The document provides an overview of the pineal gland and melatonin's crucial role in regulating biological rhythms, particularly circadian cycles. It discusses how melatonin synthesis is influenced by light exposure and its various effects on physiological processes, including hormonal regulation and oncostatic actions. Additionally, the document addresses pathology related to melatonin levels and the potential implications for cancer risk, particularly in night shift workers.

1. PRESENTER: SHARLIN LANGAT
MS/SUR/6294/24
MODERATOR: DR. MAGUTAH
PINEAL GLAND AND THE ROLE
OF MELATONIN IN THE
BIOLOGICAL CLOCK

2. Pineal Gland (Epiphysis Cerebri)
• pine cone-shaped and about 0.8 cm long.
• unpaired gland in the midline between the thalamic bodies behind the habenular
commissure.
• It is located near the corpora quadrigemina, which is behind the third ventricle.
• Cerebrospinal fluid bathes the gland through the pineal recess.
• It is outside the blood-brain barrier

4. Pineal Gland
• The principal innervation is sympathetic, arising from the superior
cervical ganglia.
• Arterial vascularization of the pineal gland is supplied by both the
anterior and posterior circulation, being the main artery supplying the
lateral pineal artery, which originates from the posterior circulation.
• In mammals, the main cell types are pinealocytes (95%) followed by
scattered glial cells (astrocytic and phagocytic subtypes).
• Pinealocytes are responsible for the synthesis and secretion of
melatonin

5. Melatonin
• During the dark phase of the day, when
there is a major increase in the activity of
serotonin-N-acetyltransferase
(arylalkylamine N-acetyltransferase, AA-
NAT)
• Both availability of NE and serotonin are
stimulatory for melatonin synthesis.
Pathological, surgical or traumatic
sympathetic denervation of the pineal gland
or administration of β-adrenergic
antagonists abolishes the rhythmic
synthesis of melatonin and the light-dark
control of its production.

6. Melatonin
• Primary secretion of pinealocytes
• Targets:
• Hypothalamus Regulates circadian rythm
• Hypothalamo-Hypophyseal-Gonadal axis  suppress secretion of gonadotropins
(delay onset of puberty until the appropriate age)
• Melatonin exerts both non-receptor and receptor-mediated actions.
• Non-receptor-mediated actions are due to amphipathic properties (of both lipo-
and hydrophilic structure) that allows melatonin to freely cross the cell and
nuclear membranes.
• Antioxidant properties are one example of non-receptor-mediated actions of
melatonin.

7. Circadian Clock
A circadian rhythm is any
biological process that displays
an endogenous, entrainable
oscillation of 24 hours .
Consists of an Input, a clock
and an output.

9. Cortisol Melatonin Relationship

10. Input- Light/Dark
• In higher vertebrates, light is sensed by the inner retina (retinal
ganglion cells) that send neural signals to the visual areas of the brain.
• However, a few retinal ganglion cells contain melanopsin and have an
intrinsic photoreceptor capability that sends neural signals to non-
image forming areas of the brain, including the pineal gland, through
complex neuronal connections.

12. Clock-SCN
• This information is transduced into a neural message which is
transferred to the anterior hypothalamus via axons of retinal ganglion
cells in the optic nerve; this is part of the so-called retino-
hypothalamic tract.
• In the hypothalamus, the axons from the retina terminate in the
suprachiasmatic nuclei (SCN), a type of nucleus whose neurons
exhibit inherent circadian electrical rhythms; these nuclei constitute
the biological clock or the central circadian pacemaker.

13. Chronobiotic Effect
The central clock is located
in the SCN of the
hypothalamus and controls
pineal melatonin secretion
in the absence of light, while
melatonin also affects the
SCN, which regulates
chronobiotic activities. In
peripheral tissues, clock
genes are synchronized by
the SCN and are also
influenced by melatonin.

14. Melatonin secretion regulation: light/dark
• The photic information from the retina is sent to the suprachiasmatic
nucleus (SCN), the major rhythm-generating system or “clock” in
mammals, and from there to other hypothalamic areas.
• When the light signal is positive, the SCN secretes gamma-amino butyric
acid, responsible for the inhibition of the neurons that synapse in the
paraventricular nucleus (PVN) of the hypothalamus, consequently the
signal to the pineal gland is interrupted and melatonin is not synthesized.
• When there is no light (darkness), the SCN secretes glutamate,
responsible for the PVN transmission of the signal along the pathway to
the pineal gland.

15. Melatonin secretion regulation: light/dark
• In continuous darkness the SCN continues to generate rhythmic
output without light suppression since it functions as an endogenous
oscillator (master pacemaker or clock).
• The rhythm deviates from 24h and ‘free-runs’ in the absence of the
important light time cue. Light-dark cycles serve to synchronize the
rhythm to 24h.

16. Melatonin secretion regulation: sympathetic
• The PVN nucleus communicates with higher thoracic segments of the
spinal column, conveying information to the superior cervical ganglion
that transmits the final signal to the pineal gland through sympathetic
postsynaptic fibers by releasing norepinephrine (NE).
• NE is the trigger for the pinealocytes to produce melatonin by
activating the transcription of the mRNA encoding the enzyme
arylalkylamine N-acetyltransferase (AA-NAT), the first molecular step
for melatonin synthesis.

17. Melatonin secretion regulation: sympathetic

18. Melatonin secretion regulation: sympathetic

19. Melatonin Receptors
• MT1 is primarily expressed in the pars tuberalis, the SCN together with other
hypothalamic areas, pituitary, hippocampus, and adrenal glands, suggesting
that circadian and reproductive effects are mediated through this receptor.
• MT2 is mainly expressed in the SCN, retina, pituitary and the other brain
areas, and is associated with phase shifting.
• The affinity of melatonin is five-fold greater for MT1 than MT2.
• Melatonin administration induces an acute suppression of neuronal firing in
the SCN via the MT1 receptor, and a phase-shifting of SCN activity through the
MT2 receptor.
• Retinoid orphan receptors (ROR), members of the steroid receptor
superfamily, which are thought to be the nuclear receptor of melatonin [

20. Factor Effect(s) on melatonin Comment
Light Suppression >30 lux white 460-480 nm most effective
Light Phase-shift/ Synchronization Short wavelengths most effective
Sleep timing Phase-shift Partly secondary to light exposure
Posture ↑ standing (night)
Exercise ↑ phase shifts Hard exercise
ß-adrenoceptor-A ↓ synthesis Anti-hypertensives
5HT UI ↑ fluvoxamine Metabolic effect
NE UI ↑ change in timing Antidepressants
MAOA I ↑ may change phase Antidepressants
α-adrenoceptor-A ↓ alpha-1, ↑ alpha-2
Benzodiazepines Variable↓ diazepam, alprazolam GABA mechanisms
Testosterone ↓ Treatment
OC ↑
Estradiol ↓? Not clear
Menstrual cycle Inconsistent ↑ amenorrhea
Smoking Possible changes ↑↓ ?
Alcohol ↓ Dose dependent
Caffeine ↑ Delays clearance (exogenous)
Aspirin, Ibuprofen ↓
Chlorpromazine ↑ Metabolic effect
Benserazide Possible phase change, Parkinson patients Aromatic amino-acid decarboxylase-I

21. Melatonin metabolism in peripheral tissues
• Half life- 40 minutes
• Liver- 6 hydroxylation
• Excreted in urine
• Overall, women have slightly higher values of plasma melatonin at
night than men.
• On average, the maximum levels of plasma melatonin in adults occur
between 02.00 and 04.00 hours

22. Chronobiotic effects
• at the level of the SCN
• Properly timed melatonin administration shifts circadian rhythms,
facilitates re-entrainment to a novel light: dark cycle and alters the
metabolic activity of the central circadian pacemaker, i.e. the SCN.

23. Oncostatic effects
• melatonin acts on specific membrane receptors to limit the transport of
linoleic acid (LA), a growth factor, into tumour cells.
• With decreased LA uptake, intracellular 13-hydroxyoctadecadienoic acid
(13-HODE) levels drop; 13-HODE is a mitogenically active metabolite
that normally increases tumour cell proliferation via MAPK.
• modulate oestrogen receptor expression and transactivation.
• reduce angiogenesis in tumours, to delay the G1 to S phase transition in
the cell cycle, to improve cellular communication between normal and
cancer cells, and to alter the intracellular redox state.
• reducing free-radical-mediated damage to DNA.4

24. Immunostimulatory effects
• increases natural killer (NK) cell activity
• regulates gene expression of several immunomodulatory cytokines
including tumour necrosis factor-a (TNFa), transforming growth factor
beta (TGFb) and stem cell factor (SCF) by peritoneal macrophages as
well as the levels of interleukin-1beta (IL-1b), interferon gamma
(INFg), TNFa and SCF by splenocytes.
• rises in the thymic production of peptides including thymosin 1a and
thymulin.
• a potent inhibitor of apoptosis in immune cells

25. Antioxidant effects
• Highly effective scavenger
of free radicals and general
antioxidant
• Exposure to light during
the “biological night” can
suppress melatonin
production, and it is also
associated to a deleterious
effect on health (i.e.,
increased risk of cancer in
most epidemiology studies
in night shift workers).

26. A Narrative Review of the Carcinogenic Effect of Night Shift
and the Potential Protective Role of Melatonin by Elvina C.
Lingas
• Night-shift workers present a higher incidence of hormone-
dependent cancer which has been related to light-induced melatonin
suppression which consequently increases estrogen production.
• A 50% increased risk to develop breast cancer in nurses exposed to
rotating shift work has been documented.
• In contrast, a reduced risk for breast cancer was observed in blind
women, with potentially higher levels of melatonin throughout all day
(although there is no evidence that blind people produce more
melatonin than sighted people) However, the mechanisms by which
melatonin exerts any of oncostatic effects remains to be established

27. Melatonin Production During Development and Across Life
• At birth, melatonin levels are almost undetectable.
• A melatonin rhythm appears around 2 to 3 months of life levels increasing
exponentially until a lifetime peak on average in prepubertal children;
• Melatonin concentrations in children are associated with Tanner stages of puberty.
• Thereafter, a steady decrease occurs reaching mean adult concentrations in late
teens
• Values are stable until 35 to 40 years, followed by a decline in amplitude of
melatonin rhythm and lower levels with ageing, associated with fragmented sleep-
wake patterns.
• In people >90 years, melatonin levels are less than 20% of young adult
concentrations.
• reasons; calcification of the pineal gland starting early in life and an impairment in
the noradrenergic innervation to the gland or light detection capacity (ocular
mydriases, cataracts).

28. Pathology
• Hypomelatoninemia is more common, and it can be due to factors that
affect directly the pineal gland, innervation, melatonin synthesis as a result
of congenital disease; or secondary as a consequence of environmental
factors and/or medications (shift work, spinal cord cervical transection,
sympathectomy, aging, neurodegenerative diseases, genetic diseases, β-
blockers, calcium channel blockers, ACE inhibitors).
• Hypermelatoninemia is less common, and except for pharmacological
effects, few conditions have been associated with high melatonin
production: spontaneous hypothermia, hyperhidrosis syndrome, polycystic
ovary syndrome, hypogonadotropic hypogonadism, anorexia nervosa, and
Rabson-Mendenhall syndrome that induces pineal hyperplasia.

29. References
• Wang, L., Wang, C., & Choi, W. S. (2022). Use of melatonin in cancer treatment:
where are we?. International journal of molecular sciences, 23(7), 3779.
https://www.mdpi.com/1422-0067/23/7/3779.
• Talib, W. H., Alsayed, A. R., Abuawad, A., Daoud, S., & Mahmod, A. I. (2021).
Melatonin in cancer treatment: current knowledge and future
opportunities. Molecules, 26(9), 2506. https://www.mdpi.com/1420-3049/26/9/2506.
• Rodríguez-Santana, C., Florido, J., Martínez-Ruiz, L., López-Rodríguez, A., Acuña-
Castroviejo, D., & Escames, G. (2023). Role of melatonin in cancer: effect on clock
genes. International Journal of Molecular Sciences, 24(3), 1919.
https://www.mdpi.com/1422-0067/24/3/1919.
• Lingas, E. C. (2023). A narrative review of the carcinogenic effect of night shift and
the potential protective role of melatonin. Cureus, 15(8).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416670/.