sign in sign up
<<
Home , Endocrine system

Copyright EMAP Publishing 2021 This article is not for distribution except for journal club use

Clinical Practice Keywords Endocrine system/ /Pineal / gland Systems of This article has been Endocrine system double-blind peer reviewed In this article... ● Endocrine functions of the pineal and thymus ● Hormones secreted by the pineal and thymus glands ● Role of the pineal and thymus glands in mediating essential physiological processes

Endocrine system 5: the function of the pineal and thymus glands

Key points Authors John Knight is associate professor in biomedical science; Zubeyde Bayram- The is Weston is senior lecturer in biomedical science; Maria Andrade is honorary associate a neuroendocrine professor in biomedical science; all at College of and Health Sciences, gland in the brain, Swansea University. which produces the Abstract The endocrine system consists of glands and tissues that produce and secrete hormones to regulate and coordinate vital bodily functions. This article, the Melatonin is key to fifth in an eight-part series on the endocrine system, explores the and synchronising the of the pineal and thymus glands, and describes how they regulate and body’s biological coordinate vital physiological processes in the body through hormonal action. rhythms and has an influence on Citation Knight J et al (2021) Endocrine system 5: pineal and thymus glands. immunity Nursing Times [online]; 117: 9, 54-58.

The thymus has both immune and he endocrine system comprises with a rich blood flow of around 4ml/ endocrine functions, glands and tissues that produce min/g, second only to that of the kidneys. and produces hormones to regulate and coor- Unlike most other brain components, the hormones that are Tdinate vital bodily functions. pineal gland is found outside of the neuro- essential to normal This fifth article in an eight-part series protective blood brain barrier (Chlubek immune function examines the anatomy, physiology and and Sikora, 2020). It increases in size function of the pineal and thymus glands. throughout early childhood and becomes An association Two of the smallest endocrine glands, fully developed at around age 5 to 7 years between the these are known to undergo significant (Patel et al, 2020). activities of the age-associated changes that influence Histologically, 95% of the cells of the thymus and pineal human physiology. pineal gland are the , the rest glands has led to the are supporting cells (Ibañez Rodriguez et postulation of a Pineal gland: location and histology al, 2016). The primary role of pinealocytes thymus–pineal axis The pineal gland, also known as the pineal is to synthesise and secrete the chronobi- body, is a neuroendocrine gland found otic hormone melatonin, which plays a key The pineal and towards the centre of the brain. It is located role in synchronising the body’s biological thymus glands both medially between the two cerebral hemi- rhythms. Structurally, pinealocytes are undergo significant spheres (Fig 1) and is attached to the rear of believed to be related to the photosensitive age-associated the third ventricle by a small pineal stalk. rods and cones of the retina; although, in changes thought The term ‘pineal’ refers to the structure , they only have an indirect to be associated of the gland, which often resembles a pine response to light, as detected at the retina, with declining cone. However, there is much variation in through a series of complex neural path- physiological shape, with many human pineal glands ways (Zhao et al, 2019). function and disease being pea-shaped or fusiform (tapering at Pinealocytes take up the essential both ends) (Afroz et al, 2014). The average tryptophan, which is adult pineal gland is a tiny brown struc- enzymatically converted into the neuro- ture, typically 5-8mm long, that weighs transmitter serotonin and then into mela- around 150mg. It is highly vascularised, tonin (Fig 2).

Nursing Times [online] September 2021 / Vol 117 Issue 9 54 www.nursingtimes.net Copyright EMAP Publishing 2021 This article is not for distribution except for journal club use Clinical Practice Systems of life

Fig 1. Location of the pineal gland

Cerebral hemisphere

Corpus callosum

Thalamus (enclosus third ventiricle) Pineal gland (part of ) Optic chiasma Cerebral aqueduct Fourth ventricle Cerebellum

Pons

Medulla oblongata

The as The major trigger for melatonin release is usually corresponds to the period of circadian clock reduced light, with neural output from the deepest . As light gradually returns, Melatonin secretion is governed by light SCN stimulating the pineal gland via sym- levels decrease again, with secretion usu- levels perceived by the retina. Action poten- pathetic originating in the superior ally ceasing around 8am. tials ( impulses) generated from ret- cervical ganglion in the neck (Fig 3). The inal rods and cones are relayed to the visual SCN establishes the basic circadian Role of melatonin cortex of the brain via the optic nerves. rhythms that influence many physiological Initially, melatonin is released into the These cross over each other at the optic processes, including the sleep/wake cycle, densely arranged local blood vessels of the chiasm (Fig 3), above which is a specialised body temperature, and pineal gland and the cerebrospinal fluid of collection of around 10,000 called appetite (Douma and Gumz, 2018). the third ventricle; it then enters the gen- the suprachiasmatic nucleus (SCN). Melatonin secretion tends to begin at eral circulation and is distributed systemi- The SCN is a vital part of the hypothal- night, around two hours before sleep (typi- cally around the body (Zisapel, 2018). It is amus and functions as the body’s biolog- cally around 10pm); it maximises in the also synthesised and released from a wide ical clock (circadian master clock). Neurons early hours of the morning (between 2am range of other human organs, tissues and in the SCN have an inherent 24-hour and 4am), with plasma concentrations cells, including the retina, marrow, rhythm synchronised to cues in light inten- typically reaching 80-150 picograms (pg)/ , platelets, skin and gastroin- sity detected by the retina (Challet, 2015). ml (Chlubek and Sikora, 2020). This testinal tract (Tordjman et al, 2017).

Fig 2. Biosynthesis of melatonin

L-tryptophan 5-hydroxytryptophan Serotonin

Melatonin N-acetylserotonin JENNIFER N.R. SMITH JENNIFER

Nursing Times [online] September 2021 / Vol 117 Issue 9 55 www.nursingtimes.net Copyright EMAP Publishing 2021 This article is not for distribution except for journal club use Clinical Practice Systems of life

Fig 3. Melatonin release in response to reduced light

Pineal gland Melatonin O HN

O HN

Inhibition

Day (Light period)

Stimulation Night (Dark period) Right retina Left retina Suprachiasmatic nucleus (SCN)

Suprachiasmatic Superior cervical Optic chiasm nucleus ganglion

Melatonin circulates in the plasma and, around one in three people in the UK (Bit. the mitochondria, where cellular respira- like most hormones, exerts its effects by ly/NHSInformInsomnia). Melatonin has tion can generate large quantities of free binding to specific receptors. These are been shown to be a non-addictive sub- radicals capable of damaging mitochon- widespread throughout the ; stance of therapeutic value in treating drial DNA and potentially causing genetic few tissues are thought to be devoid of patients experiencing insomnia. Exoge- mutation (Cipolla-Neto and Amaral, 2018). melatonin receptors (Emet et al, 2016; nous melatonin prolongs sleep, improves Omar and Saba, 2010). sleep efficiency, enhances sleep quality Age-associated changes of the and subsequently, when awake, improves pineal gland Sleep/wake cycle functional performance and mental acuity The absence of a blood–brain barrier It has long been established that melatonin (Grima et al 2017). allows the pineal gland to freely accumu- is an important regulator of sleep in The blue light emitted from the screens late minerals, such as , and trace diurnal species such as humans. Sleep, of electronic devices (such as TVs, com- elements, including zinc, cobalt, fluoride which accounts for around a third of our puters and mobile phones) is known to sup- and selenium (Chlubek and Sikora, 2020). , is recognised as a highly orchestrated press melatonin biosynthesis and secretion. The progressive accumulation of minerals neurochemical process, involving both Exposure to such displays for at least leads to the formation of and sleep-promoting regions of 30 minutes before sleep is associated with (‘brain sand’). Eventually, these mineral the brain that are influenced by a variety of increased sleep latency, poor sleep quality, aggregates enlarge to form pineal concre- chemical signals and cues (Zisapel, 2018). sleep disruption and increased daytime tions up to 1mm in size; this usually leads It is essential to both physical and psycho- sleepiness (Rafique et al, 2020). Reducing to a gradual hardening as the pineal gland logical health, and facilitates a significant blue-light exposure, particularly in the progressively becomes calcified with age reduction in external sensory input while evening before going to bed, has been dem- (Sergina et al 2018). Pineal calcification is simultaneously allowing unconscious: onstrated to improve sleep quality readily visible on X-ray and is of use clini- ● Processing of information acquired (Shechter et al, 2018) and some devices have cally as an anatomical landmark during while awake; settings or apps to restrict the amount of various forms of brain imaging. ● Consolidation of memories; blue light emitted. Spectacles with blue- Calcification of the pineal gland is rare in ● Clearance of potentially harmful light filters are also available, which can infancy, being found in only around 1% of metabolites from neural tissues. effectively block the amount of blue light children under the age of 6 years; however, The exact mechanisms by which mela- reaching the retina, thereby enhancing it quickly rises to around 39% between the tonin influences sleep remain unclear, but melatonin release (Pateras, 2020). ages of 8-14 years (Doyle and Anderson, it is recognised that it reduces sleep latency 2006). As calcification progresses, the (time taken to fall asleep), while improving Antioxidant volume of active pineal decreases and sleep quality and duration, and reducing Melatonin is a powerful antioxidant, acting the secretion of melatonin is reduced. This fragmented sleep (Grima et al, 2017). as an efficient scavenger of free radicals is thought to, at least partially, explain age- (for example, superoxide anions) that associated changes to sleep patterns such as Insomnia and sleep disruption could, otherwise, inflict significant cellular poor-quality sleep and insomnia (Song, Insomnia, defined as a difficulty in falling damage and denature and nucleic 2019). More worryingly, melatonin is recog-

JENNIFER N.R. SMITH JENNIFER or staying asleep, is estimated to affect acids. This is of particular importance in nised as an important neuroprotective

Nursing Times [online] September 2021 / Vol 117 Issue 9 56 www.nursingtimes.net Copyright EMAP Publishing 2021 This article is not for distribution except for journal club use Clinical Practice Systems of life

agent and extensive pineal calcification and (T cells) mature before being released into essential to normal immune function reduced melatonin secretion has been asso- the general circulation. T cells play many because they facilitate development and ciated with an increased risk of neurode- diverse immune roles in specific immunity. maturation of T cells in the thymic folli- generative disorders, particularly Alzhei- Most famously, they function as ‘T-helper’ cles. This ensures competent, functional mer’s disease (Tan et al, 2018). cells, helping B lymphocytes to produce T cells are released into the circulation Cysts (usually benign fluid-filled sacs) antibodies that mark out pathogens for where they can participate in effective are present in around 25-40% of pineal subsequent destruction. Other populations immune responses. Thymic hormones are glands (Gheban et al, 2019). Most are small of T cells include suppressor T cells, which used therapeutically to treat many infec- and asymptomatic, and usually only dis- dampen down immune responses, and tions, malignancies and certain autoim- covered during brain imaging. Cysts that cytoxic T cells, which target and destroy mune diseases (Severa et al, 2019). reach larger sizes of between 7mm and malignant and virally infected cells. 4cm may become symptomatic but, fortu- The thymus gland also helps pro- Thymic involution nately, are rare. Occasionally, large pineal gramme immune cells to recognise ‘self’ The thymus gland progressively atrophies cysts can weaken blood vessels, potentially antigens (the body’s own antigens) via a (shrinks) with age. Before , it is rel- resulting in sudden death through intra- process termed ‘thymic education’; this is atively large, weighing around 40g. By cystic haemorrhage (Gheban et al, 2019). essential to minimise the body’s immune 20 years of age, however, it is typically 50% responses against its own cells and tissues, smaller than at birth and, by the age of Thymus gland which could otherwise lead to autoim- 60 years, it is around a sixth of its original The thymus is a small, delicate bilobed mune disease (Nigam and Knight, 2020). size (Bilder, 2016). This progressive atrophy gland located below the manubrium is referred to as thymic involution and is (upper portion of the ). It is usu- Endocrine function thought to be associated with immunose- ally pinkish grey and resides in the medi- Internally, each lobule of the thymus con- nescence, as the aged thymus releases astinum (space between the ) resting sists of multiple follicles, composed of a fewer T cells into the circulation (Rezzani on the superior portion of the (Fig 4). framework of epithelial cells and a popula- et al, 2020). Immunosenescence is a major The gland is protected by a thin outer cap- tion of T cells in varying states of matura- feature of ageing and results in declining sule and each lobe is composed of multiple tion. The thymus gland secretes a range of immune responses, which can increase the lobules of around 2-3mm held together by hormones synthesised by the risk of infections and malignancies. loose connective tissue (Nigam and thymic epithelial cells, including thy- Knight, 2020). mulin, , thymic humoral Melatonin and immune responses The thymus is a primary lymphoid factor and (Rezzani et al, 2020). Melatonin is known to have a stimulatory recognised as having both immune The exact mechanisms by which thymic effect on both non-specific (innate) immu- and endocrine functions. Its major immune hormones exert their effects remain poorly nity and specific immune responses. role is to act as the site where T lymphocytes understood, but they are known to be Reduced melatonin secretion leads to a

Fig 4. Thymus gland

Thymus gland gland

Right lobe Left lobe

Septae

Lobule JENNIFER N.R. SMITH JENNIFER

Nursing Times [online] September 2021 / Vol 117 Issue 9 57 www.nursingtimes.net Copyright EMAP Publishing 2021 This article is not for distribution except for journal club use Clinical Practice Systems of life

immunity is frequently referred to as the e0167063. “Melatonin appears to be so Kajdaniuk D et al (1999) Oncostatic effect of immune–pineal axis (Markus et al, 2018). melatonin action - facts and hypotheses Medical effective in inhibiting the Science Monitor; 5: 2, RA350-356. proliferation of certain Melatonin and malignancy Markus RP et al (2018) Immune-pineal axis – acute The positive effect of melatonin on NK-cell inflammatory responses coordinate melatonin tumour cells that the pineal synthesis by pinealocytes and phagocytes. British numbers is thought to contribute to its Journal of ; 175: 16, 3239-3250. gland has been routinely ability to enhance immune responses Nigam Y, Knight J (2020) The 2: referred to as an ‘oncostatic against a wide range of malignancies. Mel- structure and function of the lymphoid organs. Nursing Times [online]; 116: 11, 44-48. organ’” atonin is reported to inhibit the growth Omar SH, Saba N (2010) Melatonin, receptors, and spread of several tumour cell lines, mechanism, and uses. Systematic Reviews in progressive decrease in the weights of the including those associated with melanoma Pharmacy; 1: 2, 158-171. Patel S et al (2020) Revisiting the pineal gland: a and thymus gland, and a decrease and ovarian, , , colorectal and review of calcification, masses, precocious puberty, in the numbers of circulating lympho- (Vinther and Claesson, and melatonin functions. International Journal of cytes. Most of these negative immunolog- 2015). Indeed, melatonin appears to be so Neuroscience; 130: 5, 464-475. Pateras E (2020) Blue light blocking ophthalmic ical effects are reversed by administration effective in inhibiting the proliferation of lenses and their benefits: a review. Journal of of exogenous melatonin (Carrillo-Vico et certain tumour cells that the pineal gland Materials Science Research and Reviews; 5: 3, 13-20. al, 2005). has been routinely referred to as an ‘oncos- Rafique N et al (2020) Effects of mobile use on subjective sleep quality. Nature and Science of Melatonin ‘upregulates’ many aspects tatic organ’ (Kajdaniuk et al, 1999). Sleep; 12: 357–364. of non-specific immunity, including: Exogenous melatonin is also a useful Rezzani R et al (2020) Thymus-pineal gland ● Increasing haematopoiesis adjunct to many forms of radiotherapy axis: revisiting its role in human life and ageing. International Journal of Molecular Sciences; 21: (manufacture of blood cells); and chemotherapy; it not only enhances 22, 8806. ● Elevating numbers of -fighting the effectiveness of the treatment, but also Sergina SN et al (2018) [Taxonomic and ethnical natural killer (NK) cells; helps to minimise some of the unwanted, dispersion of phenomenon of pineal concretions in the gerontological context]. Advances in ● Enhancing the pathogen-killing ability adverse side-effects (Talib et al, 2021). Gerontology; 31: 6, 913-924. of leukocytes, such as phagocytic Severa M et al (2019) in multiple macrophages. Conclusion sclerosis and its experimental models: moving from basic to clinical application. Multiple Sclerosis Administrating exogenous melatonin This article has explored the anatomy, phys- and Related Disorders; 27: 52-60. in patients with infections is reported to iology and function of the pineal and Shechter A et al (2018) Blocking nocturnal blue both reduce the duration of infection and thymus glands. Part 6 will focus on the pan- light for insomnia: a randomized controlled trial. Journal of Psychiatric Research; 96, 196–202. improve patient outcomes (Vinther and creas, liver and . NT Song J (2019) Pineal gland dysfunction in Claesson, 2015). In addition to pineal- Alzheimer’s disease: relationship with the derived melatonin, many immunologically References immune-pineal axis, sleep disturbance, and Afroz H et al (2014) Different shapes of the Human neurogenesis. Molecular Neurodegeneration; 14: 28. reactive cells, such as mast cells and lym- pineal gland: a study on 60 autopsy cases. Journal Talib WH et al (2021) Melatonin in cancer phocytes, are themselves able to synthesise of Dhaka Medical College; 23: 2, 211-214. treatment: current knowledge and future and release melatonin. This locally gener- Bilder GE (2016) Human Biological Aging: From opportunities. Molecules; 26: 2506. Macromolecules to Organ Systems. Wiley Blackwell. Tan DX et al (2018) Pineal calcification, melatonin ated melatonin is then able to participate in Carrillo-Vico A et al (2005) A review of the production, aging, associated health consequences the modulation of immune responses. multiple actions of melatonin on the immune and rejuvenation of the pineal gland. Molecules; Although melatonin is generally regarded system. Endocrine: 27: 2, 189-200. 23: 2, 301. Challet E (2015) Keeping circadian time with Tordjman S et al (2017) Melatonin: pharmacology, as an upregulator of immune function, it hormones. , and ; 17: functions and therapeutic benefits. Current also suppresses the production of many Suppl 1, 76–83. Neuropharmacology; 15: 3, 434-443. pro-inflammatory mediators, thereby Chlubek D, Sikora M (2020) Fluoride and pineal Vinther AG, Claesson MH (2015) The influence of gland. Applied Sciences; 10: 8, 2885. melatonin on and cancer. dampening inflammatory responses when Cipolla-Neto J, Amaral FG (2018) melatonin as a International Journal of Cancer and Clinical necessary (Csaba, 2013). hormone: new physiological and clinical insights. Research; 2: 024. Melatonin directly influences the Endocrine Reviews; 39: 6, 990-1028. Zhao D et al (2019) Melatonin synthesis and Csaba G (2013) The pineal regulation of the function: evolutionary history in and plants. activity of the thymus gland by inducing immune system: 40 years since the discovery. Frontiers in ; 10: 249. the secretion of thymic hormones, such as Acta Microbiologica et Immunologica Hungarica; Zisapel N (2018) New perspectives on the role of thymosin and . This is thought to 60: 2, 77–91. melatonin in human sleep, circadian rhythms and enhance the differentiation of T cells in Douma LG, Gumz ML (2018) Circadian clock- their regulation. British Journal of Pharmacology; mediated regulation of blood pressure. Free 175: 16, 3190–3199. the thymus, thereby enhancing T cell Radical Biology and Medicine; 119: 108-114. Doyle AJ, Anderson GD (2006) Physiologic mediated immune responses (Vinther and CLINICAL calcification of the pineal gland in children on SERIES Endocrine system Claesson, 2015). Conversely, hormones computed tomography: prevalence, observer generated by the thymus are able to circu- reliability and association with choroid plexus Part 1: Overview of the endocrine system calcification. Academic Radiology; 13: 7, 822-826. late in the plasma and modulate the secre- and hormones May tion of melatonin by the pineal gland Emet M et al (2016) A review of melatonin, its receptors and drugs. The Eurasian Journal of Part 2: Hypothalamus and pituitary gland Jun (Csaba, 2013). Medicine; 48: 2, 135–141. Part 3: Thyroid and parathyroid glands Jul This crosstalk between the two glands, Gheban BA et al (2019) The morphological and Part 4: Adrenal glands Aug functional characteristics of the pineal gland. and the documented link between the pro- Part 5: Pineal and thymus glands Sep Medicine and Pharmacy Reports; 92: 3, 226-234. , , liver, small duction of melatonin and activity of the Grima M et al (2017) Molecular mechanisms of the Part 6: thymus gland, has led to the speculative sleep wake cycle: therapeutic applications to intestine Oct existence of a thymus–pineal axis (Rezzani insomnia. Xjenza Online; 5, 87-97. Part 7: and testes, Ibañez Rodriguez MP et al (2016) Cellular Basis of (pregnancy) Nov et al, 2020). Additionally, the widespread Pineal Gland Development: Emerging Role of Part 8: Kidneys, heart and skin Dec and diverse influences of melatonin on Microglia as Phenotype Regulator. PLoS ONE; 11: 11,

Nursing Times [online] September 2021 / Vol 117 Issue 9 58 www.nursingtimes.net