Endocrine signaling occurs when endocrine cells in ductless glands release hormones into the bloodstream to act on distant target cells. The major glands involved include the thyroid, adrenals, pancreas, ovaries/testes, parathyroids, thymus and pineal gland. Hormones can be peptides like insulin which bind cell surface receptors, or steroids like cortisol which enter cells and affect gene expression. Many pathways operate in a negative feedback loop controlled by the hypothalamus and pituitary gland.

1. Topic: Endocrine signaling
Introduction:
Cell signaling is part of a complex system of communication that governs basic cellular activities
and coordinates cell actions. 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. Cellular signaling can be classified into following: Intracrine signaling,
paracrine signaling, Juxtacrine signaling, autocrine signaling and endocrine signaling.
Endocrine signaling:
The word endocrine is actually from the Greeks and the endo definition means "within" and krine
definition means "to separate or to secrete." The term endocrine means “secreting internally,” and
specifically refers to secretions that are distributed in the body by way of the bloodstream.
Endocrine cells are made up of ductless glands that produce chemical messages called hormones,
which are released into the internal environment of the body. These Endocrine secretions are
distinguished from exocrine secretions, which are released to the external environment. Thus,
endocrine signaling occurs when endocrine cells release hormones that act on distant target cells
in the body.
The endocrine system:
The key organs in endocrine signaling 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 signaling 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.

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

3. Peptide hormone signaling:e.g. insulin, ACTH
Steroid hormone signaling e.g. cortisol, estrogen

4. 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 signaling:
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.
 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: they are many, including liver, kidney, heart, CNS, skeletal muscle and
pituitary.
Signaling 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 signaling
Adrenal cortex
Function: release of steroid hormones. Found just above the kidney, and is divided into 3 layers:

5.  Zona glomerulosa: produces aldosterone which is regulated by angiotensin, and has a role
in water/electrolyte balance.
 Zona fasciculata: produces glucocorticoids, especially cortisol (also known as
hydrocortisone).
 Zona reticularis: produces the sex steroids, estrogen and testosterone.
Glucocorticoid signaling:
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: It is a steroid hormone. It is produced from cholesterol 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 transcription.
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 soma statin.
The most famous hormone released by the pancreas is insulin. The release of insulin is triggered
by the ingestion of glucose (sugar).

6.  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 mobilize their pre-existing stocks
of insulin, which are found packaged into secretory vesicles.
 This mobilization 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 depolarization 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. Responsible 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),
estrogen 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 luteinizing hormone (LH) from the pituitary.
Parathyroid: found adjacent to the thyroid gland. Responsible for the release of parathormone,
which helps to maintain calcium homeostasis throughout the body.

7. 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 signaling
Due to the complex nature of endocrine signaling, many disorders and illnesses are associated with
endocrine systems. More detail about the specific endocrine disorders can be found elsewhere on
Fast bleep, but this is a brief list of some medical conditions caused by defective endocrine
signaling:
Pituitary tumors: overgrowth of cells or over-secretion of hormones from this gland can lead
to several disorders, including;
 Cushing's syndrome: ACTH over secretion.
 Gigantism: growth hormone over secretion. Dwarfism can be caused by a lack of growth
hormone.
 Prolactinoma: causes lactation and amenorrhea (menstruation stops) - prolactin over
secretion. This is the most common type of pituitary tumor.
Thyroid disorders
 Goiter: enlarged thyroid, causing swelling of the neck. Caused by lack of iodine (endemic
goiter) or mutations in the thyroid signaling system, such as the TSH-receptor (toxic goiter)

8.  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 tumor over secreting ACTH, which in turn
leads to an overproduction of cortisol from the adrenal glands. May also be caused by other
tumors over secreting ACTH precursors, or tumors 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 tumor.
Symptoms include hyperkaliemia (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.

9. 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.
Reference:
 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
 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
 Cell signaling. (2015, October 2). In Wikipedia, The Free Encyclopedia. Retrieved 15:08,
December 8, 2015, from
https://en.wikipedia.org/w/index.php?title=Cell_signaling&oldid=683709097
 Structural Biochemistry/Cell Signaling Pathways/Endocrine Signaling. (2014, September
6). Wikibooks, The Free Textbook Project. Retrieved 15:09, December 8, 2015 from
https://en.wikibooks.org/w/index.php?title=Structural_Biochemistry/Cell_Signaling_Path
ways/Endocrine_Signaling&oldid=2697988.
 Endocrine Signalling written by: Louise Walker from Manchester
University,http://www.fastbleep.com/biology-notes/31/174/997
 http://www.endocrineweb.com/
 http://www.endoatsoim.com/endocrine_system.html
 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)