Endocrine System – the collection of glands that secrete hormones into the circulatory system. The effects of these molecules are far reaching and have a prolonged response. These glands are ductless , vascular, and have intracelluar vacuoles or granules to store their hormones.

There are also exocrine glands which have ducts which are used for secretion into the external environment, not hormones into the body. Neither of these to be confused with paracrine signaling which involves paracrine factors which diffuse over short distances to relay signals.

The Endocrine Organs

Organs

  • Hypothalamus – located in the brain this region is important in controlling body temperature, hunger, thirst, fatigue, sleep, and attachment behaviors.
    • Dopamine – inhibits prolactin
    • Vasopressin – increases water permeability in the distal convoluted tubule promoting water reabsorption and increased blood volume.
  • Pineal Body – important in modulating sleep patterns this is found just below and slightly behind the thalamus.
    • Melatonin – an antioxidant which monitors circadian rhythm to induce drousiness and lowering of the core body temperature.
  • Pituitary Gland – is a protrusion from the lower side of the hypothalamus, its hormones regulate other hormones and homeostasis (stable internal conditions). The pituitary can be described as the anterior or posterior lobe.
    • Growth Hormone – stimulates growth and reproduction.
    • Thyroid-stimulating hormone (TSH) – iodine absorption by the thyroid gland and also T3 and T4 (both hormones) synthesis and release from the thyroid.
    • Prolactin – milk synthesis and release from mammary glands.
  • Pancreas – an organ secreting both hormones and enzymes. Is part of the digestive system, located posterior to the stomach
    • Insulin – intake of lipids and synthesis of triglycerides in adipocytes and intake of glucose, glycogenesis and glycolysis in the liver and muscle from the blood
    • Glucagon – increases blood glucose level
  • Ovaries – the female reproductive organs, chiefly operates in the production of eggs.
    • Progestrone – supports pregnancy and is anti-inflammatory.
    • Estrogens (estradiol) – fluid balance, female secondary sex characteristics, coagulation.
  • Testes – the male reproductive organs, chiefly operates in the production of sperm.
    • Androgens (testosterone) – maturation of sex organs, formation of scrotum, increase in muscle mass and strength and bone density.
  • Thyroid Gland – located around the trachea, this gland is important in controlling the body’s energy use, protein synthesis and hormone sensitivity. This is a bi-lobed organ
    • Triiodothyronine (T3) – stimulates body oxygen and energy consumption by controlling the basal metabolic rate.
    • Thyroxine (T4) – stimulates body oxygen and energy consumption by controlling the basal metabolic rate.
  • Parathyroid Gland – There are four glands. These share much of their blood supply and drainage with the thyroid glands. Works in maintenance of calcium and phosphate levels.
    • Parathyroid Hormone – Stimulates calcium and phosphate release from the bone and calcium osteoclasts. Stimulates calcium reabsorption in the kidneys and vitamin D synthesis. Inhibits phosphate reabsorption in the kidneys.
  • Gastrointestinal Tract
    • Stomach:
      • Gastrin – secretion of gastric acid by parietal cells.
      • Somatostatin – suppresses gastrin and lowers rate of gastric emptying.
    • Duodenum:
      • Cholecystokinin – release of digestive enzymes from the pancreas.
  • Adrenal Glands – these are composed of the adrenal cortex and medulla which respond to stress and affects kidney function. They are located above the kidneys.
    • Glucocorticoids (cortex) – stimulates gluconeogenesis and prevents inflammatory and immune response and protein synthesis.
    • Adrenaline – fight or flight response. Boosts oxygen and glucose supply to the muscles and brain.
    • Dopamine – increases heart rate and blood pressure.

Hormone – (n.) class of signaling moleculars from glands (endocrine system) that are transported in the circulatory system to regulate physiology and behavior.

Hormone Classes

  1. Proteins, Peptides, and modified Amino Acids:
    • Hydrophilic molecules that bind to cell surface receptors. These receptors are transmembrane proteins that initiate a second messenger and thus a sequence of events that later cell behavior or stimulate gene expression.  Are activated when released into the blood stream.
  2. Steroids
    • Hydrophobic molecules that can traverse the cell membrane. Once inside the cell they bind to their receptor and travel to the nucleus where it binds to the ‘hormone response element’ in DNA. Is lipid soluble. Are synthesized from cholesterols and travel through the blood bound to carrier proteins.
    • There are 5 types:
      1. glucocorticoids (21C) – inflammation down regulator. prevents translation of inflammation TFs to the nucleus and upregulates anti-inflammatory proteins. Interacts with the glucocorticoid receptor. stimulates gluconeogenesis. works with adrenaline
      2. mineralocorticoids (21C) – influences salt and water balances. Aldosterone is a major one. Works by both nuclear receptors and membrane receptors and signaling cascades.
      3. androgens (19C) – synthesized in the innermost layer of the adrenal cortex. These stimulate and control the development and maintenance of male characteristics. Example is testosterone. They bind to androgen receptors.
      4. estrogens (18C) – the primary female sex hormones primarily produce by the ovaries and, during pregnancy, the placenta. Plays a role in ovulation. Binds to estrogen receptors.
      5. progestogens (21C) – binds to the progesterone receptor. Function in maintaining pregnancy and negative regulation of progestogens, androgens, and estrogens.

Hormone Signaling

Steroid Hormone Signaling

Steroids are cyclical organic compounds with 17 carbons: 3-6 membered rings, 1-5 membered ring and a 8 carbon side chain. Examples include cholesterol and hormones such as estrogen, androgen, and parathyroid hormone. Signaling molecules are typically steroid hormones. Steroid hormones are group of steroid that acts as hormones, they travel through the blood bound to carrier proteins and are fat soluble, allowing them to pass through the cell membrane. Due to their lipid soluble nature they must bind to a carrier plasma glycoprotein to travel the circulatory system. Steroid hormones bind to 5 different receptors which are either cytosolic (type I) or nuclear (type II):

  • Glucocorticoids – 21 carbons molecule that binds to glucocorticoid receptor (GR) which up-regulates anti-inflammatory proteins and blocks trans-location of pro-inflammatory transcription factors to the nucleus. Stimulates gluconeogenesis, inhibits glucose uptake in muscle and liver, and stimulates fat breakdown in adipose tissue. Ex: cortisol.
    • The GR is a nuclear receptor activated by hormone binding initiating trans-location to the nucleus. Binding occurs at the glucocorticoid response element (GRE) in the gene promoter region. Ex. MAPK phosphatase, Glucose-6-phosphatase. The GR has a N-terminal domain, a DNA binding domain, hinge region, ligand-binding domain, and C-terminal domain. Prior to hormone binding it is complexed in the cytosol with hsp90, hsp70, and FKBP52.
  • Mineralcorticoids– 21 carbon molecule that binds to cytosolic mineralcorticoid receptor (MR). Alters the salt and water balances by retention, absorption, and secretion of minerals. 100x less prevalent in circulation than glucocorticoids. Ex: aldosterone.
    • The MR is a nuclear receptor with equal affinity for mineralcorticoids and glucocorticoids. Activation of the MR occurs with ligand binding, the complex then translocates to the nucleus where it homodimerizes and binds to a hormone response element (HRE) in the promoter region of target genes.
    • Elevated levels of aldosterone is a result of renal cancers causing hypertnsion and endma from excessive sodium and water retention and muscle weakness from higher excretion of potassium ions.
  • Androgens – 19 carbon molecule composing an andrane skeleton that binds to the androgen receptor (AR). The AR is a nuclear receptor that activates by binding of an androgenic hormone in the cytoplasm. This complex is important in gene regulation in the development and maintenance of male characteristics. Progestins can block the AR. Ex: testosterone, dihydrotestosterone.
    • Binding of androgen to the AR causes a conformation change in the AR and dissociation of heat shock proteins, translocation to the nucleus and dimerzation. In the nucleus the complex binds to the HRE that affect genes including insulin-like growth factor 1 receptor (IGF-1R).
    • There are 2 isoforms of AR: A and B. AR contains an N-terminal regulatory domain which serves as the dimerization surface, DNA binding domain, hinge region, ligand binding domain, and C-terminal domain.
  • Estrogens – 18 carbon molecule that binds to the estrogen receptor (ER). This complex promotes the development of female secondary sex characteristics and fluid balance. Ex: estriol, estradiol.
    • Binding of estrogen to the ER occurs in the cytosol and causes dimerization (either homo or hetero dimer within its alpha and beta forms). The complex translocates to the nucleus where it binds to estrogen response elements and activates transcription of its target genes. Note that the N-terminal domain can weakly activate gene expression in the absence of ligand. Additionally there is a DNA binding domain, hinge region, domain that binds to co-activator/repressor proteins and ligand, and C-terminal domain.
    • There are two classes of estrogen receptors: ER, a nuclear hormone receptor, and GPER, a rhodopsin-like family of G protein coupled receptors. ERs are overexpressed in ~70% of breast cancers and it has been implicated in many other cancer.
  • Progestogens – 21 carbon molecule composing a pregnane skeleton that binds to and activate the progestrone receptor (PR). This complex is important for maintaining pregnancy and also important in menstrual cycles (decrease of progesterone triggers menstruation). Ex: progesterone.
    • The PR is a nuclear hormone receptor found in the cytosol in two isoforms A and B. Binding to progesterone induces a structural change in the PR, moving the inhibitory carboxyl terminal. Dimerzation occurs and translocation to the nucleus where it binds to its DNA element. The PR has a N-terminal regulatory domain, DNA binding domain, hinge section, and a C-terminal ligand binding domain.
  • Vitamin D derivatives (closely related hormone system) – C27H44O molecule that binds to the Vitamin D-binding protein in the circulatory system. Once delivered to the destination cell of the cell it crosses the membrane and binds to and activates the calcitriol receptor or the vitamin D receptor (VDR). This complex is involved in mineral metabolism and the hair cycle.
    • Once bound to Vitamin D, VDR activation induces the creation of a  heterodimer with the retinoid X receptor. This complex then translocates to the nucleus where it acts as a transcription factor.

Vitamin D Signaling

Summary Article

Vitamin D is a hormone that acts in the body to increase circulating levels of serum calcium and phosphate. More specifically the molecule is a group of fat-soluble secosteroids (a steroid with a “broken” ring), also called the 6th steroid hormone. Vitamin D lacks the planar fused four ring system of true steroids. These molecules enhance absorption of calcium, iron, magnesium, phosphate, and zinc. It can be absorbed from food consumed or synthesized in the skin when exposed to sunlight. There are two main forms Vitamin D2 (ergocalciferol), primarily from plant sources, and D3 (cholecalciferol), from sunlight and animal sources.

Vitamin D is created from 7-dehydroxycholesterol (7-DHC) from exposure to UVB radiation. Vitamin D (specifically Dc, cholecalciferol) is converted to calcidiol (a prohormone) in the liver by hydroxylation at position 25 by vitamin D 25-hydroxylase (enzyme produced by hepatocytes). Calcidiol is converted calcitriol (the biologically active form of Vitamin D) in the kidneys by a hydroxylation at the 1-alpha position by 25-hydroxyvitamin D3 1-alpha-hydroxylase (levels of this are controlled by parathyroid hormone). Calcitriol circulates as a hormone in the circulatory system bound to vitamin D-binding protein (DBP). DPB is a member of the albumin family.

  1. 7-DHC conversion to pre-vitamin D3 by UVB light
  2. Pre-vitamin D3 to vitamin D3 by thermo-sensitive process
  3. Vitamin D3 is converted to 25(OH)D3 in the liver by enzymes (CYP2R1)
  4. 25(OD)H3 is metabolized to the active form 1,25(OH)2D3 in the kidneys by CYP27B1 (PTH stimulated, FGF23, high Ca, & P inhibited) and CYP24A1 (FGF23, high Ca, & P stimulated, PTH inhibited).

*CPY = cytochrome P450 mixed-function oxidases.

Calcitriol binds to Vitamin D binding protein (DBP) also known as the Calcitrol Binding Protein while in circulation of the body. Calcitriol enters the cell and binds to the Vitamin D receptor (calcitriol receptor, VDR) in the cytosol. The VDR is in the steroid hormone nuclear receptor family, a phosphoprotein with three domains: N-terminal dNA binding domains with 2 zinc fingers for its VDRE (DNA binding site), C-terminal ligand binding domain, and hinge region. VDR can translocate to the nucleus independent of ligand, calcitriol, with the assistance of importin 4. This complex is a transcription factor which binds to the VDRE (Vitamin D Receptor Element) in the DNA. VDREs are located in the promoters of bone genes: beta integrin, VD 25 OHase, osteocalcin, and osteopontin. There is variability of VDREs, after binding to the VDRE coregulatory complexes are recruited that contain chromosome secondary structure remodeling proteins.

Calcitriol acts on many cells on the body but is best known for acting on the intestine, bone, and kidney cells to elevate circulating calcium. These proteins modulate calcium absorption in the intestines and by bones by increasing the number of osteoclasts. Osteoclasts is a bone cell that functions in maintenance and repair of bones, it dissolves the bone matrix releasing calcium. Osteoblasts are bone cells that synthesize bone by producing an calcium and phosphate based mineral for deposit into the matrix. Mutations in the VDR leads to rickets.

Vitamin D3 Chemical Structure

25(OH)D promotes osteoblast differentiation and increase in bone density, while 1,25(OH)D works with PTH to stimulate osteoblast secretion of RANKL which induces osteoclastogenesis. An increase in serum calcium will inhibit PTH secretion.

How Vitamin D synthesis is regulated: POMC (proopiomelanocortin) is produced in the pituitary gland. It can be cleaved to produce alpha-MSH and ACTH.  alpha-MSH (Melanocyte-Stimulating Hormone) is produced in the pituitary gland and its secretion stimulates melanocytes in the skin and hair to produce melanin which is released into melanosomes which are in skin cells of the epidermis. The melanosomes accumulate protecting the cell’s nucleus from UVB rays.

Other Hormone Signaling

Proteins, Peptides, and modified Amino Acids

Hormones can also be eicosanoids, amino acid derivates, peptides, and proteins. A specific group of hormones are the tropic hormones that stimulate hormone production in other endocrine glands. Most peptide and eicosanoid hormones signal through G protein coupled receptors in the cell membrane.

Adrenaline Signaling

Also known as epinephrine, is a hormone secreted by the adrenal gland medulla. It is a major player in the autonomic system and the sympathetic system leading to increased activation of it. It is involved in invoking a stress or ‘fight or flight’ response.

Epinephrine binds the adrenergic receptor inducing a tissue specific response. Beta-adrenergic receptors cause release of glucose and fatty acids in liver and fat cells. It increase contraction rate of heart cells. And causes relaxation of smooth muscle cells. This receptor is coupled to gs protein of the g protein complex. It activates adenylyl cyclase and increases intracellular cAMP levels.

alpha adrenergic receptors are coupled to Gi and Gq proteins of the g protein complex. These promote artery constriction. These g proteins inhibits adenylyl cyclase (which creates cAMP) and stimulates PLC promotion which generates second messengers IP3 and DAG.

Toxins such as cholera toxin specifically enter the plasma membrane creating a GTP that cannot inactivate on a Gα protein. This leads to build up of cAMP in the cells allowing permissive flow of water into the intestines and thus causing the symptoms of cholera.