Development of the Pineal Gland

Overview:

  • Emergence of pineal gland in utero

  • Role of pineal gland in fertility

  • Lack of a blood-brain barrier

  • Piezoelectricity in pineal gland crystals


When and how does the pineal gland develop?


Human pineal gland development sets us apart from other animals and even other mammals. The pineal organ begins to form as an outpocketing of the dorsal midline of the diencephalon shortly after neural tube closure. Several homeodomain (Hox) transcription factors are required for pineal development, most of which are also involved in retinal development, such as PAX6, OTX2, RAX, CRX, PAX4, and TBX2B. For example, PAX6 mutations in humans result in pineal aplasia, the absence of normal pineal gland structure/function[1].


The pineal gland becomes visible at 7 weeks gestation. The human pineal gland starts becoming innervated 16-20 weeks into fetal development, unlike in rodents where it happens after birth[2]. In infants, melatonin levels remain low until 2-3 months old, after which point babies start sleeping through the night, increasing until 1 year. Pineal gland growth stabilizes beyond the first 1–2 years of life[3].


Are children's pineal glands more sensitive?


It is interesting to note that children may be more sensitive to circadian disruption. A Japanese study of 13 9-year-olds and their parents found the kids were twice as sensitive when exposed to light at night compared to their parents[4]. The children experienced twice the inhibition of melatonin production, suggesting the pineal glands of children are more sensitive than those of adults to circadian disruption by nighttime screen exposure. Larger studies are needed to confirm this finding.


How does the pineal gland control the timing of puberty and reproduction?


The pineal gland is a crucial endocrine organ; circadian rhythm is highly connected to reproductive cycles. The pineal gland synthesizes hormones like testosterone and estradiol.


Numerous tissues possess the enzymes that convert tryptophan to melatonin, including the eyes, gut, testis, ovary, uterus, bone marrow, placenta, oocytes, red blood cells, lymphocytes, astrocytes, glia, and neurons[5]. Melatonin has been found in semen, amniotic fluid, and breast milk.


Many cell types also express melatonin receptors, including brown and white adipocytes, skin, various lymphoid organs and lymphocytes, colonocytes, epithelial cells of prostate and breast, ovary/granulosa cells, myometrium, placenta, and fetal kidney[6].


Removal of the pineal gland causes precocious puberty. Lower levels of nighttime melatonin have been found in healthy adolescents at advanced stages of puberty.


High melatonin levels are associated with exercise-related menstrual disorders, low sperm count, and delayed puberty. Melatonin regulates the secretion of gonadotrophin-releasing hormone (GnRH) from the hypothalamic neurons. Melatonin treatment in humans reduces LH and GH secretion[7]. Melatonin stimulates the secretion of progesterone from granulosa cells and suppresses the expression of estrogen receptor and estrogen activation[6].


How does melatonin production shift in adolescence?


During adolescence, the circadian cycle is shifted back, giving rise to later sleep onset and waking time, known as a "night owl" chronotype. Teenagers need about 9 hours of sleep per night but usually get around 7. Teens are among the most sleep deprived demographic because of the misalignment between biological and social cues like early school days. The dissociation of the internal clock and local time, called desynchronization, can result in fatigue, poor appetite, headaches, insomnia, irritability, mood disorders like depression, and increased risk of car accidents. Sleep deprivation lowers alertness and academic performance and increases stress and inflammation.


Exacerbating the problem, teens' biological clocks are disrupted by screens and electronic media. A 2013 survey found that on weekdays, 41% of American teenagers spend at least 3 hours online outside of schoolwork and studying. The number is undoubtedly higher now. LED exposure before bed causes a phase delay in circadian melatonin secretion. Blue light can even damage photoreceptors and cause severe photochemical damage to the retina[4].


Pineal melatonin has antidepressant and anxiolytic properties; it also plays a role in sleep regulation, cancer, and diabetes[6, 8]. Continued disturbance of sleep is linked to depression, insomnia, cardiovascular disease, metabolic syndrome, cancer, and even premature death[9]. Altered melatonin metabolism is also implicated in autoimmune conditions e.g. rheumatoid arthritis and systemic lupus erythematosus, as well as IBD[6].


Is the pineal gland affected by electric and magnetic fields?


We are continually exposed to electric and/or magnetic fields. Natural sources include the cosmic microwave background and the magnetic field of the Earth.


Four important factors determine the effects of electromagnetic fields (EMFs) on the human body: field intensity, distance, frequency, and power density. Our highest-frequency and closest-proximity exposures come from radio frequencies (100 kHz-300 GHz), which includes TV, cell phones, Internet, Wi-Fi, microwave ovens, and radar and radio transmitters. The use of a mobile phone for more than 25 minutes a day decreased the level of melatonin secretion. Exposure of non-human mammals to man-made electric and/or magnetic fields often reduces pineal melatonin production, whether the fields are sinusoidal or static pulsed[10].


Domestic exposure to a 60 Hz magnetic field decreased pineal activity in women, primarily those using medications. Humans are widely exposed to magnetic fields of 50 Hz (in Europe) and 60 Hz (in North America). These low-frequency EMFs (0-300 Hz) can come from power transmission lines, home wiring, car electric engines, electric trains/trams, and electrical devices. The level of 6-sulfatoxymelatonin excretion (a marker of melatonin levels) was lower in infants kept in incubators and rose when they were moved to a place free from electrical devices[11]. The International Agency for Research on Cancer (IARC) classifies these EMFs as 'possibly carcinogenic'. Sleep quality and melatonin secretion may be affected not just by lights but also very importantly by electric and magnetic fields.


Why doesn't the pineal gland have a blood-brain barrier?


The pineal gland, along with other circumventricular organs (CVOs) like the posterior pituitary gland, secretes hormones and mediates blood-brain and brain-CSF (ventricle) communication. Communication between the brain and periphery is facilitated by the lack of a blood-brain barrier, as well as increased vascularization through capillaries with fenestrations, or small pores. This enhanced, open communication generates vulnerability to deposits known as calcification.


calcite crystal

There's a crystal in your brain


Biomineralization, specifically calcification, has been observed in two major forms in the pineal glands of numerous animals and humans: (1) hydroxyapatite mulberry-like concretions and (2) calcite microcrystals[12]. This suggests two different mechanisms of formation and biological function. Scanning electron microscopy (SEM) has revealed these calcifications can have cubic, hexagonal, and cylindrical morphologies.


The larger, hydroxyapatite concretions are hundreds of micrometers long. They consist of mineral, protein, and glycoprotein organic components. Numerous elements have been identified in these structures, including calcium, phosphorus, copper, manganese, zinc, iron, silicon, aluminum, sodium, magnesium, chromium, potassium, strontium, titanium, cobalt, and nickel. It's interesting to note that hydroxyapatite is the chief structural component of bone.


The smaller, calcite microcrystals are well-defined and around 10-20 micrometers long. They are primarily composed of calcium, carbon, and oxygen, with trace levels of silicon, aluminum, sodium, and magnesium.


Baconnier et al. propose that calcite microcrystals are probably responsible for second harmonic generation in pineal tissue, with possible piezoelectricity occurring.


Piezoelectricity, literally “pressure electricity,” is the conversion of mechanical energy (tension/compression) into electrical energy. Squeezing certain non-centrosymmetric crystals (like quartz) causes electricity to flow through them. For example, in bone, pressure recruits osteoblasts to promote calcium mineralization. Conversely, if you apply electricity or an electric field, the crystals squeeze themselves by vibrating back and forth (this is called the reverse piezoelectric effect).


Second harmonic generation occurs when two photons of the same frequency combine and generate a new photon with twice the energy. The larger the crystal, the greater the effect. In this optical process, an electric field of a given frequency is applied to a non-centrosymmetric crystal and is radiated back as an electric field of twice the frequency.


Baconnier et al. suggested that tissues might respond to EMFs with electromechanical coupling. They proposed that minute crystals of magnetite present in the human brain could couple to microwave radiation[12]. Electromagnetic fields could distort calcified pineal tissue, affecting downstream signals; thus, further investigation of the mechanism behind this interaction is warranted.


Key Takeaways

  • The pineal gland appears at week 7 and is innervated at 4-5 months into fetal development.

  • Many cells of the reproductive system also produce melatonin.

  • The pineal gland controls the timing of puberty; exercise can increase melatonin and delay puberty.

  • Blue LED light and EMFs can inhibit melatonin secretion.

  • Sleep disturbances are linked to numerous health problems, from depression to heart disease.

  • The pineal gland lacks a blood-brain barrier, making it one of the most susceptible organs in the body to calcification.

  • A calcified pineal gland could be vulnerable to EMF activity, which could affect downstream messengers; future studies are needed to uncover mechanisms behind pineal crystal and EMF interactions.


This is Part 2 of a 3 part series on the pineal gland:

  1. Overview of the Pineal Gland

  2. Development of the Pineal Gland

  3. Aging of the Pineal Gland


References


  1. Kiecker, C., The origins of the circumventricular organs. J Anat, 2018. 232(4): p. 540-553.

  2. Moller, M., P. Phansuwan-Pujito, and C. Badiu, Neuropeptide Y in the adult and fetal human pineal gland. Biomed Res Int, 2014. 2014: p. 868567.

  3. Whitehead, M.T., et al., Physiologic pineal region, choroid plexus, and dural calcifications in the first decade of life. AJNR Am J Neuroradiol, 2015. 36(3): p. 575-80.

  4. Touitou, Y., D. Touitou, and A. Reinberg, Disruption of adolescents' circadian clock: The vicious circle of media use, exposure to light at night, sleep loss and risk behaviors. J Physiol Paris, 2016. 110(4 Pt B): p. 467-479.

  5. Tan, D.X., et al., Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland. Molecules, 2018. 23(2).

  6. Emet, M., et al., A Review of Melatonin, Its Receptors and Drugs. Eurasian J Med, 2016. 48(2): p. 135-41.

  7. Macchi, M.M. and J.N. Bruce, Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol, 2004. 25(3-4): p. 177-95.

  8. Borjigin, J., L.S. Zhang, and A.A. Calinescu, Circadian regulation of pineal gland rhythmicity. Mol Cell Endocrinol, 2012. 349(1): p. 13-9.

  9. Pfeffer, M., H.W. Korf, and H. Wicht, Synchronizing effects of melatonin on diurnal and circadian rhythms. Gen Comp Endocrinol, 2018. 258: p. 215-221.

  10. Reiter, R.J., Electromagnetic fields and melatonin production. Biomed Pharmacother, 1993. 47(10): p. 439-44.

  11. Lewczuk, B., et al., Influence of electric, magnetic, and electromagnetic fields on the circadian system: current stage of knowledge. Biomed Res Int, 2014. 2014: p. 169459.

  12. Baconnier, S., et al., Calcite microcrystals in the pineal gland of the human brain: first physical and chemical studies. Bioelectromagnetics, 2002. 23(7): p. 488-95.

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