyclical DNA methylation of a transcriptionally active promoter. Nature 2008; 452: 45-50
  CrossrefPubMedGoogle Scholar
• 66 Kim MS, Kondo T, Takada I, Youn MY, Yamamoto Y, Takahashi S, Matsumoto T, Fujiyama S, Shirode Y, Yamaoka I. DNA demethylation in hormone-induced transcriptional derepression. Nature 2009; 461: 1007-1012
  CrossrefPubMedGoogle Scholar
• 67 Kurian JR, Forbes-Lorman RM, Auger AP. Sex difference in mecp2 expression during a critical period of rat brain development. Epigenetics 2007; 2: 173-178
  CrossrefPubMedGoogle Scholar
• 68 Jessen HM, Kolodkin MH, Bychowski ME, Auger CJ, Auger AP. The nuclear receptor corepressor has organizational effects within the developing amygdala on juvenile social play and anxiety-like behavior. Endocrinology 2010; 151: 1212-1220
  CrossrefPubMedGoogle Scholar
• 69 Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, review fundamental particle of the eukaryote chromosome. Cell 1999; 98: 285-294
  CrossrefPubMedGoogle Scholar
• 70 Hansen JC, Tse C, Wolffes AP. Structure and Function of the Core Histone N-Termini: More Than Meets the Eye. Biochemistry 1998; 37: 17637-17641
  CrossrefPubMedGoogle Scholar
• 71 Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 40: 41-45
  PubMedGoogle Scholar
• 72 Kuo MH, Allis CD. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 1998; 20: 615-626
  CrossrefPubMedGoogle Scholar
• 73 Matsuda KI, Mori H, Nugent BM, Pfaff DW, McCarthy MM, Kawata M. Histone Deacetylation during Brain Development Is Essential for Permanent Masculinization of Sexual Behavior. Endocrinology 2011; 152: 2760-2767
  CrossrefPubMedGoogle Scholar
• 74 Hernandez ER, Jimenez JL, Payne DW, Adashi EY. Adrenergic regulation of ovarian androgen biosynthesis is mediated via β2-adrenergic theca-interstitial cell recognition sites. Endocrinology 1988; 122: 1592-1602
  CrossrefPubMedGoogle Scholar
• 75 Ricu M, Paredes A, Greiner M, Ojeda SR, Lara HE. Functional development of the ovarian noradrenergic innervation. Endocrinology 2008; 149: 50-56
  PubMedGoogle Scholar
• 76 Lara HE, Porcile A, Espinoza J, Romero C, Luza SM, Fuhrer J, Miranda C, Roblero L. Release of norepinephrine from human ovary. Endocrine 2001; 15: 187-192
  CrossrefPubMedGoogle Scholar
• 77 Heider U, Pedal I, Spanel-Borowski K. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Fertil Steril 2001; 75: 1141-1147
  CrossrefPubMedGoogle Scholar
• 78 Greiner M, Paredes A, Araya V, Lara HE. Role of stress and sympathetic innervation in the development of polycystic ovary syndrome. Endocrine 2005; 28: 319-324
  CrossrefPubMedGoogle Scholar
• 79 Lara H, Dorfman M, Venegas M, Luza S, Luna S, Mayerhofer A, Guimaraes M, Rosa e Silva A, Ramirez V. Changes in sympathetic nerve activity of the mammalian ovary during a normal estrous cycle and in polycystic ovary syndrome: studies on norepinephrine release. Microsc Res Tech 2002; 59: 495-502
  CrossrefPubMedGoogle Scholar
• 80 Jedel E, Waern M, Gustafson D, Landén M, Eriksson E, Holm G, Nilsson L, Lind AK, Janson PO, Stener-Victorin E. Anxiety and depression symptoms in women with polycystic ovary syndrome compared with controls matched for body mass index. Human Reprod 2010; 25: 450-456
  CrossrefPubMedGoogle Scholar
• 81 Stener-Victorin E, Ploj K, Larsson BM, Holmäng A. Rats with steroid-induced polycystic ovaries develop hypertension and increased sympathetic nervous system activity. Reprod Biol Endo 2005; 3: 44
  PubMedGoogle Scholar
• 82 Barria A, Leyton V, Ojeda S, Lara HE. Ovarian steroidal response to gonadotropins and β-adrenergic stimulation is enhanced in polycystic ovary syndrome: Role of Sympathetic Innervation. Endocrinology 1993; 133: 2696-2703
  CrossrefPubMedGoogle Scholar
• 83 Lara H, Ferruz J, Luza S, Bustamante D, Borges Y, Ojeda S. Activation of ovarian sympathetic nerves in polycystic ovary syndrome. Endocrinology 1993; 133: 2690-2695
  CrossrefPubMedGoogle Scholar
• 84 Goldstein DS, Kopin IJ. Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: a meta-analysis. Endocr Regul 2008; 42: 111-119
  PubMedGoogle Scholar
• 85 Bernuci MP, Szawka RE, Helena CVV, Leite CM, Lara HE, Anselmo-Franci JA. Locus coeruleus mediates cold stress-induced polycystic ovary in rats. Endocrinology 2008; 149: 2907-2916
  CrossrefPubMedGoogle Scholar
• 86 Dorfman M, Arancibia S, Fiedler J, Lara H. Chronic intermittent cold stress activates ovarian sympathetic nerves and modifies ovarian follicular development in the rat. Biol Reprod 2003; 68: 2038-2043
  PubMedGoogle Scholar
• 87 Fiedler J, Jara P, Luza S, Dorfman M, Grouselle D, Rage F, Lara HE, Arancibia S. Cold stress induces metabolic activation of thyrotrophin-releasing hormone-synthesising neurones in the magnocellular division of the hypothalamic paraventricular nucleus and concomitantly changes ovarian sympathetic activity parameters. J Neuroendocrinol 2006; 18: 367-376
  CrossrefPubMedGoogle Scholar
• 88 Jara P, Rage F, Dorfman M, Grouselle D, Barra R, Arancibia S, Lara H. Cold-induced glutamate release in vivo from the magnocellular region of the paraventricular nucleus is involved in ovarian sympathetic activation. J Neuroendocrinol 2010; 22: 979-986
  CrossrefPubMedGoogle Scholar
• 89 Gomes CM, Donadio MVF, Anselmo-Franci J, Franci CR, Lucion AB, Sanvitto GL. Neonatal handling induces alteration in progesterone secretion after sexual behavior but not in angiotensin II receptor density in the medial amygdala: implications for reproductive success. Life Sci 2006; 78: 2867-2871
  CrossrefPubMedGoogle Scholar
• 90 Gomes C, Raineki C, de Paula PR, Severino G, Helena C, Anselmo-Franci J, Franci C, Sanvitto G, Lucion A. Neonatal handling and reproductive function in female rats. J Endocrinol 2005; 184: 435-445
  CrossrefPubMedGoogle Scholar
• 91 Raineki C, De Souza M, Szawka R, Lutz M, De Vasconcellos L, Sanvitto G, Izquierdo I, Bevilaqua L, Cammarota M, Lucion A. Neonatal handling and the maternal odor preference in rat pups: involvement of monoamines and cyclic AMP response element-binding protein pathway in the olfactory bulb. Neuroscience 2009; 159: 31-38
  CrossrefPubMedGoogle Scholar
• 92 Raineki C, Szawka RE, Gomes CM, Lucion MK, Barp J, Belló-Klein A, Franci CR, Anselmo-Franci JA, Sanvitto GL, Lucion AB. Effects of neonatal handling on central noradrenergic and nitric oxidergic systems and reproductive parameters in female rats. Neuroendocrinology 2008; 87: 151-159
  CrossrefPubMedGoogle Scholar
• 93 Anderson H, Fogel N, Grebe SK, Singh RJ, Taylor RL, Dunaif A. Infants of women with polycystic ovary syndrome have lower cord blood androstenedione and estradiol levels. J Clin Endo Metab 2010; 95: 2180-2186
  CrossrefPubMedGoogle Scholar
• 94 Bzoskie L, Blount L, Kashiwai K, Humme J, Padbury J. The contribution of transporter-dependent uptake to fetal catecholamine clearance. Neonatology 1997; 71: 102-110
  CrossrefPubMedGoogle Scholar
• 95 Gu W, Jones CT. The effect of elevation of maternal plasma catecholamines on the fetus and placenta of the pregnant sheep. J Dev Physiol 1986; 8: 173-186
  PubMedGoogle Scholar
• 96 Broekmans FJ, Knauff EAH, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trend Endo Metab 2007; 18: 58-65
  PubMedGoogle Scholar
• 97 Faddy M, Gosden R, Gougeon A, Richardson SJ, Nelson J. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Human Reproduction 1992; 7: 1342-1346
  PubMedGoogle Scholar
• 98 Acuņa E, Fornes R, Fernandois D, Garrido MP, Greiner M, Lara HE, Paredes AH. Increases in norepinephrine release and ovarian cyst formation during ageing in the rat. Reprod Biol Endo 2009; 7: 64
  PubMedGoogle Scholar
• 99 Lara H, McDonald J, Ahmed C, Ojeda S. Guanethidine-mediated destruction of ovarian sympathetic nerves disrupts ovarian development and function in rats. Endocrinology 1990; 127: 2199-2209
  CrossrefPubMedGoogle Scholar
• 100 Ferruz J, Barria A, Galleguillos X, Lara H. Release of norepinephrine from the rat ovary: local modulation of gonadotropins. Biol Reprod 1991; 45: 592-597
  CrossrefPubMedGoogle Scholar
• 101 Aguado L, Petrovic S, Ojeda S. Ovarian β-adrenergic receptors during the onset of puberty: characterization, distribution, and coupling to steroidogenic responses. Endocrinology 1982; 110: 1124-1132
  CrossrefPubMedGoogle Scholar
• 102 Menken J, Trussell J, Larsen U. Age and infertility. Science 1986; 233: 1389-1394
  CrossrefPubMedGoogle Scholar
• 103 Lenton EA, DeKretser DM, Woodward AJ, Robertson MD. Inhibin concentrations throughout the menstrual cycles of normal, infertile, and older women compared with those during spontaneous conception cycles. J Clin Endo Metab 1991; 73: 1180-1190
  CrossrefPubMedGoogle Scholar
• 104 Margolin E, Zhornitzki T, Kopernik G, Kogan S, Schattner A, Knobler H. Polycystic ovary syndrome in post-menopausal women – marker of the metabolic syndrome. Maturitas 2005; 50: 331-336
  CrossrefPubMedGoogle Scholar
• 105 Dissen G, Parrott J, Skinner M, Hill D, Costa M, Ojeda S. Direct effects of nerve growth factor on thecal cells from antral ovarian follicles. Endocrinology 2000; 141: 4736-4750
  CrossrefPubMedGoogle Scholar
• 106 Bai YH, Lim SC, Song CH, Bae CS, Jin CS, Choi BC, Jang CH, Lee SH, Pak SC. Electro-acupuncture reverses nerve growth factor abundance in experimental polycystic ovaries in the rat. Gynecol Obstet Invest 2004; 57: 80-85
  CrossrefPubMedGoogle Scholar
• 107 Lara H, Dissen G, Leyton V, Paredes A, Fuenzalida H, Fiedler J, Ojeda S. An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Endocrinology 2000; 141: 1059-1072
  CrossrefPubMedGoogle Scholar
• 108 Chávez-Genaro R, Lombide P, Domínguez R, Rosas P, Vázquez-Cuevas F. Sympathetic pharmacological denervation in ageing rats: effects on ovulatory response and follicular population. Reprod Fertil Dev 2007; 19: 954-960
  CrossrefPubMedGoogle Scholar
• 109 Sir-Petermann T, Maliqueo M, Angel B, Lara H, Perez-Bravo F, Recabarren S. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Human Reprod 2002; 17: 2573-2579
  CrossrefPubMedGoogle Scholar
• 110 Sir-Petermann T, Maliqueo M, Codner E, Echiburú B, Crisosto N, Pérez V, Pérez-Bravo F, Cassorla F. Early metabolic derangements in daughters of women with polycystic ovary syndrome. J Clin Endo Metab 2007; 92: 4637-4642
  CrossrefPubMedGoogle Scholar
• 111 Sir-Petermann T, Codner E, Pérez V, Echiburú B, Maliqueo M, Ladrón de Guevara A, Preisler J, Crisosto N, Sánchez F, Cassorla F. Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J Clin Endo Metab 2009; 94: 1923-1930
  CrossrefPubMedGoogle Scholar
• 112 Sir-Petermann T, Márquez L, Cárcamo M, Hitschfeld C, Codner E, Maliqueo M, Echiburú B, Aranda P, Crisosto N, Cassorla F. Effects of birth weight on anti-Müllerian hormone serum concentrations in infant girls. J Clin Endo Metab 2010; 95: 903-910
  CrossrefPubMedGoogle Scholar
• 113 Franks S. Do animal models of polycystic ovary syndrome help to understand its pathogenesis and management? Yes, but their limitations should be recognized. Endocrinology 2009; 150: 3983-3985
  CrossrefPubMedGoogle Scholar
• 114 Padmanabhan V, Veiga-Lopez A, Abbott D, Recabarren S, Herkimer C. Developmental programming: impact of prenatal testosterone excess and postnatal weight gain on insulin sensitivity index and transfer of traits to offspring of overweight females. Endocrinology 2010; 151: 595-605
  CrossrefPubMedGoogle Scholar
• 115 Roland AV, Nunemaker CS, Keller SR, Moenter SM. Prenatal androgen exposure programs metabolic dysfunction in female mice. J Endocrinol 2010; 207: 213-223
  CrossrefPubMedGoogle Scholar
• 116 Abbott DH, Tarantal AF, Dumesic DA. Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys. Am J Primatol 2009; 71: 776-784
  CrossrefPubMedGoogle Scholar
• 117 Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endo Metabol Dis 2007; 8: 127-141
  PubMedGoogle Scholar
• 118 New MI. Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). Am J Med 1995; 98: S2-S8
  PubMedGoogle Scholar
• 119 Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endo Metab 2001; 86: 3070-3078
  CrossrefPubMedGoogle Scholar
• 120 Reisch N, Flade L, Scherr M, Rottenkolber M, Pedrosa Gil F, Bidlingmaier M, Wolff H, Schwarz HP, Quinkler M, Beuschlein F. High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J Clin Endo Metab 2009; 94: 1665-1670
  CrossrefPubMedGoogle Scholar
• 121 Recabarren SE, Smith R, Rios R, Maliqueo M, Echiburú B, Codner E, Cassorla F, Rojas P, Sir-Petermann T. Metabolic profile in sons of women with polycystic ovary syndrome. J Clin Endo Metab 2008; 93: 1820-1826
  CrossrefPubMedGoogle Scholar
• 122 Recabarren SE, Sir-Petermann T, Rios R, Maliqueo M, Echiburú B, Smith R, Rojas-García P, Recabarren M, Rey RA. Pituitary and testicular function in sons of women with polycystic ovary syndrome from infancy to adulthood. J Clin Endo Metab 2008; 93: 3318-3324
  CrossrefPubMedGoogle Scholar
• 123 Recabarren SE, Rojas-García PP, Recabarren MP, Alfaro VH, Smith R, Padmanabhan V, Sir-Petermann T. Prenatal testosterone excess reduces sperm count and motility. Endocrinology 2008; 149: 6444-6448
  CrossrefPubMedGoogle Scholar
• 124 Rojas-García P, Recabarren MP, Palmer S, Tovar H, Gabler C, Einspanier R, Maliqueo M, Sir-Petermann T, Recabarren SE. Prenatal testosterone excess alters seminal and cellular characteristics in male sheep via its androgenic actions. Androgen Excess & PCO Society. 2010. Munich, Germany:
  Google Scholar
• 125 Rojas-García PP, Recabarren MP, Sarabia L, Schön J, Gabler C, Einspanier R, Maliqueo M, Sir-Petermann T, Rey R, Recabarren SE. Prenatal testosterone excess alters Sertoli and germ cell number and testicular FSH receptor expression in rams. Am J Physiol Endo Metab 2010; 299: E998-E1005
  PubMedGoogle Scholar