The endocrine system is contrasted both toexocrine glands, which secrete hormones to the outside of the body, and to the system known asparacrine signalling between cells over a relatively short distance. Endocrine glands have noducts, are vascular, and commonly have intracellular vacuoles or granules that store their hormones. In contrast, exocrine glands, such assalivary glands,mammary glands, andsubmucosal glands within thegastrointestinal tract, tend to be much less vascular and have ducts or a hollowlumen.Endocrinology is a branch ofinternal medicine.[3]
The human endocrine system consists of several systems that operate viafeedback loops. Several important feedback systems are mediated via thehypothalamus and pituitary.[4]
The hypothalamus and the anterior pituitary are two out of the three endocrine glands that are important in cell signaling. They are both part of the HPA axis which is known to play a role in cell signaling in the nervous system.
Hypothalamus: The hypothalamus is a key regulator of the autonomic nervous system. The endocrine system has three sets of endocrine outputs[5] which include the magnocellular system, the parvocellular system, and autonomic intervention. The magnocellular is involved in the expression of oxytocin or vasopressin. Theparvocellular is involved in controlling the secretion of hormones from the anterior pituitary.
Anterior Pituitary: The main role of the anterior pituitary gland is to produce and secretetropic hormones.[6] Some examples of tropic hormones secreted by the anterior pituitary gland include TSH, ACTH, GH, LH, and FSH.
There are many types of cells that make up the endocrine system and these cells typically make up larger tissues and organs that function within and outside of the endocrine system.
The posterior pituitary gland is a section of the pituitary gland. This organ does not produce any hormone but stores and secretes hormones such asantidiuretic hormone (ADH) which is synthesized by supraoptic nucleus of hypothalamus and oxytocin which is synthesized by paraventricular nucleus of hypothalamus. ADH functions to help the body to retain water; this is important in maintaining a homeostatic balance between blood solutions and water.Oxytocin functions to induce uterine contractions, stimulate lactation, and allows for ejaculation.[7][8]
Pancreas contain nearly 1 to 2 millionislets of Langerhans (a tissue which consists cells that secrete hormones) and acini. Acini secretes digestive enzymes.[citation needed]
The alpha cells of the pancreas secrete hormones to maintainhomeostatic blood sugar. Insulin is produced and excreted to lower blood sugar to normal levels. Glucagon, another hormone produced by alpha cells, is secreted in response to low blood sugar levels; glucagon stimulatesglycogen stores in the liver to release sugar into the bloodstream to raise blood sugar to normal levels.[9]
60% of the cells present inislet of Langerhans are beta cells. Beta cells secreteinsulin. Along with glucagon, insulin helps in maintaining glucose levels in our body. Insulin decreases blood glucose level ( a hypoglycemic hormone) whereas glucagon increases blood glucose level.[citation needed]
The fetaladrenal cortex can be identified within four weeks ofgestation. The adrenal cortex originates from the thickening of the intermediatemesoderm. At five to six weeks of gestation, themesonephros differentiates into a tissue known as the genital ridge. The genital ridge produces the steroidogenic cells for both the gonads and the adrenal cortex. The adrenal medulla is derived fromectodermal cells. Cells that will become adrenal tissue move retroperitoneally to the upper portion of the mesonephros. At seven weeks of gestation, the adrenal cells are joined by sympathetic cells that originate from the neural crest to form theadrenal medulla. At the end of the eighth week, the adrenal glands have been encapsulated and have formed a distinct organ above the developing kidneys. At birth, the adrenal glands weigh approximately eight to nine grams (twice that of the adult adrenal glands) and are 0.5% of the total body weight. At 25 weeks, the adultadrenal cortex zone develops and is responsible for the primary synthesis ofsteroids during the early postnatal weeks.
Thethyroid gland develops from two different clusterings of embryonic cells. One part is from the thickening of the pharyngeal floor, which serves as the precursor of the thyroxine (T4) producingfollicular cells. The other part is from the caudal extensions of the fourth pharyngobranchial pouches which results in the parafollicular calcitonin-secreting cells. These two structures are apparent by 16 to 17 days of gestation. Around the 24th day of gestation, the foramencecum, a thin, flask-likediverticulum of the mediananlage develops. At approximately 24 to 32 days of gestation the median anlage develops into abilobed structure. By 50 days of gestation, the medial and lateral anlage have fused together. At 12 weeks of gestation, the fetal thyroid is capable of storing iodine for the production ofTRH,TSH, and free thyroid hormone. At 20 weeks, the fetus is able to implement feedback mechanisms for the production of thyroid hormones. During fetal development, T4 is the major thyroid hormone being produced while triiodothyronine (T3) and its inactive derivative, reverse T3, are not detected until the third trimester.
A lateral and ventral view of anembryo showing the third (inferior) and fourth (superior) parathyroid glands during the 6th week of embryogenesis
Once the embryo reaches four weeks of gestation, theparathyroid glands begins to develop. The human embryo forms five sets ofendoderm-lined pharyngeal pouches. The third and fourth pouch are responsible for developing into the inferior and superior parathyroid glands, respectively. The third pharyngeal pouch encounters the developing thyroid gland and they migrate down to the lower poles of the thyroid lobes. The fourth pharyngeal pouch later encounters the developing thyroid gland and migrates to the upper poles of the thyroid lobes. At 14 weeks of gestation, the parathyroid glands begin to enlarge from 0.1 mm in diameter to approximately 1 – 2 mm at birth. The developing parathyroid glands are physiologically functional beginning in the second trimester.
Studies inmice have shown that interfering with theHOX15 gene can cause parathyroid glandaplasia, which suggests the gene plays an important role in the development of the parathyroid gland. The genes,TBX1,CRKL,GATA3,GCM2, andSOX3 have also been shown to play a crucial role in the formation of the parathyroid gland. Mutations in TBX1 and CRKL genes are correlated withDiGeorge syndrome, while mutations in GATA3 have also resulted in aDiGeorge-like syndrome. Malformations in the GCM2 gene have resulted inhypoparathyroidism. Studies on SOX3 gene mutations have demonstrated that it plays a role in parathyroid development. These mutations also lead to varying degrees of hypopituitarism.
The human fetalpancreas begins to develop by the fourth week of gestation. Five weeks later, the pancreaticalpha andbeta cells have begun to emerge. Reaching eight to ten weeks into development, the pancreas starts producinginsulin,glucagon,somatostatin, andpancreatic polypeptide. During the early stages of fetal development, the number of pancreatic alpha cells outnumbers the number ofpancreatic beta cells. The alpha cells reach their peak in the middle stage of gestation. From the middle stage until term, the beta cells continue to increase in number until they reach an approximate 1:1 ratio with the alpha cells. Theinsulin concentration within the fetal pancreas is 3.6 pmol/g at seven to ten weeks, which rises to 30 pmol/g at 16–25 weeks of gestation. Near term, the insulin concentration increases to 93 pmol/g. The endocrine cells have dispersed throughout the body within 10 weeks. At 31 weeks of development, theislets of Langerhans have differentiated.
While the fetal pancreas has functional beta cells by 14 to 24 weeks of gestation, the amount of insulin that is released into the bloodstream is relatively low. In a study of pregnant women carrying fetuses in the mid-gestation and near term stages of development, the fetuses did not have an increase in plasma insulin levels in response to injections of high levels of glucose. In contrast to insulin, the fetal plasma glucagon levels are relatively high and continue to increase during development. At the mid-stage of gestation, the glucagon concentration is 6 μg/g, compared to 2 μg/g in adult humans. Just like insulin, fetal glucagon plasma levels do not change in response to an infusion of glucose. However, a study of an infusion of alanine into pregnant women was shown to increase the cord blood and maternal glucagon concentrations, demonstrating a fetal response to amino acid exposure.
As such, while the fetal pancreatic alpha and beta islet cells have fully developed and are capable of hormone synthesis during the remaining fetal maturation, the islet cells are relatively immature in their capacity to produce glucagon and insulin. This is thought to be a result of the relatively stable levels of fetalserum glucose concentrations achieved via maternal transfer of glucose through the placenta. On the other hand, the stable fetal serum glucose levels could be attributed to the absence of pancreatic signaling initiated by incretins during feeding. In addition, the fetal pancreatic islets cells are unable to sufficiently producecAMP and rapidly degrade cAMP byphosphodiesterase necessary to secrete glucagon and insulin.
During fetal development, the storage of glycogen is controlled by fetalglucocorticoids andplacental lactogen. Fetal insulin is responsible for increasing glucose uptake andlipogenesis during the stages leading up to birth. Fetal cells contain a higher amount of insulin receptors in comparison to adults cells and fetal insulin receptors are not downregulated in cases ofhyperinsulinemia. In comparison, fetal haptic glucagon receptors are lowered in comparison to adult cells and the glycemic effect of glucagon is blunted. This temporary physiological change aids the increased rate of fetal development during the final trimester. Poorly managed maternaldiabetes mellitus is linked tofetal macrosomia, increased risk of miscarriage, and defects in fetal development. Maternal hyperglycemia is also linked to increased insulin levels and beta cell hyperplasia in the post-term infant. Children of diabetic mothers are at an increased risk for conditions such as:polycythemia,renal vein thrombosis,hypocalcemia,respiratory distress syndrome,jaundice,cardiomyopathy,congenital heart disease, and improper organ development.
The reproductive system begins development at four to five weeks of gestation with germ cell migration. The bipotential gonad results from the collection of the medioventral region of theurogenital ridge. At the five-week point, the developinggonads break away from the adrenal primordium. Gonadal differentiation begins 42 days following conception.
For males, thetestes form at six fetal weeks and the sertoli cells begin developing by the eight week of gestation.SRY, the sex-determining locus, serves to differentiate theSertoli cells. The Sertoli cells are the point of origin foranti-Müllerian hormone. Once synthesized, the anti-Müllerian hormone initiates the ipsilateral regression of the Müllerian tract and inhibits the development of female internal features. At 10 weeks of gestation, the Leydig cells begin to produce androgen hormones. The androgen hormone dihydrotestosterone is responsible for the development of the male external genitalia.
The testicles descend during prenatal development in a two-stage process that begins at eight weeks of gestation and continues through the middle of the third trimester. During the transabdominal stage (8 to 15 weeks of gestation), thegubernacular ligament contracts and begins to thicken. The craniosuspensory ligament begins to break down. This stage is regulated by the secretion ofinsulin-like 3 (INSL3), a relaxin-like factor produced by the testicles, and the INSL3 G-coupled receptor, LGR8. During the transinguinal phase (25 to 35 weeks of gestation), the testicles descend into the scrotum. This stage is regulated by androgens, the genitofemoral nerve, and calcitonin gene-related peptide. During the second and third trimester, testicular development concludes with the diminution of the fetal Leydig cells and the lengthening and coiling of theseminiferous cords.
For females, theovaries become morphologically visible by the 8th week of gestation. The absence of testosterone results in the diminution of the Wolffian structures. The Müllerian structures remain and develop into the fallopian tubes, uterus, and the upper region of the vagina. Theurogenital sinus develops into the urethra and lower region of the vagina, the genital tubercle develops into the clitoris, the urogenital folds develop into the labia minora, and the urogenital swellings develop into the labia majora. At 16 weeks of gestation, the ovaries produceFSH andLH/hCG receptors. At 20 weeks of gestation, the theca cell precursors are present and oogoniamitosis is occurring. At 25 weeks of gestation, the ovary is morphologically defined andfolliculogenesis can begin.
Studies ofgene expression show that a specific complement of genes, such as follistatin and multiple cyclin kinase inhibitors are involved in ovarian development. An assortment of genes and proteins - such as WNT4, RSPO1, FOXL2, and various estrogen receptors - have been shown to prevent the development of testicles or the lineage of male-type cells.
Thepituitary gland is formed within the rostral neural plate. The Rathke's pouch, a cavity of ectodermal cells of theoropharynx, forms between the fourth and fifth week of gestation and upon full development, it gives rise to the anterior pituitary gland. By seven weeks of gestation, the anterior pituitary vascular system begins to develop. During the first 12 weeks of gestation, the anterior pituitary undergoes cellular differentiation. At 20 weeks of gestation, thehypophyseal portal system has developed. The Rathke's pouch grows towards the third ventricle and fuses with the diverticulum. This eliminates the lumen and the structure becomes Rathke's cleft. The posterior pituitary lobe is formed from the diverticulum. Portions of the pituitary tissue may remain in the nasopharyngeal midline. In rare cases this results in functioning ectopic hormone-secreting tumors in the nasopharynx.
The functional development of the anterior pituitary involvesspatiotemporal regulation of transcription factors expressed in pituitary stem cells and dynamic gradients of local soluble factors. The coordination of the dorsal gradient of pituitary morphogenesis is dependent on neuroectodermal signals from the infundibular bone morphogenetic protein 4 (BMP4). This protein is responsible for the development of the initial invagination of the Rathke's pouch. Other essential proteins necessary for pituitary cell proliferation areFibroblast growth factor 8 (FGF8), Wnt4, and Wnt5. Ventral developmental patterning and the expression of transcription factors is influenced by the gradients of BMP2 andsonic hedgehog protein (SHH). These factors are essential for coordinating early patterns of cell proliferation.
Six weeks into gestation, thecorticotroph cells can be identified. By seven weeks of gestation, the anterior pituitary is capable of secreting ACTH. Within eight weeks of gestation,somatotroph cells begin to develop withcytoplasmic expression of human growth hormone. Once a fetus reaches 12 weeks of development, the thyrotrophs begin expression of Beta subunits for TSH, whilegonadotrophs being to express beta-subunits for LH and FSH. Male fetuses predominately produced LH-expressing gonadotrophs, while female fetuses produce an equal expression of LH and FSH expressing gonadotrophs. At 24 weeks of gestation, prolactin-expressinglactotrophs begin to emerge.
Hormones affect distant cells by binding to specificreceptor proteins in the target cell resulting in a change in cell function. This may lead to cell type-specific responses that include rapid changes to the activity of existing proteins, or slower changes in theexpression of target genes. Amino acid–based hormones (amines andpeptide or protein hormones) are water-soluble and act on the surface of target cells viasignal transduction pathways;steroid hormones, being lipid-soluble, move through theplasma membranes of target cells to act within theirnuclei.
The typical mode ofcell signalling in the endocrine system is endocrine signaling, that is, using the circulatory system to reach distant target organs. However, there are also other modes, i.e., paracrine, autocrine, andneuroendocrine signaling. Purely neurocrine signaling betweenneurons, on the other hand, belongs completely to thenervous system.
Autocrine signaling is a form of signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on the same cell, leading to changes in the cells.
Some endocrinologists and clinicians include the paracrine system as part of the endocrine system, but there is not consensus. Paracrines are slower acting, targeting cells in the same tissue or organ. An example of this issomatostatin which is released by some pancreatic cells and targets other pancreatic cells.[3]
Juxtacrine signaling is a type of intercellular communication that is transmitted via oligosaccharide, lipid, or protein components of a cell membrane, and may affect either the emitting cell or the immediately adjacent cells.[13]
It occurs between adjacent cells that possess broad patches of closely opposed plasma membrane linked by transmembrane channels known asconnexons. The gap between the cells can usually be between only 2 and 4 nm.[14]
Endocrinopathies are classified as primary, secondary, or tertiary. Primary endocrine disease inhibits the action of downstream glands. Secondary endocrine disease is indicative of a problem with the pituitary gland. Tertiary endocrine disease is associated with dysfunction of the hypothalamus and its releasing hormones.[16]
As thethyroid, and hormones have been implicated in signaling distant tissues to proliferate, for example, theestrogen receptor has been shown to be involved in certainbreast cancers. Endocrine, paracrine, and autocrine signaling have all been implicated in proliferation, one of the required steps ofoncogenesis.[17]
Other common diseases that result from endocrine dysfunction includeAddison's disease,Cushing's disease andGraves' disease. Cushing's disease and Addison's disease are pathologies involving the dysfunction of the adrenal gland. Dysfunction in the adrenal gland could be due to primary or secondary factors and can result in hypercortisolism orhypocortisolism. Cushing's disease is characterized by the hypersecretion of the adrenocorticotropic hormone (ACTH) due to a pituitary adenoma that ultimately causes endogenous hypercortisolism by stimulating the adrenal glands.[18] Some clinical signs of Cushing's disease include obesity, moon face, and hirsutism.[19] Addison's disease is an endocrine disease that results from hypocortisolism caused by adrenal gland insufficiency. Adrenal insufficiency is significant because it is correlated with decreased ability to maintain blood pressure and blood sugar, a defect that can prove to be fatal.[20]
Graves' disease involves the hyperactivity of the thyroid gland which produces the T3 and T4 hormones.[19]Graves' disease effects range from excess sweating,fatigue, heat intolerance andhigh blood pressure to swelling of the eyes that causes redness, puffiness and in rare cases reduced or double vision.[14]
A DALY (Disability-Adjusted Life Year) is a measure that reflects the total burden of disease. It combines years of life lost (due to premature death) and years lived with disability (adjusted for the severity of the disability). The lower the DALY rates, the lower the burden of endocrine disorders in a country.[22]
The map shows that large parts of Asia have lower DALY rates (pale yellow), suggesting that endocrine disorders have a relatively low impact on overall health, whereas some countries in South America and Africa (specifically Suriname and Somalia) have higher DALY rates (dark orange to red), indicating a higher disease burden from endocrine disorders.
A neuroendocrine system has been observed in allanimals with a nervous system and allvertebrates have a hypothalamus–pituitary axis.[23] All vertebrates have a thyroid, which inamphibians is also crucial for transformation of larvae into adult form.[24][25] All vertebrates have adrenal gland tissue, with mammals unique in having it organized into layers.[26] All vertebrates have some form of a renin–angiotensin axis, and alltetrapods have aldosterone as a primarymineralocorticoid.[27][28]
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^Wilson JX (1984). "The renin-angiotensin system in nonmammalian vertebrates".Endocrine Reviews.5 (1):45–61.doi:10.1210/edrv-5-1-45.PMID6368215.
^Colombo L, Dalla Valle L, Fiore C, Armanini D, Belvedere P (April 2006). "Aldosterone and the conquest of land".Journal of Endocrinological Investigation.29 (4):373–9.doi:10.1007/bf03344112.PMID16699307.S2CID25316873.
