Abstract
Purpose
Obstructive sleep apnea (OSA) is associated with a variety of neuroendocrine disorders and may lead to many complications, including cognitive dysfunction. The aim of this study was to assess the change of somatotropic axis and to detect the relation between somatotropic axis hormone and cognitive dysfunction.
Methods
Sixty-six patients with OSA and 16 healthy controls were enrolled in this cross-sectional study. Cognitive function assessment using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) and polysomnography were performed on all individuals. Blood samples were taken the next morning following the polysomnography and the level of serum growth hormone-releasing hormone (GHRH) and growth hormone (GH) were analyzed by enzyme-linked immunosorbent assay.
Results
Compared with the control group, OSA patients showed significantly lower serum GH level (p < 0.05), whereas no statistical significance of GHRH level was found. In addition, lower MMSE and MoCA scores were found only in the severe OSA patients when compared with the controls. Furthermore, in severe OSA patients with cognitive dysfunction (MMSE score < 27 and MoCA score < 26), serum GHRH and GH levels were significantly lower than those without cognitive dysfunction. Logistic analysis revealed that cognitive dysfunction in severe OSA patients was associated with micro-arousal index and the level of serum GHRH and GH.
Conclusion
Decreased serum GH and GHRH levels were found among severe OSA patients with cognitive dysfunction who were overweight, which might promote the occurrence of cognitive dysfunction.
References
Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG (2017) Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American Academy of Sleep medicine clinical practice guideline. J Clin Sleep Med 13(3):479–504
Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM (2013) Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 177(9):1006–1014
Liu CL, Wu CS (2017) Assessing whether the association between sleep apnea and diabetes is bidirectional. Can J Diabetes 41(2):197–203
Brenner R, Kivity S, Peker M, Reinhorn D, Keinan-Boker L, Silverman B (2019) Increased risk for cancer in young patients with severe obstructive sleep apnea. Respiration 97(1):15–23
Qi Q, Wang W, Shen H, Qin Z, Wang L, Xu JH et al (2019) The influence of excessive daytime sleepiness and sleep quality on anxiety and depression in patients with obstructive sleep apnea hypopnea syndrome. Zhonghua Nei Ke Za Zhi 58(2):119–124
Kim JS, Kim S, Lee SH, Lee HY, Lee SY, Im KB (2018) Increased risk of ischemic stroke during sleep in apneic patients. J Clin Neurol 14(2):174–178
Bucks RS, Olaithe M, Eastwood P (2013) Neurocognitive function in obstructive sleep apnoea: a meta-review. Respirology 18(1):61–70
Chang WP, Liu ME, Chang WC, Yang AC, Ku YC, Pai JT, Huang HL, Tsai SJ (2013) Sleep apnea and the risk of dementia: a population-based 5-year follow-up study in Taiwan. PLoS One 8:e78655
Sartorio A, Conti A, Molinari E, Riva G, Morabito F, Faglia G (1996) Growth, growth hormone and cognitive functions. Horm Res 45(1–2):23–29
Devesa J, Núñez I, Agra C, Bejarano A, Devesa P (2018) Treatment with growth hormone (GH) increased the metabolic activity of the brain in an elder patient, not GH-deficient, who suffered mild cognitive alterations and had an ApoE 4/3 genotype. Int J Mol Sci 19(8):E2294
Ong LK, Chow WZ, TeBay C, Kluge M, Pietrogrande G, Zalewska K et al (2018) Growth hormone improves cognitive function after experimental stroke. Stroke 49(5):1257–1266
Winston CN, Goetzl EJ, Baker LD, Vitiello MV, Rissman RA (2018) Growth hormone-releasing hormone modulation of neuronal exosome biomarkers in mild cognitive impairment. J Alzheimers Dis 66(3):971–981
Leone S, Recinella L, Chiavaroli A, Ferrante C, Orlando G, Vacca M, Salvatori R, Brunetti L (2018) Behavioural phenotyping, learning and memory in young and aged growth hormone-releasing hormone-knockout mice. Endocr Connect 7(8):924–931
Liao F, Zhang TJ, Mahan TE, Jiang H, Holtzman DM (2015) Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model. Brain Behav Immun 47:163–171
Baker LD, Barsness SM, Borson S, Merriam GR, Friedman SD, Craft S, Vitiello MV (2012) Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol 69(11):1420–1429
Banks WA, Morley JE, Farr SA, Price TO, Ercal N, Vidaurre I et al (2010) Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice. Proc Natl Acad Sci U S A 107:22272–22277
Elbornsson M, Horvath A, Götherström G, Bengtsson BÅ, Johannsson G, Svensson J (2017) Seven years of growth hormone (GH) replacement improves quality of life in hypopituitary patients with adult-onset GH deficiency. Eur J Endocrinol 176(2):99–109
Shin DH, Lee E, Kim JW, Kwon BS, Jung MK, Jee YH, Kim J, Bae SR, Chang YP (2004) Protective effect of growth hormone on neuronal apoptosis after hypoxia-ischemia in the neonatal rat brain. Neurosci Lett 354:64–68
Mu L, Peng L, Zhang Z, Jie J, Jia S, Yuan H (2017) Memory and executive screening for the detection of cognitive impairment in obstructive sleep apnea. Am J Med Sci 354(4):399–407
Feng XW, Kang J, Wang ZF, Wang QY, Yu RJ (2006) Regulation of hypothalamus-pituitary-adrenal axis and growth hormone axis in obstructive sleep apnea-hypopnea syndrome patients. Zhonghua Jie He He Hu Xi Za Zhi 29(4):230–232
Wang LJ (2016) Determination of level of serum osteocalcin and growth hormone and its relationship with height and weight of children with adenoid hyperplasia. Jilin University
Peng LL, LI JR, Sun JJ, Li WY, Sun YM, Zhang R et al (2011) Reliability and validity of the simplified Chinese version of Epworth sleepiness scale. Chin J Otorhinolaryngol Head Neck Surg 46(1):44–49
Liu XC, Tang MQ, Hu L (1996) Reliability and validity of the Pittsburgh sleep quality index. Chin J Psychiatry 29(1):103–107
Sun YC, Qin B (2011) The application of Chinese MoCA and MMSE in mild cognitive impairment. Chin J Neuroimmunol Neurol 8(2):91–93+97
Folstein MF, Robins LN, Helzer JE (1983) The mini-mental state examination. Arch Gen Psychiatry 40:812
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I et al (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53(4):695–699
(1999) Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 22(5):667–689
Rechtschaffen A, Kales A (1968) A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Government printing office, Washington, D.C
Yetkin O, Aydogan D (2018) Effect of CPAP on sleep spindles in patients with OSA. Respir Physiol Neurobiol 247:71–73
Cai C, Ahmad T, Valencia GB, Aranda JV, Xu J, Beharry KD (2018) Intermittent hypoxia suppression of growth hormone and insulin-like growth factor-I in the neonatal rat liver. Growth Hormon IGF Res 41:54–63
Van Cauter E, Leproult R, Plat L (2000) Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 284(7):861–868
Weigent DA (2013) Hypoxia and cytoplasmic alkalinization upregulate growth hormone expression in lymphocytes. Cell Immunol 282(1):9–16
Nair D, Ramesh V, Li RC, Schally AV, Gozal D (2013) Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse. J Neurochem 127(4):531–540
Li RC, Guo SZ, Raccurt M, Moudilou E, Morel G, Brittian KR, Gozal D (2011) Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats. Neuroscience 196:237–250
Nair D, Zhang SX, Ramesh V, Hakim F, Kaushal N, Wang Y et al (2011) Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse. Am J Respir Crit Care Med 184(11):1305–1312
Ramesh V, Nair D, Zhang SX, Hakim F, Kaushal N, Kayali F et al (2012) Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway. J Neuroinflammation 9:91
Gozal D, Sans Capdevila O, McLaughlin Crabtree V, Serpero LD, Witcher LA, Kheirandish-Gozal L (2009) Plasma IGF-1 levels and cognitive dysfunction in children with obstructive sleep apnea. Sleep Med 10(2):167–173
Zhang H, Han M, Zhang X, Sun X, Ling F (2014) The effect and mechanism of growth hormone replacement on cognitive function in rats with traumatic brain injury. PLoS One 9(9):e108518
Chen A, Xiong LJ, Tong Y, Mao M (2013) The neuroprotective roles of BDNF in hypoxic ischemic brain injury. Biomed Rep 1(2):167–176
Portero-Tresserra M, Martí-Nicolovius M, Tarrés-Gatius M, Candalija A, Guillazo-Blanch G, Vale-Martínez A (2018) Intra-hippocampal D-cycloserine rescues decreased social memory, spatial learning reversal, and synaptophysin levels in aged rats. Psychopharmacology 235(5):1463–1477
Park H, Popescu A, Poo MM (2014) Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP. Neuron 84(5):1009–1022
Zhang FX, Sun QJ, Zheng XY, Lin YT, Shang W, Wang AH, Duan RS, Chi ZF (2014) Abnormal expression of synaptophysin, SNAP-25, and synaptotagmin 1 in the hippocampus of kainic acid-exposed rats with behavioral deficits. Cell Mol Neurobiol 34(6):813–824
Wang B, Jin X, Kuang X, Tian S (2017) Chronic administration of parecoxib exerts anxiolytic-like and memory enhancing effects and modulates synaptophysin expression in mice. BMC Anesthesiol 17(1):152
Dayyat EA, Zhang SX, Wang Y, Cheng ZJ, Gozal D (2012) Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea. BMC Neurosci 13:77
Hu A, Yuan H, Wu L, Chen R, Chen Q, Zhang T, Wang Z, Liu P, Zhu X (2016) The effect of constitutive over-expression of insulin-like growth factor 1 on the cognitive function in aged mice. Brain Res 1631:204–213
Bonnet MH, Doghramji K, Roehrs T, Stepanski EJ, Sheldon SH, Walters AS et al (2007) The scoring of arousal in sleep: reliability, validity, and alternatives. J Clin Sleep Med 3(2):133–145
Hoedlmoser K, Heib DP, Roell J, Peigneux P, Sadeh A, Gruber G et al (2014) Slow sleep spindle activity, declarative memory, and general cognitive abilities in children. Sleep 37(9):1501–1512
Gorgoni M, Lauri G, Truglia I, Cordone S, Sarasso S, Scarpelli S et al (2016) Parietal fast sleep spindle density decrease in Alzheimer’s disease and amnesic mild cognitive impairment. Neural Plast 2016:8376108
Hoyos CM, Killick R, Keenan DM, Baxter RC, Veldhuis JD, Liu PY (2014) Continuous positive airway pressure increases pulsatile growth hormone secretion and circulating insulin-like growth factor-1 in a time-dependent manner in men with obstructive sleep apnea: a randomized sham-controlled study. Sleep 37(4):733–741
Acknowledgments
X-JH: study design, data analysis, manuscript drafting, and final approval of the version to be published. L-WY, QZ, L-XM, SH: in charge of the process of enzyme-linked immunosorbent assay and patient collection and critical manuscript revision. WW: study design, data interpretation, critical manuscript revision, and final approval of the version to be published.
Funding
This study was funded by the National Natural Science Foundation of China (81670085) and the Distinguished Professor of Liaoning Province (Liao Jiao Fa [2015] No. 153).
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Xu, J., Qin, Z., Li, W. et al. Effects of somatotropic axis on cognitive dysfunction of obstructive sleep apnea. Sleep Breath 24, 175–182 (2020). https://doi.org/10.1007/s11325-019-01854-y
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DOI: https://doi.org/10.1007/s11325-019-01854-y