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Table of Contents
Vol. 75, No. 5, 2002
Issue release date: May 2002
Neuroendocrinology 2002;75:296–305
(DOI:10.1159/000057339)

Sex Hormone Receptors Are Present in the Human Suprachiasmatic Nucleus

Kruijver F.P.M. · Swaab D.F.
Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Amsterdam, TheNetherlands

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Abstract

The suprachiasmatic nucleus (SCN) is the clock of the brain that orchestrates circadian and circannual biological rhythms, such as the rhythms of hormones, body temperature, sleep and mood. These rhythms are frequently disturbed in menopause and even more so in dementia and can be restored in postmenopausal women by sex hormone replacement therapy (SHRT). Although it seems clear, both from clinical and experimental studies, that sex hormones influence circadian rhythms, it is not known whether this is by a direct or an indirect effect on the SCN. Therefore, using immunocytochemistry in the present study, we investigated whether the human SCN expresses sex hormone receptors in 5 premenopausal women and 5 young men. SCN neurons appeared to contain estrogen receptor-α (ERα), estrogen receptor-β (ERβ) and progesterone receptors. Median ratings of ER immunoreactivity per individual and per gender group revealed a statistically significantly stronger nuclear ERα expression pattern in female SCN neurons (p < 0.05). No significant sexual dimorphic tendency was observed for nuclear ERβ (p > 0.1) and progesterone receptors (p > 0.7). These data seem to support previously reported functional and structural SCN differences in relation to sex and sexual orientation and indicate for the first time that estrogen and progesterone may act directly on neurons of the human biological clock. In addition, the present findings provide a potential neuroendocrine mechanism by which SHRT can act to improve or restore SCN-related rhythm disturbances, such as body temperature, sleep and mood.



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References

  1. Rusak B, Zucker I: Neural regulation of circadian rhythms. Physiol Rev 1979;59:449–526.

    External Resources

  2. Dai J, Swaab DF, van der Vliet J, Buijs RM: Postmortem tracing reveals the organization of hypothalamic projections of the suprachiasmatic nucleus in the human brain. J Comp Neurol 1998;400:87–102.
  3. Swaab DF, van Someren EJ, Zhou JN, Hofman MA: Biological rhythms in the human life cycle and their relationship to functional changes in the suprachiasmatic nucleus. Prog Brain Res 1996;111:349–368.
  4. Dai J, van der Vliet J, Swaab DF, Buijs RM: Human retinohypothalamic tract as revealed by in vitro postmortem tracing. J Comp Neurol 1998;397:357–370.
  5. Buijs RM, Kalsbeek A: Hypothalamic integration of central and peripheral clocks. Nat Rev Neurosci 2001;2:521–526.

    External Resources

  6. Van der Beek EM, Horvath TL, Wiegant VM, Van den Hurk R, Buijs RM: Evidence for a direct neuronal pathway from the suprachiasmatic nucleus to the gonadotropin-releasing hormone system: Combined tracing and light and electron microscopic immunocytochemical studies. J Comp Neurol 1997;384:569–579.
  7. Kalsbeek A, Fliers E, Franke AN, Wortel J, Buijs RM: Functional connections between the suprachiasmatic nucleus and the thyroid gland as revealed by lesioning and viral tracing techniques in the rat. Endocrinology 2000;141:3832–3841.

    External Resources

  8. Scheer FA, Ter Horst GJ, van der Vliet J, Buijs RM: Physiological and anatomic evidence for regulation of the heart by suprachiasmatic nucleus in rats. Am J Physiol Heart Circ Physiol 2001;280:H1391–H1399.

    External Resources

  9. Dijk DJ, Czeisler CA: Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526–3538.
  10. Swaab DF: Biological rhythms in health and disease: The suprachiasmatic nucleus and the autonomic nervous system; in Appenzeller O (ed): Handbook of Clinical Neurology. Amsterdam, Elsevier Science, 1999, pp 467–521.
  11. Eastman CI, Young MA, Fogg LF, Liu L, Meaden PM: Bright light treatment of winter depression: A placebo-controlled trial. Arch Gen Psychiatry 1998;55:883–889.
  12. Swaab DF, Fliers E, Hoogendijk WJ, Veltman DJ, Zhou JN: Interaction of prefrontal cortical and hypothalamic systems in the pathogenesis of depression. Prog Brain Res 2000;126:369–396.
  13. Buijs RM, Wortel J, van Heerikhuize JJ, Feenstra MG, Ter Horst GJ, Romijn HJ, Kalsbeek A: Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 1999;11:1535–1544.
  14. Freedman RR, Norton D, Woodward S, Cornelissen G: Core body temperature and circadian rhythm of hot flashes in menopausal women. J Clin Endocrinol Metab 1995;80:2354–2358.
  15. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG: A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351–358.

    External Resources

  16. Dell DL, Stewart DE: Menopause and mood. Is depression linked with hormone changes? Postgrad Med 2000;108:34–36, 39–43.
  17. Seeman TE, Singer B, Wilkinson CW, McEwen B: Gender differences in age-related changes in HPA axis reactivity. Psychoneuroendocrinology 2001;26:225–240.

    External Resources

  18. Sherwin BB, Gelfand MM: Sex steroids and affect in the surgical menopause: A double-blind, cross-over study. Psychoneuroendocrinology 1985;10:325–335.
  19. Wiklund I, Berg G, Hammar M, Karlberg J, Lindgren R, Sandin K: Long-term effect of transdermal hormonal therapy on aspects of quality of life in postmenopausal women. Maturitas 1992;14:225–236.
  20. Polo-Kantola P, Erkkola R, Helenius H, Irjala K, Polo O: When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol 1998;178:1002–1009.
  21. Brooks EM, Morgan AL, Pierzga JM, Wladkowski SL, O’Gorman JT, Derr JA, Kenney WL: Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women. J Appl Physiol 1997;83:477–484.
  22. Halbreich U: Role of estrogen in postmenopausal depression. Neurology 1997;48:S16–S19.
  23. Gudmundsson A, Goodman B, Lent S, Barczi S, Grace A, Boyle L, Ershler WB, Carnes M: Effects of estrogen replacement therapy on the circadian rhythms of serum cortisol and body temperature in postmenopausal women. Exp Gerontol 1999;34:809–818.
  24. Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R: Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996;348:429–432.
  25. Duff SJ, Hampson E: A beneficial effect of estrogen on working memory in postmenopausal women taking hormone replacement therapy. Horm Behav 2000;38:262–276.

    External Resources

  26. Westendorp IC, in’t Veld BA, Grobbee DE, Pols HA, Meijer WT, Hofman A, Witteman JC: Hormone replacement therapy and peripheral arterial disease: The Rotterdam study. Arch Intern Med 2000;160:2498–2502.
  27. Cummings SR, Browner WS, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B: Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1998;339:733–738.
  28. Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H: Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 1998;352:1965–1969.
  29. Garcia-Segura LM, Azcoitia I, DonCarlos LL: Neuroprotection by estradiol. Prog Neurobiol 2001;63:29–60.

    External Resources

  30. Morin LP, Fitzgerald KM, Zucker I: Estradiol shortens the period of hamster circadian rhythms. Science 1977;196:305–307.
  31. Albers HE: Gonadal hormones organize and modulate the circadian system of the rat. Am J Physiol 1981;241:R62–66.

    External Resources

  32. Le Blond CB, Morris S, Karakiulakis G, Powell R, Thomas PJ: Development of sexual dimorphism in the suprachiasmatic nucleus of the rat. J Endocrinol 1982;95:137–145.
  33. Shinohara K, Funabashi T, Mitushima D, Kimura F: Effects of estrogen on the expression of connexin32 and connexin43 mRNAs in the suprachiasmatic nucleus of female rats. Neurosci Lett 2000;286:107–110.
  34. Jechura TJ, Walsh JM, Lee TM: Testicular hormones modulate circadian rhythms of the diurnal rodent, octodon degus. Horm Behav 2000;38:243–249.

    External Resources

  35. Shughrue PJ, Lane MV, Merchenthaler I: Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 1997;388:507–525.
  36. Laflamme N, Nappi RE, Drolet G, Labrie C, Rivest S: Expression and neuropeptidergic characterization of estrogen receptors (ERalpha and ERbeta) throughout the rat brain: Anatomical evidence of distinct roles of each subtype. J Neurobiol 1998;36:357–378.
  37. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996;93:5925–5930.
  38. Mosselman S, Polman J, Dijkema R: ER beta: Identification and characterization of a novel human estrogen receptor. FEBS Lett 1996;392:49–53.
  39. Bevitt DJ, Milton ID, Piggot N, Henry L, Carter MJ, Toms GL, Lennard TW, Westley B, Angus B, Horne CH: New monoclonal antibodies to oestrogen and progesterone receptors effective for paraffin section immunohistochemistry. J Pathol 1997;183:228–232.
  40. Fernandez-Guasti A, Kruijver FP, Fodor M, Swaab DF: Sex differences in the distribution of androgen receptors in the human hypothalamus. J Comp Neurol 2000;425:422–435.
  41. Kruijver FP, Zhou JN, Pool CW, Hofman MA, Gooren LJ, Swaab DF: Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endocrinol Metab 2000;85:2034–2041.
  42. Kruijver FP, Fernandez-Guasti A, Fodor M, Kraan EM, Swaab DF: Sex differences in androgen receptors of the human mamillary bodies are related to endocrine status rather than to sexual orientation or transsexuality. J Clin Endocrinol Metab 2001;86:818–827.
  43. Ishunina TA, Kruijver FP, Balesar R, Swaab DF: Differential expression of estrogen receptor alpha and beta immunoreactivity in the human supraoptic nucleus in relation to sex and aging. J Clin Endocrinol Metab 2000;85:3283–3291.

    External Resources

  44. Snijders MP, de Goeij AF, Koudstaal J, Thunnissen EB, de Haan J, Bosman FT: Oestrogen and progesterone receptor immunocytochemistry in human hyperplastic and neoplastic endometrium. J Pathol 1992;166:171–177.
  45. Mai JK, Assheuer J, Paxinos G: Atlas of the Human Brain. San Diego, Academic Press, 1997, p 162.
  46. Greenblatt RB, Nezhat C, Roesel RA, Natrajan PK: Update on the male and female climateric. J Am Geriatr Soc 1979;27:481–490.

    External Resources

  47. Sternbach H: Age-associated testosterone decline in men: Clinical issues for psychiatry. Am J Psychiatry 1998;155:1310–1318.
  48. Seidman SN, Walsh BT: Testosterone and depression in ageing men. Am J Geriatr Psychiatry 1999;7:18–33.

    External Resources

  49. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA: Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682–688.
  50. Charkoudian N, Johnson JM: Modification of active cutaneous vasodilation by oral contraceptive hormones. J Appl Physiol 1997;83:2012–2018.
  51. Silva NL, Boulant JA: Effects of testosterone, estradiol, and temperature on neurons in preoptic tissue slices. Am J Physiol 1986;250:R625–R632.

    External Resources

  52. Palm IF, Van der Beek EM, Wiegant VM, Buijs RM, Kalsbeek A: Vasopressin induces a luteinizing hormone surge in ovariectomized, estradiol-treated rats with lesions of the suprachiasmatic nucleus. Neuroscience 1999;93:659–666.
  53. Zhou JN, Riemersma RF, Unmehopa UA, Hoogendijk WJ, van Heerikhuize JJ, Hofman MA, Swaab DF: Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression. Arch Gen Psychiatry 2001;58:655–662.

    External Resources

  54. Warner P, Bancroft J: Mood, sexuality, oral contraceptives and the menstrual cycle. J Psychosom Res 1988;32:417–427.
  55. Driver HS, Dijk DJ, Werth E, Biedermann K, Borbely AA: Sleep and the sleep electroencephalogram across the menstrual cycle in young healthy women. J Clin Endocrinol Metab 1996;81:728–735.
  56. Van Goozen SH, Wiegant VM, Endert E, Helmond FA, Van de Poll NE: Psychoendocrinological assessment of the menstrual cycle: The relationship between hormones, sexuality, and mood. Arch Sex Behav 1997;26:359–382.

    External Resources

  57. Campbell SS, Gillin JC, Kripke DF, Erikson P, Clopton P: Gender differences in the circadian temperature rhythms of healthy elderly subjects: Relationships to sleep quality. Sleep 1989;12:529–536.

    External Resources

  58. Moe KE, Prinz PN, Vitiello MV, Marks AL, Larsen LH: Healthy elderly women and men have different entrained circadian temperature rhythms. J Am Geriatr Soc 1991;39:383–387.
  59. Ticher A, Sackett-Lundeen L, Ashkenazi IE, Haus E: Human circadian time structure in subjects of different gender and age. Chronobiol Int 1994;11:349–355.
  60. Swaab DF, Fliers E, Partiman TS: The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res 1985;342:37–44.
  61. Swaab DF, Zhou JN, Ehlhart T, Hofman MA: Development of vasoactive intestinal polypeptide neurons in the human suprachiasmatic nucleus in relation to birth and sex. Dev Brain Res 1994;79:249–259.
  62. Zhou JN, Hofman MA, Swaab DF: VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiol Aging 1995;16:571–576.

    External Resources

  63. Swaab DF, Slob AK, Houtsmuller EJ, Brand T, Zhou JN: Increased number of vasopressin neurons in the suprachiasmatic nucleus (SCN) of ‘bisexual’ adult male rats following perinatal treatment with the aromatase blocker ATD. Dev Brain Res 1995;85:273–279.

    External Resources

  64. Swaab DF, Hofman MA: An enlarged suprachiasmatic nucleus in homosexual men. Brain Res 1990;537:141–148.
  65. Nakamura TJ, Shinohara K, Funabashi T, Kimura F: Effect of estrogen on the expression of Cry1 and Cry2 mRNAs in the suprachiasmatic nucleus of female rats. Neurosci Res 2001;41:251–255.

    External Resources

  66. Axelson JF, Van Leeuwen FW: Differential localization of estrogen receptors in various vasopressin synthesizing nuclei of the rat brain. J Neuroendocrinol 1990;2:209–216.
  67. Simerly RB, Chang C, Muramatsu M, Swanson LW: 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.
  68. Su JD, Qiu J, Zhong YP, Chen YZ: Expression of estrogen receptor-alpha and -beta immunoreactivity in the cultured neonatal suprachiasmatic nucleus: With special attention to GABAergic neurons. Neuroreport 2001;12:1955–1959.
  69. Goldsmith PC, Boggan JE, Thind KK: Estrogen and progesterone receptor expression in neuroendocrine and related neurons of the pubertal female monkey hypothalamus. Neuroendocrinology 1997;65:325–334.

    External Resources

  70. Dabbs JM Jr: Age and seasonal variation in serum testosterone concentration among men. Chronobiol Int 1990;7:245–249.

    External Resources

  71. Juneja HS, Karanth S, Dutt A, Parte P, Meherjee P: Diurnal variations and temporal coupling of bioactive and immunoactive luteinizing hormone, prolactin, testosterone and 17-beta-estradiol in adult men. Horm Res 1991;35:89–94.

    External Resources

  72. Panico S, Pisani P, Muti P, Recchione C, Cavalleri A, Totis A, Berrino F: Diurnal variation of testosterone and estradiol: A source of bias in comparative studies on breast cancer. J Endocrinol Invest 1990;13:423–426.
  73. Touitou Y, Haus E: Biological rhythms and ageing; in Touitou Y, Haus E (eds): Biologic Rhythms in Clinical and Laboratory Medicine. Budapest, Springer, 1992, pp 188–207.
  74. Nilsson K, Heimer G: Endogenous estrogen levels in postmenopausal women with severe urogenital atrophy. Gynecol Obstet Invest 1992;34:234–236.
  75. Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno A: Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol secretion before the onset of female puberty in short children. J Clin Endocrinol Metab 2000;85:1074–1080.
  76. Hofman MA, Swaab DF: Alterations in circadian rhythmicity of the vasopressin-producing neurons of the human suprachiasmatic nucleus (SCN) with aging. Brain Res 1994;651:134–142.
  77. Hofman MA, Swaab DF: Influence of aging on the seasonal rhythm of the vasopressin-expressing neurons in the human suprachiasmatic nucleus. Neurobiol Aging 1995;16:965–971.

    External Resources

  78. Baehr EK, Revelle W, Eastman CI: Individual differences in the phase and amplitude of the human circadian temperature rhythm: With an emphasis on morningness-eveningness. J Sleep Res 2000;9:117–127.
  79. Dabbs JM Jr: Salivary testosterone measurements: Reliability across hours, days, and weeks. Physiol Behav 1990;48:83–86.
  80. Wise PM, Krajnak KM, Kashon ML: Menopause: the aging of multiple pacemakers. Science 1996;273:67–70.
  81. Manly JJ, Merchant CA, Jacobs DM, Small SA, Bell K, Ferin M, Mayeux R: Endogenous estrogen levels and Alzheimer’s disease among postmenopausal women. Neurology 2000;54:833–837.
  82. Liu RY, Zhou JN, Hoogendijk WJ, van Heerikhuize J, Kamphorst W, Unmehopa UA, Hofman MA, Swaab DF: Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression. J Neuropathol Exp Neurol 2000;59:314–322.
  83. Stopa EG, Volicer L, Kuo-Leblanc V, Harper D, Lathi D, Tate B, Satlin A: Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J Neuropathol Exp Neurol 1999;58:29–39.
  84. Satlin A, Volicer L, Stopa EG, Harper D: Circadian locomotor activity and core-body temperature rhythms in Alzheimer’s disease. Neurobiol Aging 1995;16:765–771.

    External Resources

  85. van Someren EJ: Circadian and sleep disturbances in the elderly. Exp Gerontol 2000;35:1229–1237.
  86. Prinz P, Bailey S, Moe K, Wilkinson C, Scanlan J: Urinary free cortisol and sleep under baseline and stressed conditions in healthy senior women: Effects of estrogen replacement therapy. J Sleep Res 2001;10:19–26.

    External Resources

  87. Carlson LE, Sherwin BB, Chertkow HM: Relationships between mood and estradiol (E2) levels in Alzheimer’s disease (AD) patients. J Gerontol B Psychol Sci Soc Sci 2000;55:P47–53.

    External Resources

  88. Mercuro G, Zoncu S, Piano D, Pilia I, Lao A, Melis GB, Cherchi A: Estradiol-17beta reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension. Am J Hypertens 1998;11:909–913.
  89. Goncharuk V, van Heerikhuize J, Dai J, Swaab D, Buijs R: Neuropeptide changes in the suprachiasmatic nucleus in primary hypertension indicate functional impairment of the biological clock. J Comp Neurol 2001;431:320–330.


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