Group 1 hormone: Hormones have intracellular receptors and affect gene expression.

1. Hormones in this group are lipophilic and derived from cholesterol and amino acid derivative T3 and T4.

2. After secretion from specific glands, these hormones associate with transport proteins.

3. As soon as they bind to the plasma membrane of target cells, they detached from binding protein (carrier protein).

4. The free hormone readily traverses the plasma membrane of target cells, and encounter receptors in either the cytosol or nucleus of the target cells.

5. The ligand receptor complex assumed to be intracellular messenger in this group.
The general feature of these hormones are:
a) The hormone diffuses through the plasma membrane of all cells but only encounter their specific, high affinity receptor in target cells.

b) The hormone receptor complex undergoes a temperature and self dependent activation reaction that results in size, conformation, and surface charge changes that render it able to bind to (DNA) chromatin.

c) The hormone receptor complex binds to a specific region of DNA called the hormone response element (HRE) and activates or inactivates specific genes.

d) By selectively affecting gene expression and the production of the respective messenger RNAs, the amount of specific proteins are changed and metabolic processes are influenced.

Classification of hormone by general mechanism of action

1. Group 1. Hormones that bind to intracellular receptors

2. Group 2. Hormones that bind to cell surface receptors
a) Second messenger is c AMP
Eg. ACTH, ADH, PTH, TSH, glucagon
b) Second messenger is c GMP Eg. ANP, NO
c) Second messenger is calcium or phosphoinocitol or both Eg.Ach, α ADRENERGIC, TRH
d) Second messenger is a kinase or phosphatase cascade Eg. GROWTH FACTORS, INSULIN

General mechanism of hormone Action

1. Group 1 hormone: Hormones have intracellular receptors and affect gene expression.

2. Group 2 hormone: Hormones have membrane receptors and use intracellular messengers

Breakdown of hormones

1. Peptide and protein hormones are broken down into amino acid that enter into the amino acid pool.

2. Steroid hormones are hydroxylated in the endoplasmic recticulum and then conjugated with glucuronic acid, sulfate and phosphate. Thus, the end product of steroid hormones are conjugated compounds.

Receptor For Steroid Hormones

Intracellular receptors or intra nuclear receptors have several functional domains.

1. Site for binding of hormone

2. Site that bind to specific DNA binding region

3. Site that concern to activates or repress the gene transcription on DNA

4. High affinity binding to DNA

The Receptor For Water Soluble Hormone-Cellular surface receptors

Classified into three types:
1. Ion- channel linked receptors → Transmitter gated ion channels Eg.Ach, Na+,Ca+

2. G- Protein linked receptors → The interaction between the receptor and target protein is mediated by third protein called G Protein

3. Enzyme linked receptors → When activated, either function directly as enzyme or associated with enzymes.

Membrane Receptors & Nuclear Receptors

1. Imbedded in target cell membrane; integral proteins/ glycoproteins; penetrate through membrane.

2. For protein & charged hormones (peptides or neurotransmitters)

3. 3 major groups: Serpentine = 7 transmembrane domains, Growth factor/cytokine = 1 transmembrane domain, Ion channels.

4. Nuclear Receptors
Nuclear proteins that usually act in pairs & bind to specific Hormone Recognition Elements (HREs) = sequences on the DNA in the promoter regions of target genes.
For small, hydrophobic molecules (steroids, thyroid hormones)

What is a hormone receptor?

1. Hormone Receptors are cellular proteins that bind with high affinity to hormones & are altered in shape & function by binding; they exist in limited numbers.

2. Binding to hormone is non-covalent & reversible.

3. Hormone binding will alter binding to other cellular proteins & may activate any receptor protein enzyme actions.

RECEPTORS

1. The first step in action of hormone is its binding to a specific molecules called receptors. All are protein in nature.


2. There are two types of receptors:

a) The receptor for water soluble hormone- Cell surface receptors
b) The receptor for fat soluble hormones – Intracellular receptors.

CLASSIFICATION OF HORMONE BY GENERAL MECHANISM ACTION

1. Hormones that bind to intracellular receptors.


2. Hormones that bind to cell surface receptors

a) Second messenger is c AMP
Eg. ACTH, ADH, PTH

b) Second messenger is c GMP Eg. ANP,NO

c) Second messenger is calcium or phosphoinocitol or both Eg.Ach, α ADRENERGIC,TRH

d) Second messenger is a kinase or phosphatase cascade Eg. GROWTH FACTORS,INSULIN

Factors influencing hormone production

There are many factors that influence hormone levels:

1. Time of day (cortisol - diurnal variation)

2. Time of month (LH/FSH/estradiol in menstrual cycle)

3. Time of year (melatonin levels higher in winter)

4. Age (T3 lower in elderly subjects, sex steroid levels lower in pre pubertal children)

5. Sex (testosterone/estradiol levels in men and women)

6. Stress (cortisol, adrenaline increase during stress )

7. Diet (insulin , growth hormone, cortisol change in fasting/feeding states)

8. Illness (thyroid function tests in non thyroidal illness)

9. Drugs (amiodarone/contraceptive pill effect TFT results)

Concentration of Hormones in body fluids

1. Hormones are present at very low concentration in the extra cellular fluid especially in the blood. Generally ranges from 10-15 to 10-9 mol/ L

2. Some hormone level higher up to 10-5 to 10-3 mol/ L in the plasma at physiological variations.

Transport of Hormones

1. Steroid hormone need to transport proteins to go to the target cell.

2. T4 is bound to albumin as well as globulin. (TBG) The protein bound form of T4 is 99.98% and the remainder exist as the free form.

3. Glucocorticoids bind to a globulin called transcortin or cortico steroid binding globulin . (CBG)

4. Testerone and estrogen bind to plasma globulin called sex hormone binding globulin (SHBG) or testerone estrogen binding globulin (TEBG).

Biosynthesis of hormones

1. Hormones may be synthesized and secreted in the active form directly. Eg, estriol, aldosterone, hydrocortisone and catecholamines.

2. Hormones that are modified in the secreting cells prior to secretion. Eg. Insulin and parathyroid hormone. Both are synthesized as the prepro hormone and during their passage through the organelles in the process of synthesis the prepro segment are removed and the active hormone is secreted. The anterior pituitary produces pro-opiomelanocortin (POMC) which is cleaved to yield 3 basic peptide groups of hormones- ACTH, beta lipocortin and gamma MSH.

3. Hormones that are converted into active form in the peripheral tissues. The peripheral tissue may be:

a) Target tissue; Conversion of T4 to more active form T3 in liver and pituitary. Conversion of testosterone to dihydrotesterone secondary sex tissues. In both cases, T4 and testosterone act as prohormone.

b) Non target tissue
The prohormone dehydroepianderosterone (DHEA) is converted to the active form by sulfation in the liver. By removal of sulfate, reactivate the hormone which is then converted to androstenedione ( 4 androstene- 3, 17- dione) which on reduction from testerone (17 β hydroxy- 4 androsten trione)

c) Combination of target and non target tissues
Conversion of vitamin D3 (formed from UV light radiation on 7- dehydrocholesterol) to 25 hydroxy cholecalceferol in the liver (nontarget tissue) with subsequent conversion to 1,25- dihydroxy cholecalceferol in the kidney (target tissue).

Feed back regulation of hormones

1. The plasma level of some hormones control by feed back mechanisms. If the circulating hormone level is increases, the hormone can control it’s synthesis by negative feed back regulation.

2. Conversely decrease circulating hormone level will positively regulate its synthesis by positive feed back regulation

3. Eg.hypothalamic pituitary target gland system, thyroid hormone, adrenal, ovarian testicular hormones.

4. Positive feed back regulation can be seen in secretion of progesterone which are required for the acute burst of LH secretion that result in ovulation and follicular luteinization and further production of these steroid hormones.

5. Negative feed back regulation - The levels of circulating hormones are regulated by a feed-back mechanism. Increased levels of circulating oestrogen and progesterone have in inhibitory effect on the hypothalamic neurons, which through GnRH decrease the secretion of FSH and LH. 

HORMONAL CASCADE OF SIGNALS FROM CNS TO ULTIMATE HORMONES

1. For many hormonal systems in higher animals, the signaling pathway originates in the brain and culminates in the target cell.

2. The stimulus may originate in the external environment or within the organism in this cascade.

Chemical nature of hormones

Hormones have many different types of chemical nature. Some of them are

1. Steroids- Adrenocortical hormones, sex hormones and dihydroxycholecalceferol.

2. Peptides and proteins- Insulin, parathyroid hormone, antidiuretic hormones (ADH), glucagon, adrenocorticotropic hormone (ACTH), beta lipotropin, MSH, endorphins, oxytocin, thyrotropin releasing hormone (TRH); growth hormone, prolactin and chorionic sommatotropin.

3. Glycoprotein- Thyroid stimulating hormones (TSH), follicular stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG)

4. Amino acid derivatives- Catecholamines and thyroid hormones are derived from amino acid tyrosine.

5. Some local hormones are derived from lipids: prostaglandins from arachidonicacid which is derived from essential fatty acid linoleic acid.

What kinds of hormone are there?

Known Hormonal Classes

1. Proteins & peptides

2. Lipids (steroids, eicosanoids)

3. Amino acid derived (thyroxines, neurotransmitters)

4. Gases (NO, CO)

Other kinds of hormones

1. Paracrine hormones
It arise from a cell and travel a relatively small distance to interact with their cognate receptors on another cell. For example, insulin-like growth factors secreted by a muscle cell may promote the growth of neighboring muscle cells and connective tissues.

2. Autocrine hormones
They are produced by the same cells that is also a target. (near by cells may be targets)

Hormones

1. Hormones are chemical messenger that carries a signal to generate some alteration at the cellular level.

2. Thus, endocrine hormones are class of hormones that arise in one gland and travel a considerable distance through the circulation to reach a target cell bearing its cognate receptors.

What are the elements of an endocrine system?

1. Sender = Sending Cell

2. Signal = Hormone

3. Nondestructive Medium = Serum & Hormone Binders

4. Selective Receiver = Receptor Protein

5. Transducer = Transducer Proteins & 2º Messengers

6. Amplifier = Transducer/Effector Enzymes

7. Effector = Effector Proteins

8. Response = Cellular Response (2º hormones)

What are endocrine systems for?

Endocrine Functions:

1. Maintain Internal Homeostasis

2. Support Cell Growth

3. Coordinate Development

4. Coordinate Reproduction

5. Facilitate Responses to External Stimuli

Two main regulatory system

1. Regulatory systems do communicate within the cells and between groups of cells or tissues.

2. In human, there are two main regulatory systems: central nervous system and endocrine system.

3. The hormonal elements are a number of agents involved in these regulatory systems.

4. They control and regulate cellular activity.

5. The nervous system exerts point-to-point control through nerves, similar to sending messages by conventional telephone. Nervous control is electrical in nature and fast.

6. The Endocrine System broadcasts its hormonal messages to essentially all cells by secretion into blood and extra cellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

7. As will be repeatedly demonstrated, the nervous and endocrine systems often act together to regulate physiology. Indeed, some neurons function as endocrine cells.

Two main regulatory system

1. Regulatory systems do communicate within the cells and between groups of cells or tissues.

2. In human, there are two main regulatory systems: central nervous system and endocrine system.

3. The hormonal elements are a number of agents involved in these regulatory systems.

4. They control and regulate cellular activity.

5. The nervous system exerts point-to-point control through nerves, similar to sending messages by conventional telephone. Nervous control is electrical in nature and fast.

6. The Endocrine System broadcasts its hormonal messages to essentially all cells by secretion into blood and extra cellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

7. As will be repeatedly demonstrated, the nervous and endocrine systems often act together to regulate physiology. Indeed, some neurons function as endocrine cells.

What is Endocrinology?

Endocrinology = Intercellular Chemical Communication

Endocrinology is about communication systems & information transfer.

Physiology of Pituitary hormones

Anterior Pituitary Hormones

1. Polypeptides/proteins – ACTH, prolactin, growth hormone


2. Glycoproteins – TSH, LH, FSH


3. Tropic hormones (ACTH, TSH, FSH, LH, GH) – stimulate secretion of hormonally active substances by other endocrine glands or in case of GH, the liver and other tissues.


4. A number of other peptides are synthesized and secreted from anterior pituitary together with ACTH: endogenous opiate beta endorphin, precursor of Melanocyte-stimulating hormone (Melanotropins).


5. Prolactin
a) Prolactin secretion may be influenced by PRH but is mainly controlled by PIH (probably dopamine).

b) During pregnancy, stimuli which reduce PIH release from hypothalamus raises prolactin levels- favouring development of breast ready for lactation and as part of suckling reflex during lactation.


6. Growth Hormone
Long arm of human chromosone 17 contains GH-hCS cluster genes:
a) hGH-N (normal)
b) hGH-V (variant)
c) hCS (2 codes)
d hCS pseudogene

Species specificty

7. Growth Hormone Receptor
Somatomedins – effects of GH on growth, cartilage and protein metabolism depend on interaction between GH and Somatomedins (peptide growth factors).


8. Actions of GH
a)Effects on growth -stimulates the growth of long bones, accelerated chondrogenesis, more matrix at the end of long bones, stature is maintained.

Abnormalities of GH may lead to gigantism.

When epiphyses are closed, GH produces pattern of bone & soft tissue deformity (Acromegaly)


b) Effects on protein & electrolyte metabolism
Produces positive nitrogen and phosphorus balance.

Fall in blood urea nitrogen and amino acid levels.

Increase in metabolic rate.

Fall in plasma cholesterol.

Gastrointestinal absorption of calcium is increased.

Sodium and potassium excretion is reduced.

Stimulates synthesis of soluble collagen.


c) Effects on carbohydrate & fat metabolism

Diabetogenic – increases hepatic glucose output and anti-insulin effect on muscle.

Ketogenic – increases circulating FFA levels.

Increases ability of pancreas to respond to insulinogenic stimuli such as arginine and glucose.


9. Regulation of GH

The secretion of GH undergoes marked and rapid spontaneous fluctuation in children and young adults before it declines in old age.

Hypothalamic control

a) Growth hormone-releasing hormone (GRH)
b) Growth hormone release-inhibiting factor (somatostatin)
c) ghrelin – has GH stimulating activity.