Endocrinology, lecture on Hormones from the Brain
XXIX. Brain Hormones
A. Peripheral hormones effect the brain
1. Steroids and Thyroid hormones pass through the Blood-Brain-Barrier
2. Active uptake
a. tanycytes in the median eminence
i. deliver to CSF
3. de novo synthesis
a. monoamine hormones/neurotransmitters
i. indoleamines
(1) serotonin (5-HT) made in the brain is a neurotransmitter
(2) hormonal melatonin from the pineal
ii. catecholamines are neurotransmitters
b. neurosteroids
c. neuropeptides
B. Melatonin
1. synthesized from 5-HT in the pineal gland
æ5-HT-N-acetyltransferase ä æHIOMT (hydroxyindole-O-methyltransferase )ä
a. 5-HT ® N-acetyl 5-HT ® melatonin
b. the pineal is connected to a 3rd eye:
parietal eye in some vertebrates
i. fishes, amphibians, and some reptiles
have a photoreceptive pineal organ
ii. glandular pineal in birds and mammals
c. melatonin is also produced by the parietal eye
i. by the retina in the lateral eyes
ii. may be necessary for photoreception
d. production and release is circadian
i. daily pattern, even without exogenous cues
2. production and secretion of melatonin inhibited by light
a. photic information in mammals delivered via the lateral eyes,
suprachiasmatic nucleus, to the PVN, spinal cord and
superior cervical ganglion ® pineal
i. melatonin synthesis is stimulated by
a-adrenergic activation (NE)
b. pronounced diurnal rhythm
i. production and secretion stimulated by darkness
c. melatonin strongly affects and is affected by
endogenous biological rhythms
i. endogenous rhythms generated in mammals by
the suprachiasmatic nucleus
(1) circannual, circadian, and ultradian rhythms
ii. pineal melatonin may play a central role in the circadian
organization of fishes, lizards and some birds
(1) e.g. pinealectomy in house sparrows abolishes freely
running circadian rhythms of both locomotion and body To
(2) but pinealectomy in the Japanese quail does not
affect rhythms at all
3. Seasonal Affective Disorder and Depression
a. long nights, as in winter, stimulate more melatonin production
and is correlated with depression = SAD
b. treatment can be affected with strong lights in the morning
i. administration with melatonin in the evening
is not effective
(1) does not stimulate obvious endocrine changes
(2) makes people sleepy
(a) possible jet lag remedy
4. Reproduction
a. plays a role in regulating the GnRH pulse generator
i. an ultradian oscillator with frequency code
(1) may ¯ the amplitude or frequency of GnRH secretion
ii. affects sensitivity to steroid feedback
iii. regulation is seasonal
(i.e. affected by circannual rhythms)
b. seasonally breeding animals
i. melatonin signals change depending upon environmental lighting
(1) times reproductive cycles by adjustment to seasonal
photophase (daylength) and scotophase (darkness) changes
(a) winter = longer nights ® Ý melatonin
Ý melatonin® ¯ GnRH pulse frequency ®
® ¯ LH pulse frequency ® ¯ E2 for positive feedback
(b) melatonin stimulates reproduction in
short day breeders (e.g. deer, sheep)
c. puberty
i. melatonin levels are high in humans from ages 1 to 5,
and then decrease until puberty
ii. lesions of the pineal result in precocious puberty
(1) those with secretory pineal tumors exhibit delayed puberty
5. has an anti-MSH effect in fishes and amphibians
a. melatonin influences color change as in background adaptation
by controlling melanophore responses
b. melatonin decreases pituitary MSH in mammals as well
i. melatonin induces the differentiation of a winter/white
pelage in weasels
6. Thermoregulation
a. pineal involvement in body temperature regulation is more
readily demonstrated in more classes of vertebrates than
any other function of melatonin
b. hot and cold result in cytological changes in the pineal
(mammals + reptiles)
c. NAT + HIOMT activity change with temperature
(mammals, reptiles, amphibians)
d. removal of parietal eye in lizards elevates behaviorally selected Tob
i. pinealectomy lowers Tob
ii. melatonin injection lowers panting threshold
e. pinealectomy abolishes circadian Tob rhythms in sparrows
i. also results in abnormally high Tob
ii. hyperthermia may be reversed by melatonin
f. melatonin induces hyperthermia in rats, but hypothermia in mice
i. pinealectomy Ý Tob of sheep and rabbits, ¯ Tob of rats
ii. Brown adipose tissue may be regulated by the pineal
(1) catabolism of brown fat produces heat
(a) thermogenic response
(2) melatonin stimulates increased brown adipose tissue
(a) pinealectomy reduces brown fat reserve
h. hibernation
i. pineal may regulate cycles of Tob changes in hibernators
B. Neurosteroids
1. Steroids are accumulated in the brain from peripheral sources
and produced de novo
a. P450scc, 3b-HSD, 5a-reductase, 3a-oxidoreductase
present centrally in glia
2. Peripheral steroids bind to classical cytoplasmic/nuclear receptors
to activate genomic actions
a. especially immediate-early genes with products important for
neurochemical and endocrine function
i. code for G-proteins, receptors,
protein kinases, transcription factors...
3. Non-genomic actions
a. de novo central neurosteroids bind to
ionotropic receptors, especially GABAA
i. ligand-gated channels for ions (Cl-, Ca++)
b. allosteric modulators of ion influx
i. ionotropic receptors have multiple membrane spanning
subunits (usually 5) with
more than one ligand binding site
a. unique binding site for steroids
c. positive allosteric modulators of GABAA Cl- influx
i. THP = allopregnanolone
ii. THDOC = tetrahydrodeoxycorticosterone
(1) less potent: androsterone (from DHEA)
iii. result: neuronal inhibition
(1) reversible structural regression in hippocampus
(2) ratio between excitatory & inhibitory steroids
shape synaptic activity
iv. effects: anxiolytic, antiaggressive,
anesthetic, sedative, hypnotic
(1) blunted reaction to stimuli
(a) antisocial behavior, inclination to substance abuse?
d. negative allosteric modulators of GABAA Cl- influx
i. Preg-S = pregnenolone sulfate
(1) less potent : Preg
ii. DHEAS = dehydroepiandrosterone sulfate
(1) less potent: DHEA, androstenedione,
(2) binding site distinct from Preg-S,
close to barbiturate binding site
iii. positively modulate NMDAGlu-R Ca++ influx
(1) excitatory steroids
iv. effects: enhance neuronal and glial survival &
structural growth, neuronal differentiation, neuroprotective,
enhance memory, Ý anxiety, Ý basal CNS arousal
Ý convulsions, Ý seizures, Ý sedation threshold
(1) positive correlations with longevity, vigor,
resistance to cancer and cardiovascular diseases
e. specific G-protein mediated receptors
have been discovered for B, P & E2
C. Neuropeptides
1. Many peptide hormones are also secreted within the brain
to modulate neural actions
2. Classes of neuropeptides:
a. opiates: Met-enkephalon, Leu-enkephalon, b-endorphin, dynorphin
b. gut-brain: SP, VIP, CCK, NT, NPY, galanin, insulin, glucagon,
GRP/bombesin, gastrin, secretin, motilin
c. hypothalamic: CRH, GHRH, GnRH, TRH, somatostatin
i. neurohypophysial: AVP, Oxy
d. pituitary: ACTH, GH, LH, a-MSH, PrL, TSH
e. other: Ang2, ANP, CGRP, bradykinin
3. Functional roles (examples):
a. opiates: analgesic, anxiolytic, sedative
b. gut-brain: CCK is anxiogenic
SP ® pain transmission
c. hypothalamic:
CRF ® coordinates neural control of stress responses
TRH ® stimulant (antagonizes sedative drugs Ý arousal and locomotion )
i. neurohypophysial: AVP Ý learning, memory and aggression
(1) OT Ý sexual receptivity and behavior
+ parental behavior
d. pituitary: ACTH ® anxiogenic, depression
