A closed literature-based discovery technique finds a mechanistic link between hypogonadism and diminished sleep quality in aging men.

STUDY OBJECTIVES Sleep quality commonly diminishes with age, and, further, aging men often exhibit a wider range of sleep pathologies than women. We used a freely available, web-based discovery technique (Semantic MEDLINE) supported by semantic relationships to automatically extract information from MEDLINE titles and abstracts. DESIGN We assumed that testosterone is associated with sleep (the A-C relationship in the paradigm) and looked for a mechanism to explain this association (B explanatory link) as a potential or partial mechanism underpinning the etiology of eroded sleep quality in aging men. MEASUREMENTS AND RESULTS Review of full-text papers in critical nodes discovered in this manner resulted in the proposal that testosterone enhances sleep by inhibiting cortisol. Using this discovery method, we posit, and could confirm as a novel hypothesis, cortisol as part of a mechanistic link elucidating the observed correlation between decreased testosterone in aging men and diminished sleep quality. CONCLUSIONS This approach is publically available and useful not only in this manner but also to generate from the literature alternative explanatory models for observed experimental results.

[1]  T F Gallagher,et al.  Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. , 1971, The Journal of clinical endocrinology and metabolism.

[2]  H. P. Krieger,et al.  Characterization of the normal temporal pattern of plasma corticosteroid levels. , 1971, The Journal of clinical endocrinology and metabolism.

[3]  Y. Hishikawa,et al.  Circadian rhythm of serum testosterone and its relation to sleep: comparison with the variation in serum luteinizing hormone, prolactin, and cortisol in normal men. , 1980, The Journal of clinical endocrinology and metabolism.

[4]  J. Palmblad,et al.  Adrenocortical and gonadal steroids during sleep deprivation. , 1980, Sleep.

[5]  H. Roffwarg,et al.  Plasma Testosterone and Sleep: Relationship to Sleep Stage Variables , 1982, Psychosomatic medicine.

[6]  V. Cortes-gallegos,et al.  Sleep deprivation reduces circulating androgens in healthy men. , 1983, Archives of andrology.

[7]  J. C. Zimmerman,et al.  Cortisol secretion is inhibited during sleep in normal man. , 1983, The Journal of clinical endocrinology and metabolism.

[8]  S. Yen,et al.  Acute suppression of circulating testosterone levels by cortisol in men. , 1983, The Journal of clinical endocrinology and metabolism.

[9]  D. Swanson Fish Oil, Raynaud's Syndrome, and Undiscovered Public Knowledge , 2015, Perspectives in biology and medicine.

[10]  D. Swanson Migraine and Magnesium: Eleven Neglected Connections , 2015, Perspectives in biology and medicine.

[11]  B. Kemp,et al.  Ambulatory Monitoring of Sleep‐Wakefulness Patterns in Healthy Elderly Males and Females (>88 Years): The “Senieur” Protocol , 1992 .

[12]  Alexa T. McCray,et al.  Representing biomedical knowledge in the UMLS semantic network , 1993 .

[13]  E. Leibenluft,et al.  Effects of leuprolide-induced hypogonadism and testosterone replacement on sleep, melatonin, and prolactin secretion in men. , 1997, The Journal of clinical endocrinology and metabolism.

[14]  S. Markovic,et al.  Neuroendocrine responses following graded traumatic brain injury in male adults. , 1999, Brain injury.

[15]  K. Häkkinen,et al.  Effects of heavy-resistance training on hormonal response patterns in younger vs. older men. , 1999, Journal of applied physiology.

[16]  D. Purdie,et al.  Effects of sex steroids on sleep. , 1999, Annals of medicine.

[17]  P. Lavie,et al.  The association between melatonin and sleep stages in normal adults and hypogonadal men. , 1999, Sleep.

[18]  Marc Weeber,et al.  Text-based discovery in biomedicine: the architecture of the DAD-system , 2000, AMIA.

[19]  Storey,et al.  Hormonal correlates of paternal responsiveness in new and expectant fathers. , 2000, Evolution and human behavior : official journal of the Human Behavior and Evolution Society.

[20]  E. van Cauter,et al.  Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. , 2000, JAMA.

[21]  J. Tihanyi,et al.  Hormonal responses to whole-body vibration in men , 2000, European Journal of Applied Physiology.

[22]  J M Overhage,et al.  Text-based discovery in biomedicine , 2000 .

[23]  P. Lavie,et al.  Disruption of the nocturnal testosterone rhythm by sleep fragmentation in normal men. , 2001, The Journal of clinical endocrinology and metabolism.

[24]  E. Bixler,et al.  Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: clinical implications. , 2001, The Journal of clinical endocrinology and metabolism.

[25]  G. Chrousos,et al.  Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. , 2002, Endocrinology and metabolism clinics of North America.

[26]  Marcelo Fiszman,et al.  The interaction of domain knowledge and linguistic structure in natural language processing: interpreting hypernymic propositions in biomedical text , 2003, J. Biomed. Informatics.

[27]  P. Herer,et al.  Middle-aged men secrete less testosterone at night than young healthy men. , 2003, The Journal of clinical endocrinology and metabolism.

[28]  David Handelsman,et al.  The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. , 2003, The Journal of clinical endocrinology and metabolism.

[29]  Olivier Bodenreider,et al.  The Unified Medical Language System (UMLS): integrating biomedical terminology , 2004, Nucleic Acids Res..

[30]  M. Opp,et al.  A corticotropin-releasing hormone antisense oligodeoxynucleotide reduces spontaneous waking in the rat , 2004, Regulatory Peptides.

[31]  A. Schatzberg,et al.  On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. , 2005, The Journal of clinical endocrinology and metabolism.

[32]  C. Marmar,et al.  Hypothalamic–Pituitary–Adrenal Axis Activity and Sleep in Posttraumatic Stress Disorder , 2005, Neuropsychopharmacology.

[33]  T. Åkerstedt,et al.  Effects of acutely displaced sleep on testosterone. , 2005, The Journal of clinical endocrinology and metabolism.

[34]  R. Gitau,et al.  Fetal plasma testosterone correlates positively with cortisol , 2005, Archives of Disease in Childhood - Fetal and Neonatal Edition.

[35]  D. Rubinow,et al.  Testosterone Suppression of CRH-Stimulated Cortisol in Men , 2005, Neuropsychopharmacology.

[36]  S. Tufik,et al.  Endocrinological and catecholaminergic alterations during sleep deprivation and recovery in male rats , 2005, Journal of sleep research.

[37]  F. Turek Gender (sex) and sleep: shh. . . not in front of the children. , 2006, Sleep.

[38]  Bin Zhang,et al.  Sex differences in insomnia: a meta-analysis. , 2006, Sleep.

[39]  Carol Friedman,et al.  Exploiting Semantic Relations for Literature-Based Discovery , 2006, AMIA.

[40]  Short‐term fasting leads to inhibition of responsiveness to LH‐stimulated testosterone secretion in the adult male bonnet monkey , 2007, American journal of primatology.

[41]  N. Rogers,et al.  SLEEP AND METABOLIC CONTROL: WAKING TO A PROBLEM? , 2007, Clinical and experimental pharmacology & physiology.

[42]  O. Bottasso,et al.  Endocrine and cytokine responses in humans with pulmonary tuberculosis , 2007, Brain, Behavior, and Immunity.

[43]  C. Iadecola,et al.  Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress. , 2007, American journal of physiology. Endocrinology and metabolism.

[44]  P. Penev Association between sleep and morning testosterone levels in older men. , 2007, Sleep.

[45]  M. Visser,et al.  The relationship between cortisol, muscle mass and muscle strength in older persons and the role of genetic variations in the glucocorticoid receptor , 2008, Clinical endocrinology.

[46]  Thuy-Tien L. Dam,et al.  The association of testosterone levels with overall sleep quality, sleep architecture, and sleep-disordered breathing. , 2008, The Journal of clinical endocrinology and metabolism.

[47]  J. Krueger The role of cytokines in sleep regulation. , 2008, Current pharmaceutical design.

[48]  J. Espiritu,et al.  Aging-related sleep changes. , 2008, Clinics in geriatric medicine.

[49]  M. Kryger,et al.  Influence of sex on sleep regulatory mechanisms. , 2008, Journal of women's health.

[50]  S. Tufik,et al.  The effects of testosterone on sleep and sleep-disordered breathing in men: its bidirectional interaction with erectile function. , 2008, Sleep medicine reviews.

[51]  F. Turek,et al.  Reproductive hormone replacement alters sleep in mice , 2009, Neuroscience Letters.

[52]  O. Bottasso,et al.  Immunoendocrine Alterations during Human Tuberculosis as an Integrated View of Disease Pathology , 2009, Neuroimmunomodulation.

[53]  Sonia Ancoli-Israel,et al.  Sleep Disorders in the Older Adult – A Mini-Review , 2009, Gerontology.

[54]  Fred W. Turek,et al.  The ability of stress to alter sleep in mice is sensitive to reproductive hormones , 2009, Brain Research.

[55]  S L Lightman,et al.  A Glucocorticoid Sensitive Biphasic Rhythm of Testosterone Secretion , 2009, Journal of neuroendocrinology.

[56]  Phil Evans,et al.  The cortisol awakening response: More than a measure of HPA axis function , 2010, Neuroscience & Biobehavioral Reviews.

[57]  C. Kirschbaum,et al.  Identifying patterns in cortisol secretion in an older population. Findings from the Whitehall II study , 2010, Psychoneuroendocrinology.

[58]  V. H. Goh,et al.  Sleep, sex steroid hormones, sexual activities, and aging in Asian men. , 2010, Journal of andrology.

[59]  J. Sorkin,et al.  Effects of testosterone administration on nocturnal cortisol secretion in healthy older men. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.