The pineal Gland, melatonin and hormones rythms regulation

The pineal gland, melatonin, and the regulation of hormonal rhythms Dr. H Valdés-Socin. Head of clinic. Department of Endocrinology. CHU de Liège The pineal gland is known by Anatomists since the middle ages. Andrea Vesalius described it in the chap VII of his monumental book "De humani corporis fabrica (1555)". René Descartes had the intuition that the pineal gland is a "third eye" and that is how his illustrator Florent Schuyl represented it in figure 34 of Descartes book "De Homine" (1662). As for the artists, some of them illustrated from their paintings some craniotomies in which the surgeon performs the extraction of the stone of madness. Thus, "the extraction of the stone of madness" from Pieter Huys, is exposed in the Museum of the Périgord (1561). Jan Sanders showed the same subject in his painting "The surgeon" (1550) exhibited in the Museo Nacional del Prado, Madrid. During the 20th century the anatomy and the physiology of the pineal gland will be revisited: it appears so that the pinealocytes are in close relationship to the photoreceptors. In certain animal species (birds, reptiles) the pinealocytes are also photosensitive: their pineal gland is directly sensitive to light. In addition, in humans, the pinealoblastomes may occur related to the "trilateral retinoblastoma syndrome" caused by mutations in the RB1 gene (13q14.2) (Plowman & al Clin Oncol 2004). These patients present with retinoblastoma in both eyes but also in the pineal. This only strengthens the intuition of Descartes as the pineal as a "third eye". As for the genetic and hereditary aspect, we had the opportunity as well as other authors, to describe the family presentation of pineal lesions with hypersecretion of melatonin (Allouch & al 2002). With the greater availability of Radiology and brain scans, it was discovered with interest that the pineal gland is often calcified. This calcification can be observed since the second decade of life. It is not yet established if the pineal gland should be considered a"stone of madness " however it is a sort of “cerebral lithiasis”. Indeed, during this oral presentation, we will show some data linking the pineal gland and the light to seasonal depression. "Folly" induced by the long winter nights can be prevented from light therapy treatment. Severe head trauma is associated to Hypopituitarism up to 10-35% of cases, depending on the dynamic tests used to diagnose hypopituitarism (Valdés-Socin & al 2009, Valdés-Socin & al 2015). A current research topic is the study of disturbance of circadian hormonal cycles and secretion of melatonin. The secretion of melatonin occurs at night, and its synthesis is made in the pineal gland and then discharged to the general circulation. However, there is a quantitatively most important melatonin production at the level of the digestive tract. This melatonin would have essentially a paracrine effect. The administration of melatonin in humans results in variable pharmacokinetics due to its hepatic metabolism and its urinary excretion. Membrane melatonin MT1 and MT2 receptors use G proteins transduction. They are distributed mainly in the CNS at the level of the retina, hypothalamic nuclei and the pineal gland. They are also found in the periphery and in endocrine glands. A third melatonin receptor or MT3 is intracellular: this is the quinone reductase enzyme that has an important role in protection against oxidative stress (Lucchetti & al FASEB 2010). A current research topic is the role of a variant MT2 receptor (Variant rs 10830963) in diabetology. Patients harbouring this variant has been shown to have a a decrease in the early phase of insulin secretion(Langenberg & al Diabetologia 2009), and have a higher fasting morning glycemia, and consequently, an increased risk of developing a type 2 diabetes. These findings were demonstrated in a meta-analysis involving 170 000 patients (Mao & al PLOS one 2012). The same variant has been identified in patients at risk of developing glucose intolerance and gestational diabetes (al Diabetologia 2012, Liao, Walford & al PLO one 2012) Melatonin is synthesized in the pineal gland from the conversion of tryptophan to serotonin. Enzymes such as alkylamine N-acetyltransferase (NAT) and of acetylserotonin O-methyltransferase (ASMT) ensure the synthesis of melatonin from serotonin. Apart from melatonin which can be prescribed as such in Belgium, there are synthetic analogs of melatonin such as CIRCADIN. AGOMELATONINE is available in France (lab SERVIER). VALDOXAN is a structural analogue of melatonin developed as a sedative antidepressant daily, which must be taken at sunset. It is a MT1 and MT2 melatonin receptor agonist and antagonist of the serotonin 5HT2C receptors. We can also mention RAMELTEON (TAKEDA lab), which is registered as an hypnotic. Références B Claustrat. Médecine du Sommeil 2009 Allouch A , Valdes Socin H, Hendrick JC, Beckers A et Legros JJ. Pinéalomes familiaux: études biologiques et génétiques préliminaires. Annales Endocrinol 2002 (abstract). H Valdes-Socin, L Vroonen, P Robe, D Martin, A Beckers. Hypopituitarisme consécutive aux dommages cérébraux: le trauma crânien et l’hémorragie sous-arachnoïdienne mis en cause. Rev Med Liège 2009 ;64(9),457-464. Valdes-Socin, Potorac , Matagne, Bonneville & Beckers. Etude et prévalence des troubles neuroendocriniens dans une série de 65 patients avec dommages cérébraux post traumatiques (TBI) recrutés à partir de la médecine d'expertise. Annales d'Endocrinologie (abstract) 2015 Goyal &l. Diabetol Metab Syndr. Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial.2014 Nov 18;6:124. doi: 10.1186/1758-5996-6-124. eCollection 2014. Romo-Nava & al. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014 Jun;16(4):410-21. doi: 10.1111/bdi.12196. Epub 2014 Mar 17