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Endocrine Signalling

Introduction

There are many ways that cells can use to communicate with each other. The method used often depends on the proximity of the cell sending the signal to the one which will receive it. Examples include autocrine, where the cell signals to itself, and paracrine, where a cell signals to a nearby neighbour.

However, when cells need to communicate a message over a long distance, they can use the endocrine system. Endocrine signalling uses chemicals called hormones to send messages throughout the body. The hormones are released from the cell into the bloodstream and can travel around the entire body. In contrast, the exocrine system secretes its products into the extracellular environment.

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Ever wonder why you're feeling a bit stressed? Why you grow during puberty? What causes that lovely womanly gift once a month? All of these things and many others are controlled by the hormones of the endocrine system.

Hormones have a very diverse array of functions. Their secretion is a tightly controlled process and varies throughout your life, sometimes daily, monthly or yearly. Different hormones can have effects on your growth, both as a child and in puberty (the imaginatively named growth hormone), sexual development and libido (oestrogen and testosterone), and menstruation (follicle-stimulating hormone (FSH), luteinising hormone (LH), oestrogen and progesterone). Hormones are also released in response to stress (adrenocorticotropic hormone (ACTH) and cortisol). They have other functions too, including in metabolism and homeostasis. In short, they are very important and very complex. This is why so many diseases and illnesses can be caused by hormonal imbalances.

Pregnancy is associated with fluctuations in hormone levels, including oestrogen, progesterone, prolactin and oxytocin. This is both for the mother (prolactin is involved in lactation) as well as hormones to help the foetus develop, such as placental growth hormone. These changes in hormonal levels explain why pregnant women can sometimes be a bit ... uh ... changeable in mood!

The endocrine system

The key organs in endocrine signalling are glands. Glands are the target for signals, often coming from the brain. In response to these signals they will release the appropriate hormone. A gland involved in endocrine signalling specifically releases hormones into the bloodstream. Examples of glands include the islets of Langerhans in the pancreas, and the thyroid gland.

The endocrine system mostly starts in the area of the brain known as the hypothalamus. When a particular response is required, the hypothalamus releases a signal. This signal will usually be targeted to another area of the brain, the pituitary gland. The pituitary gland interprets the signal and then itself releases the appropriate chemical signal, usually a hormone. This signal will then travel through the body via the bloodstream to reach its required destination, which will be a gland. The gland then responds to the signal from the pituitary to secrete a particular hormone into the bloodstream. This will produce a response in the body.



Hormones

There are many types of hormones - the chemicals which are responsible for endocrine signalling. Like most signalling pathways, hormones will bind to receptors on specific cells. This will produce the desired response within the cell.

The different types of hormones include:

Peptide hormones: these are made from strings of amino acids. They are often made in the cell in advance and packaged into secretory vesicles until the signal is received for them to be released via exocytosis. Peptide hormones are often made in a longer form (called pre-hormone or pre-pro-hormone) which are then cleaved to create the mature form. When released, they will bind to cell-surface receptors and trigger a response inside the target cell. Peptide hormones usually bind to G-protein coupled receptors (GPCR) or tyrosine kinase receptors. Examples of peptide hormones include insulin, ACTH and thyroid stimulating hormone (TSH).

Steroid hormones: these are lipids formed from cholesterol. They travel around the body bound to carrier proteins as they are water-insoluble. Once they have entered the target cell, they bind directly to nuclear receptors, which then travel into the nucleus. These hormones directly regulate gene expression of target genes. Examples include cortisol and oestrogen.

 

Peptide hormone signalling e.g. insulin, ACTH



Steroid hormone signalling e.g. cortisol, oestrogen



Endocrine pathways

Each separate endocrine pathway is regulated by a specific set of hormones released from certain glands. The hormones will be released in response to a change in the body - e.g. insulin will be released when sugar has been eaten and ACTH is released in response to stress and in turn triggers the release of cortisol.

Many of the endocrine pathways also operate on a negative feedback loop - one of the target organs of many of the final-stage hormones is the pituitary gland, which then prevents the release of more hormone - for example the thyroid hormones T3 and T4 feedback to the pituitary gland and prevent the release of TSH.

Some examples of hormone pathways and glands are detailed below:

Thyroid signalling

Function: metabolic control (conversion of food to energy). The thyroid hormones T4 and T3 require iodine to function. A lack of iodine can lead to thyroid-related diseases (see below).

  • Hormone released from the hypothalamus: thyrotropin releasing hormone (TRH).
  • Hormone released from the pituitary gland: thyroid stimulating hormone (TSH).
  • Key gland and hormones: thyroid gland. Releases thyroxine (T4) which is converted to its active form triiodothyronine (T3) in the target tissue.
  • Target tissues: many, including liver, kidney, heart, CNS, skeletal muscle and pituitary.
  • Signalling mechanism: T3 and T4 function much like steroid hormones, in that they require binding proteins for transport around the bloodstream. The hormones usually travel around the body as T4 bound to a carrier protein such as thyroxine binding globulin or albumin. When they reach the target tissue, T4 is released from the binding protein and travels into the cell. It is then converted to T3 by iodothyronine deiodinase. T3 binds to the nuclear steroid receptor and this travels as a complex into the nucleus where the hormone directly regulates gene transcription.


Adrenal signalling

Adrenal cortex

Function: release of steroid hormones. Found just above the kidney, and is divided into three layers:

  • Zona glomerulosa: produces aldosterone which is regulated by angiotensin, and has a role in water/electrolyte balance.
  • Zona fasciculata: produces glucocorticoids, especialy cortisol (also known as hydrocortisone).
  • Zona reticularis: produces the sex steroids, oestrogen and testosterone.

 

Glucocorticoid signalling

Function: Stress response, immune/inflammatory response, carbohydrate and protein metabolism.

  • Hormone released from the hypothalamus: corticotropin releasing hormone (CRH).
  • Hormone released from the pituitary gland:adrenocorticotropic hormone (ACTH)
  • Key gland and hormone: adrenal cortex, section zona fasciculata. The main hormone released is cortisol.
  • Target tissues: liver, immune cells such as mast cells, pituitary gland, muscles.
  • Cortisol is a steroid hormone. It is produced from cholestserol and is transported around the body by a binding protein such as corticosteroid binding globulin/transcortin. It can travel through the cell membrane and binds to its receptor inside the cell. The hormone-receptor complex then travels to the nucleus to regulate gene transcritpion.

 

Other notes:

  • ACTH is released from the pituitary in response to stress.
  • Cortisol regulates ACTH release through a negative feedback loop.
  • Cortisol is converted to cortisone in the liver. This has a role in metabolism.


Pancreatic hormones

The pancreas is divided into two sections - exocrine and endocrine. The exocrine pancreas is responsible for the release of enzymes and other products to aid digestion. The endocrine cells in the pancreas are responsible for a range of hormones.

The endocrine cells in the pancreas are called the islets of Langerhans. Specific endocrine cells include the alpha-cells which release glucagon,beta-cells, which are responsible for the release of insulin, and C-cells, which release somastatin.

The most famous hormone released by the pancreas is insulin. The release of insulin is triggered by the ingestion of glucose (sugar).

  • Upon receiving the signal that glucose is present (the glucose binds to the GLUT2 receptor displayed on the surface of the beta cells) the beta-cells mobilise their pre-existing stocks of insulin, which are found packaged into secretory vesicles.
  • This mobilisation happens due to the closing of potassium channels by the downstream response to the GLUT2 receptor, which includes the release of ATP.
  • The closing of the potassium channels causes depolarisation of the cell and triggers calcium channels to open. The influx of calcium into the cell moves the insulin granules to the cell surface. Insulin will then be released from the cell.
  • Insulin acts on the liver, where it triggers the conversion of glucose to its storage form glycogen. It also acts on adipose (fat) tissue where it converts glucose to fat, and in muscles where glucose is converted to amino acids.

 

Glucagon, released from the alpha-cells, has the opposite effect to insulin and is released when glucose levels are low. Glucagon therefore triggers the production of glucose from stores such as glycogen.

Other endocrine glands/hormone systems

Glands

Pineal: found buried deep in the brain. Reponsible for the production of melatonin, an important hormone for circadian (time-dependent) rhythms. It is responsive to changes in light.

Ovaries/testes: responsible for the release of the sex steroids (also called gonadotrophins), oestrogen and testosterone (small amounts of these are also secreted from the zona reticularis of the adrenal cortex). These are steroid hormones and are responsible for sexual development as well as secondary sexual characteristics such as facial and body hair. They are released in response to gonadotrophin releasing hormone (GnRH) from the hypothalamus and follicle stimulating hormone (FSH) and luteinising hormone (LH) from the pituitary.

Parathyroid: found adjacent to the thyroid gland. Responsible for the release of parathormone, whcih helps to maintain calcium homeostasis throughout the body.

Thymus: found in the chest. Responsible for the release of the hormone thymosin, which is important for development of the immune T cells. The thymus is only functional as an endocrine gland until puberty.

 

Other hormone systems

Growth hormone: released from the pituitary in response to growth-hormone releasing hormone (GHRH) from the hypothalamus. It is a peptide hormone which signals through the janus-kinase-signal transducer and activation of transcription (JAK-STAT) pathway (tyrosine kinase receptors). Targets the liver to release insulin-like growth factor-1 (IGF-1). Responsible for growth in adolescence as well as bone mass, protein and carbohydrate metabolism.

Prolactin: similar to growth hormone in structure. Binds to a cytokine receptor. Responsible for lactation during pregnancy.

 

Disorders in endocrine signalling

Due to the complex nature of endocrine signalling, many disorders and illnesses are associated with endocrine systems. More detail about the specific endocrine disorders can be found elsewhere on Fastbleep, but this is a brief list of some medical conditions caused by defective endocrine signalling:

 

Pituitary tumours: overgrowth of cells or over-secretion of hormones from this gland can lead to several disorders, including;

  • Cushing's syndrome: ACTH oversecretion (see below).
  • Gigantism: growth hormone oversecretion. Dwarfism can be caused by a lack of growth hormone.
  • Prolactinoma: causes lactation and amenorrhoea (menstruation stops) - prolactin oversecretion. This is the most common type of pituitary tumour.

 

Thyroid disorders

  • Goitre: enlarged thyroid, causing swelling of the neck. Caused by lack of iodine (endemic goitre) or mutations in the thyroid signalling system, such as the TSH-receptor (toxic goitre)
  • Grave's disease: an overactive thyroid caused by antibodies binding to or stimulating the TSH receptor leading to stimulation of thyroid hormones without the signal. Symptoms include protruding eyes, muscle wasting, tremor and heat intolerance. 
  • Hashimoto's thyroiditis: underactive thyroid due to destruction of the follicular cells of the thyroid. Symptoms include weight gain, depression and memory loss.

 

Adrenal disorders

  • Cushing's syndrome: caused by a pituitary tumour oversecreting ACTH, which in turn leads to an overproduction of cortisol from the adrenal glands. May also be caused by other tumours oversecreting ACTH precursors, or tumours in the adrenal glands producing cortisol. Symptoms vary but can include "moon face", "buffalo hump", diabetes, truncal obesity, osteoporosis, easy bruising, poor wound healing.
  • Conn's syndrome: overproduction of aldosterone, sometimes due to an adrenal tumour. Symptoms include hyperkalaemia (high levels of potassium in the blood), muscle weakness and hypertension (high blood pressure).
  • Addison's disease: underproduction of aldosterone due to damage to the adrenal tissue (either through infarction (tissue death) or removal of adrenal glands in surgery). Symptoms include faintness and and hypotension (low blood pressure).

 

Pancreatic disorders

  • Diabetes mellitus Type 1 (a.k.a. juvenile-onset diabetes): this is caused by a destruction of the beta-cells of the pancreas, either by a virus or an autoimmune attack (by the body's own immune cells). This results in a total lack of insulin, which could be very dangerous. It is treated by injections of insulin, usually a recombinant human form of the protein.
  • Diabetes mellitus Type 2: This occurs when the cells which are normally responsive to insulin stop recognising it due to a problem with the insulin receptors. In Type 2 diabetes, the insulin is produced and released as normal, but it has less of an effect. It often occurs in patients who are obese. It can be controlled by diet and exercise.

 

In both cases of diabetes, diagnosis can be made by testing blood sugar levels - it is usually elevated in diabetes sufferers. If left untreated, diabetes can lead to blindness, chronic kidney disease and neuropathy (damage to the nerves), especially in hands and feet. Severe neuropathy can lead to the hand or foot needing to be amputated.

     

     

    References and further reading

    University of Manchester FLS Lecture Courses - Endocrinology and Reproduction (2nd Year, 2006-2007, co-ordinator Dr. Steve Bidey) and Clinical Endocrinology (3rd Year, 2008-2009, co-ordinator Dr. Donald Ward).

    Textbooks

    • Alberts et al, (2002) "Molecular Biology of the Cell" (4th Edition) Garland Science
    • Lodish et al, (2003) "Molecular Cell Biology" (5th Edition) W.H. Freeman

     

    Papers

    • Mayer et al (2007) "Insulin Structure and Function" Peptide Science 88 (5) 687-713
    • Lisurek and Bernhardt (2004) "Modulation of aldosterone and cortisol synthesis on the molecular level" Molecular and Cellular Endocrinolgy 215 (1-2) 149-159

     

    Websites

    http://www.endocrineweb.com/ 

    http://www.endoatsoim.com/endocrine_system.html

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