Endocrinology Topics   

Basic Concepts

Hormones

Hormones are chemical substances secreted into body fluid by one cell or a group of cells which will ultimatelly have a physiological effect on other cells or tissue in the body.

Hormones are secreted in response to specific stimuli. The rate of hormone secretion depends on nature and intensity of the stimuly.

Hormones are secreted by endocrine glands into the bloostream to act upon specific target organs. Many organs are endocrine glands (see list in Box 2). Endocrine glands are ductless, have a good blood supply, respond to regulatory signals, have diverse embryological origins, and are usually of small size.

The target organs are acted on by the hormone because the organ has receptors for the hormone. At the target organ, hormones modify existing metabolic processess.

Hormones are present in blood in minute quantities and are continuously inactivated and excreted.

Hormones are of a varied chemical nature. They include amines like epinephrine, polypeptides like ADH, complex proteins like TSH, thyroid hormones like T3, steroids like testosterone, and arachidonic acid derivatives like protaglanding F2a.

Signals of the endocrine system are propagated by the secretion of hormone from the endocrine gland into the bloodstream, distribution of hormone by blood to all organs, and action of hormone at their specific target organs because only those organs have the receptors to receive the signal. This is different from other signaling methods, like that of the nervous system. Neurotransmitters are released into the synaptic cleft between neurons by the axon of one neuron and received by receptors in the dendrites of the next neuron. In some cases, hormones can also act as neurotransmitters. Hormones may act locally on neighboring cells (paracrine action) or themselves (autocrine action). Hormones that are released by by nerve cells but act on target tissues in an endocrine fashion are said to have neuroendocrine action.

The stimuli to release hormone may be humoral (increased concentrations of a chemical in blood, ex. blood glucose), neural (neuroendocrine signaling, ex. ??), or hormonal (endocrine signaling from one gland to another, ex. FSH from pituitary affects steroid release from gonads).

While amine, peptide and small protein hormones can usually travel freely in the blood, others must travel bound to transport proteins. Steroids and thyroid homones have their own binding proteins: thyroid hormone-binding globulin (TBG), cortisol binding globulin (CBG), etc. Even some small proteins like the insuline-like growth factors (IGFs) and grothe hormone (GH) have specificv binding proteins. GH in plasma is mostly bound to growth hormone binding protein (GHBP).

Most hormones in plasma are eventually metabolized by the liver or kidneys into more soluble, inactive compounds that can be excreted. Only about 1% is excreted intact. Carrier proteins affect the rate of hormone clearance, ex. the half-life of thyroid hormone is about 1 day, while the half time of free peptides is minutes to hours. The metabolic clearance rate (MCR) of an hormone is the volume of plasma cleared of hormone by unit of time:

MCR   =   Vp / t   =   mL / min

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General Signaling Pathways

Endocrine function is carefully controlled by five mechanisms: simple control, negative feedback, positive feedback, inhibitory control and metabolic control. In a simple control mechanism, hormone is produced in small amounts and for short time periods. Often the target organ can only respond to certain hormone level. An example of simple control ???

Negative feedback is common mechanism in which the response of the target organ acts on receptors in the endocrine gland to inhibit hormone release.

An example of negative feedback is the represion of TSH release from the pituitary by thyroid hormone.

Positive feedback mechanism are less common. The target organ's response will act on the endocrine gland to increase hormone relese until the stimulus stops.

An example of positive feedback is the increased oxytocin release after milk ejection. Sensation on the nipple, either by the baby suckling or by the presence of milk on the nipple will increase hormone release.

Hormones with broad actions are often controlled by inhibitory hormones. Suppression of the inhibitory hormone leads to target hormone release.

For example, prolactin release is continually blocked by dopamine from the hypothalamus.

Some hormones are converted to their active form by metabolic enzymes in the target tissue, and these enzymes may be controlled locally.

For example, testosterone is converted to dihydroxytestosterone in the testis.

After the hormone has reached its target organ, it will bind and activate its receptor. The receptor will be either a membrane receptor or a nuclear receptor. While some hormones are structuarally very similar, their receptors are specific enough that they only bind their cognate ligand and not others, ex. estradiol and testosterone. Activation of membrane receptors triggers cytosolic signaling cascades, and each receptor is able to trigger one or more types of signaling cascades. Active nuclear receptors act as transcription factors, directing expression of specific genes.

Cytosolic signaling cascades commonlly activated by hormones include cyclic AMP pathways, phosphatidyl inositol pathways, MAP kinase pathways and JAK/STAT pathways. Hormone receptors that activate the cyclic AMP pathway are G-protein coupled receptors (GPCR), i.e. they are linked to GTP-dependent proteins (G proteins) that in turn can indrease or inhibit the activity of adenylate cyclase. The enzyme adenylate cyclase converts ATP into cAMP. Increased concentrations of the second messenger cAMP inside the cell lead to the cellular effects of the hormone --activation of kinases, proteins phosphorylation-- which in turn mediate the physiological effects of the hormone.

Hormone receptors that activate the phosphatidyl inositol pathway may be receptor tyrosine kinases (RTK) or GPCR. <more about this later>

Hormone receptors that activate the MAP kinase pathway <more about this later>

Growth hormone, prolactin and cytokines signal thru the JAK/STAT pathway. Ligand-induced dimerization of the receptor induces the reciprocal tyrosine phosphorylation of the associated Janus tyrosine kinase (JAK), which, in turn, phosphorylates tyrosine residues on the cytoplasmic tail of the receptor. These phosphorylated tyrosines serve as docking sites for the Src Homology-2 (SH-2) domain of the signal transducer and activation of transcription (STATs 1, 3 and 5) protein, and JAK catalyzes the tyrosine phosphorylation of the receptor-bound STAT. Phosphorylation of STAT at a conserved tyrosine residue induces SH-2-mediated homo- or heterodimerization, followed by translocation of the STAT dimer to the nucleus.

The steroid and thyroid hormones signal through nuclear receptors. <more about this later>

RANKL, a signaling molecule involved in hormonal control of calcium homeostasis, signals through the Ras/MEKK/JNK/Jun pathway.

Anotherpathway important in hormonal regulation of calcium homeostasis is the Wnt/Fz/GSK3/b-catenin pathway:

Endocrine diseases may be due to one or more causes: lack of hormone (s), lack of receptor (s) excess hormone or lack of control(s) system. The defect may be in the organ originating the hormone, in the target organ, or in some other related organ. For example, if a patient has growth hormone deficiency it may be because of a mutation in growth hormone releasing hormone (GHRH) in the hypothalamus, mutation of the GHRH receptor in the pituitary, or an increase in somatostatin (negative regulator of GH) levels.

If a hormone is defective or missing, it can be replaced. Small molecules like thyroid hormone or estrogen can be given orally, but larger molecules like insuline or growth hormone must be delivered by injection. If a receptor s missing, the patient can take molecules that act dowstream of the receptor, or hopefully in the future defective/missing receptors will be replaced by gene therapy.

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Research and Diagnosis Techniques

Several techniques are used: bioassays, surgical assays, hormone assays, receptor assays, gene expression analysis, gene structure analysis, gene function analysis, microscopy, chromatography, scanning, and structural studies.

Bioassays: frog skin bioassay for melanocite stimulating hormone (MSH) measures color change.

Surgical assays: parabiosis experiments by Coleman (1978), surgically joining blods treams of ob/ob obese mouse and normal mouse will decrease the obesity of the ob/ob mouse. ob/ob = mutant leptin ; db/db mouse = mutant leptin receptor. Same procedure done for a db/db mouse will have no effect.

Four types of hormone assays: competition/saturation assay, sandwich/immunometric assay, western blot and immunohistochemistry. Both competition/saturation assay, sandwich/immunometric assay use antibodies which must be specific and sensitive. Competition/saturation: antibody is limited in relation to labeled hormone thus equilibrium of free vs. bound hormone can be measured and estimatepresence of non-labeled hormone. <more later about RIA>

Sandwich/immunometric assay: Excess antibody linked to solid phase binds hormone, then add second labeled antibody recognizing a different epitope, hormone can be measured more sesitive and faster. <more about this later>

Wester blot for hormone protein <more about this later>

Immunohistochemistry <more about this later>

Autoradiography <more about this later>

RadioReceptor Assay <more about this later>

Gene expression analysis: reporter gene assays, PCR, DNA sequencing, sothern blot, northern blot, transgenic animals, gel-shift assay. <more about this later>

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