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Sleep Endocrine Physiology

• Most neuroendocrine secretions
Changes in • Rhythmic pulsatile fashion

Endocrine secretions
• Behavioral
during sleep • Environmental
• Endogenous timing system

Sleep Endocrine Physiology

Schematic
representation of
the central
mechanisms
involved in the
control of temporal
variations in
pituitary hormone
secretions over a
24-hour cycle

Melatonin
• Robust circadian rhythmicity
• with low level during the biological day
• high level during the biological night
• The best-known and most-studied physiological function regulated by
the SCN via the autonomic nervous system
• Dysfunction of the pathway abolishes rhythmic production

https://www.neurology.org/content/71/8/594/extract

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Melatonin
• Plays an important role of human sleep regulation
• Exogenous administration can decrease sleep latency Sack et al., 1997; Sharkey et al., 2001

• Exogenous melatonin induces specific changes in the spectral composition of

the sleep EEG Dijk et al., 1997;,Knoblauch et al., 2003; Aeschbach et al., 2009

• Pharmacological suppression of nocturnal melatonin (with beta-blocker) DLMO

increases total wake time during a sleep opportunity
van den Heuvel et al., 1997

• Chronobiotic effects on SCN

• Circadian phase marker
Vanecek et al. 1987; Williams and Morgan, 1988

From Wyatt JK, Stepanski EJ, Kirkby J: Circadian phase in delayed sleep phase syndrome:
predictors and temporal stability across multiple assessments. Sleep 2006;29:1075–1080

Cortisol Strong Circadian

Rhythmicity

• The ACTH-cortisol rhythm is mainly controlled by circadian

rhythmicity but clearly modulated by the sleep-wake state.
• Sleep onset is associated with a decrease in cortisol secretion, but
with a rapid elevation in the later part of the sleep at night and with
subsequent decline throughout the day.
• Daytime sleep fails to significantly inhibit cortisol secretion,
suggesting that sleep suppresses cortisol release only within a limited
range of entrainment.
• Sleep fragmentation is associated with pulsatile increase in cortisol
secretion
Modifed from Van Cauter E, Spiegel K: Circadian and sleep control of
hormonal secretions. In Zee PC, Turek FW [eds]: Regulation of sleep and circadian
rhythms, vol 133 of Lung biology in health and disease [Lenfant C, series ed], New
York: Marcel Dekker, 1999, pp. 397–426.

Thyroid Stimulating Hormone

Increased level
• TSH levels are low during the daytime, increase rapidly in the early without slow
wave sleep
evening, peak shortly before sleep onset, and are followed by a
progressive decline during sleep.
• Sleep deprivation is associated with nocturnal rise of TSH levels.
• TSH secretion is not suppressed significantly during daytime sleep,
but sleep-related inhibition of TSH secretion occurs following
nighttime elevation of TSH.

Modifed from Van Cauter E, Spiegel K: Circadian and sleep control of

hormonal secretions. In Zee PC, Turek FW [eds]: Regulation of sleep and circadian
rhythms, vol 133 of Lung biology in health and disease [Lenfant C, series ed], New
York: Marcel Dekker, 1999, pp. 397–426.

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Growth Hormone Strong Sleep-

Wake
Homeostasis
Regulation
• Two-thirds of GH secretion during sleep is associated with SWS.
• The sleep-related release of GH is reduced in old age, and there is no
sleep-related release of GH before the age of 3 months.
• GH secretion occurs shortly after sleep onset during SWS and is
inhibited during awakenings and sleep fragmentation.
• Age-related decrements in GH secretion play a major role in the
hyposomatotropism of senescence.
Van Cauter E, Plat L (1996) Physiology of growth hormone
secretion during sleep. J Pediatr 128:S32

Modifed from Van Cauter E, Spiegel K: Circadian and sleep control of

hormonal secretions. In Zee PC, Turek FW [eds]: Regulation of sleep and circadian
rhythms, vol 133 of Lung biology in health and disease [Lenfant C, series ed], New
York: Marcel Dekker, 1999, pp. 397–426.

Prolactin
Sleep-related
• The pulsatile plasma prolactin (PRL) secretion is sleep dependent but Regulation
is not related to any specific sleep stage
• The PRL secretion shows a rise about 60 - 90 min after sleep onset
and peaks in the early morning hours around 5 - 7 AM.
• It is notable that the secretory pattern of prolactin does not decline
with age, unlike that of GH.

Modifed from Van Cauter E, Spiegel K: Circadian and sleep control of

hormonal secretions. In Zee PC, Turek FW [eds]: Regulation of sleep and circadian
rhythms, vol 133 of Lung biology in health and disease [Lenfant C, series ed], New
York: Marcel Dekker, 1999, pp. 397–426.

Mean (+SEM)
hormonal profiles
Glucose Regulation and Hunger
obtained in a
protocol • The levels of glucose and insulin secretion rate increased during
designed to sleep, returned to baseline in the morning, then gradually increased
delineate the during the day.
respective • During daytime sleep, glucose and insulin also increased suggesting a
contributions of circadian effect
the circadian
rhythmicity and
the sleep-wake
homeostasis

Modifed from Van Cauter E, Spiegel K: Circadian and sleep control of

hormonal secretions. In Zee PC, Turek FW [eds]: Regulation of sleep and circadian
rhythms, vol 133 of Lung biology in health and disease [Lenfant C, series ed], New
York: Marcel Dekker, 1999, pp. 397–426.

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Glucose Regulation and Hunger

• Leptin, a satiety hormone produced by fat cells, and Ghrelin, a hunger
hormone produced by gastric cells, demonstrate diurnal variation.
Mean (+SEM) profiles of • The 24-hour variation in Leptin levels depends on when meals are taken;
glucose and insulin • low in the morning
secretion in a group of • increase gradually during the day
normal young men • highest at night
• Ghrelin is also high at night. During the daytime, levels decrease after
eating, then increase in anticipation of the next meal

(Modifed from Van Cauter E, Blackman JD, Roland D, et al:

Modulation of glucose regulation by circadian rhythmicity and
sleep. J Clin Invest 1991;88:934–942.)

Relationship Between Sleep and Ghrelin, Leptin, and Cholecystokinin (CCK):

Plasma and Hypothalamic Levels

Atlas of Clinical Sleep Medicine, Kryger, Second Edition : Biology of sleep. Page 60 Atlas of Clinical Sleep Medicine, Kryger, Second Edition : Biology of sleep. Page 57

GnRH, LH and FSH Renin-Angiotensin-Aldosterone Activity

• There has not been a clear relationship between LH and FSH plasma • Plasma renin activity (PRA) is synchronized with the NREM-REM
levels and the sleep-wake cycle or sleep stages, nor any distinct cycles in an ultradian rhythm
circadian rhythms. • higher values during NREM sleep
• Plasma testosterone levels show an increase at sleep onset and are • lowest values during REM sleep
consistent with the sleep-associated rise of LH levels in normal men. • Sleep-related aldosterone levels are related to PRA oscillations,
• In women, sleep-related inhibitory effect on LH secretion has been whereas during daytime wakefulness, aldosterone levels parallel
found in the early parts of the follicular and luteal phases of the cortisol pulses.
menstrual cycle.

Brandenberger G, Follenius M, Muzet A et al (1985)

Ultradian oscillations in plasma renin activity: their relationships to meals and sleep stages. J Clin Endocrinol Metab 61:280

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REM Sleep
Renin-Angiotensin-Aldosterone Activity
• No demonstration of circadian rhythm in the levels of plasma or urine
angiotensinogen
• No specific study examined the hormone circadian expression
• Angiotensin II and aldosterone both display a circadian rhythm in
plasma/serum concentrations, peaking in the morning and reaching a
nadir at night J.G. Johnston, D.M. Pollock.
Free Radical Biology and Medicine 119 (2018) 93–107

• Antidiuretic hormone (ADH) shows episodic secretion without any

relationship to sleep, sleep stages, or circadian system; however,
seems to increase during the second half of the night
Avidan, Alon Y.. Review of Sleep Medicine E-Book (Kindle Location 4153). Elsevier Health Sciences. Kindle Edition.

Modified from Brandenberger G, Follenius M, Muzet A et al (1985)

Ultradian oscillations in plasma renin activity: their relationships to meals
and sleep stages. J Clin Endocrinol Metab 61:280

Esophageal function
• Gastroesophageal reflux (GER) may be exacerbated by sleep through
Changes in the various mechanisms
•
Alimentary system •
Swallowing frequency
Saliva flow
• Esophageal peristalsis
during sleep • Esophageal sphincters

• The majority of postprandial transient relaxations are associated with

brief periods of UES relaxations.

Avidan, Alon Y.. Review of Sleep Medicine E-Book (Kindle

Locations 4231-4232). Elsevier Health Sciences. Kindle Edition.

Gastric acid secretion and gastric motility Intestinal motility

• A special pattern of motor activity, called migrating motor complex (MMC),
recurs every 90 min in the stomach and small intestine
• Peak gastric acid secretion is at
• Similar to but not correlated to cyclic REM-NREM sleep
between 10:00 P.M. and 2:00 A.M.
• Circadian rhythmicity
• The oscillation of gastric acid secretion
▪ Slowest velocity during sleep
has been controlled mainly by vagal ▪ Shorter in both cycle length and duration
nerve stimulation • During sleep, colonic motility in the transverse, descending,
• ?? Ultradian rhythm and sigmoid colon decrease
• No definite statement regarding gastric • Increased periodic rectal motor activity during sleep
motility • Retrograde fashion
• Prevent passive leakage of rectal contents
• Anal sphincter tone is constantly higher than rectal pressure
Moore JG, Halberg F (1986) Circadian rhythm of gastric acid Chokroverty S. Physiological changes of sleep. In: Chokroverty S, editor.
secretion in men with active duodenal ulcer. Dig Dis Sci 31:1185 Sleep Disorder Medicine 4th ed. 2017. 175-6

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Physiologic Changes During Normal Wakefulness and Sleep in the Gastrointestinal System
Physiologic states Wakefulness Sleep

Swallowing frequency Normal Decreased

Changes in the
Salivary flow Normal Decreased
Esophageal acid clearance time Normal Prolonged
Lower and upper esophageal sphincter pressure
Esophageal peristaltic contraction
Normal
Normal
Decreased
Decreased Genitourinary system
Gastric motility Normal Decreased
Gastric secretion Depends on food Peak between during sleep
ingestion 10pm-2am
Migratory motor complex (MMC) Normal velocity Reduced velocity
Colonic motility Normal Decreased
Rectal motor activity and anal periodic canal pressure Normal Increased activity with
propagation and
higher anal canal
pressure
Avidan, Alon Y.. Review of Sleep Medicine E-Book (Kindle Locations 4199-4200). Elsevier Health Sciences. Kindle Edition.

Glomerular filtration rate

• Multiple studies have shown evidence of circadian variation in
glomerular function rate which reaches a maximum during the day, Urine output as a function
peaking around 2–3 p.m., and a minimum in the middle of the night of time in
• In healthy young people, nighttime urine output is lower than healthy young (black line)
daytime output and older (red line) adults
• Fluid intake studied in constant
• Posture conditions.
• Hormonal changes
• RAAS
• AVP
• ANP

J.G. Johnston, D.M. Pollock.

Joanne F Duffy. Et al. Curr Aging Sci.
Free Radical Biology and Medicine 119 (2018) 93–107
2016 ; 9(1): 34–43

“Nocturia”
• “Nocturia” is defined as
“requiring >1 void per night to meet the criteria of nocturia”
(recently waking 1 or more times during the night to void)
only becomes clinically relevant when it causes comorbidities or
bother for the patient
• A common cause of sleep disruption in older people
• <5% in young adults and about half of those in their 60’s
• Non-gender specific problem
• Can lead to other health problems eg. falling, depression, reduce QoL Obstructive
• Remains an underreported, undertreated and poorly managed medical and Sleep Apnea
social problem

Oalke M. et al. Int J Clin Pract. 2017;71:e13027

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Genital organ
• Sleep-related penile erections occur in all age groups
• Overall, small age-related decline is noted for total
tumescence time, but there is little or no age-related decline
in maximum circumference increase and number of erection Thermoregulation
episodes
• Similar tumescence occurs in the clitoris, associated with
during sleep
increased vaginal blood flow and uterine contractility during
REM sleep in women.

Avidan, Alon Y.. Review of Sleep Medicine E-Book (Kindle Locations 4289-4293).
Elsevier Health Sciences. Kindle Edition

Core body temperature

• While body temperature is linked to the sleep-wake cycle, it has its
own distinct and independent circadian rhythm.
• Body temperature follows a sinusoidal rhythm with a peak around 9
PM and a minimum (nadir) around 5 am as a result of circadian
rhythmicity
• The core temperature nadir occurs 2-3 hours before habitual wake
time
• Crucial importance in the detection and treatment of circadian rhythm
disorders

Physiologicalweb.com
Harding EC et al. Front. Neurosci. 2019 13:336

Core body temperature

• Reduced body temperature and peripheral heat loss promote sleep onset
and enhance SWS, and sleep in turn causes a further decrease in body Immune Function and
temperature and increases heat loss, thus consolidating sleep.
• Thermoregulatory neurons – medial preoptic anterior hypothalamus Cytokines
promotes heat dissipation
• Cutaneous vasodilation
• Panting
during sleep
• Suppression of shivering
• Thermoregulatory homeostasis is lost during REM sleep
• No sweat
• No pant

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Pflugers Arch - Eur J Physiol (2012) 463:121–137

Immune regulation
• Sleep is thought to act as a host defense against infection and
facilitates healing process.
• Sleep supports the initiation of an adaptive immune response, in
particular slow wave sleep (SWS).
• Pro-inflammatory hormonal milieu with enhanced growth hormone
and prolactin release as well as reduced levels of the anti-
inflammatory stress hormone cortisol support the early steps in the
generation of an adaptive immune response in the lymph nodes

Pflugers Arch - Eur J Physiol (2012) 463:121–137

Cytokines and sleep

• Leukocyte-produced cytokines such as interleukin (IL), interferon-
alpha, and tumor necrosis factor-alpha (TNF-α) promote sleep.
• Cytokines play an important role in the pathogenesis of excessive
daytime sleepiness in a variety of sleep disorders and in sleep
deprivation.

Pflugers Arch - Eur J Physiol (2012) 463:121–137

Atlas of Clinical Sleep Medicine, Kryger, Second Edition : Normal sleep. page 43 Atlas of Clinical Sleep Medicine, Kryger, Second Edition : Normal sleep. page 43

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Take home messages
• Neuroendocrine secretions and sleep are tightly linked, and hence
sleep disturbances may result in the disruption of the endocrine
functions. A disturbance of the link between GH secretion and SWS
may impair somatotropism in patients with sleep disorders.
• Sleep is a highly vulnerable time for patients with GERD because of
decreased swallowing and salivation, as well as decreased esophageal
peristaltic waves causing prolonged acid clearance.
• Body temperature is strongly linked to the sleep-wake cycle, however,
it has its own distinct and independent circadian rhythm.
Thank you
for
attention
If you have any question, please send them to Somprasong.l@hotmail.com
7/21/2021
Take home messages
• Since the thermoregulatory mechanism is inoperative during REM
sleep, thermoregulatory homeostasis is lost. Thus thermoregulatory
responses such as sweating and panting, which are noted in NREM
sleep, are absent in REM sleep.
• Sleep promotes host defense against infection (bacterial, viral, and
fungal infections enhance NREM but suppress REM sleep) and
facilitates the healing process. Sleep deprivation or disorders may
impair immune regulation leading to a variety of diseases.