Endocrinology - Lecture notes 12,13,14,15 PDF

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Lecture notes/Exam notes for ucl human physiology endocrinology section...

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Physiology Lecture (12) Notes ENDOCRINOLOGY; Introduction to the Endocrine System; Endocrine System; > One of the two communication systems of the body, the other being the nervous system. > The endocrine system operates through chemical messengers or hormones which circulate in the blood to target organs. > Hormones co-ordinate the minute to minute and day to day functions of the various tissues of the animal > Hormones help regulate such diverse activities such as - Growth and development of physical, sexual and mental characteristics - Utilization of nutrients by the cells - Adjustments of salt and water balance - Metabolic rate - Dealing with stress

Principal Endocrine Glands; > The principal endocrine organs are ; - The pituitary - The Thyroid - Parathyroid - Adrenals - Gonads (Ovaries/Testes) > Other organs such as the islets of Langerhans, heart. Gastrointestinal tract, brain and kidney also secrete hormones > Definitions; - Endocrine Cells; Secrete hormones into a blood vessel and hormone transported to target cells - Paracrine cells; Secrete hormones which act on neighboring cells - Autocrine cells; secrete hormones which act on the same cell - Neuroendocrine cells; Secrete hormones from neural axon terminals straight into blood stream

Hormones;

> Can be made from a number of molecules; - Proteins or polypeptides eg. Insulin - Glycoproteins eg. LH, FSH and TSH - Derivatives of the amino acid tyrosine eg; adrenaline, thyroid hormones (T3 and T4) - Steroids derived from cholesterol - Lipid-derived molecules such as prostaglandins > Regulate a number of biochemical processes - Growth; development of physical sexual and mental characteristics - Growth hormones, thyroid hormones, testosterone and estrogens - Utilization of nutrients by cells - Insulin glucagon, cortisol, growth adrenaline - Adjustment of salt and water balance - Aldosterone, vasopressin (ADH) Atrial Naturistic Factor (ANF) ) - Metabolic Rate - Thyroid Hormones - Dealing with Stress - Cortisol, adrenaline

Major Categories of Hormones; > Amines; (amino acid tyrosine based) - Eg; Adrenaline, dopamine, thyroid hormone > Steroid; Derived form Cholesterol - Eg; Testosterone, Estrogens > Proteins - Eg; Glyco-proteins eg TSH, LH, FSH

Classification of Hormones; > Hydrophilic; - Will not enter cells and must bind to cell surface receptors - Receptors are integral membrane proteins - Hormones can be stored in secretory vesicles - Eg; adrenaline, HGH, vasopressin > Hydrophobic; - Will enter cells and receptor is a soluble protein inside cytoplasm and can enter nucleus - Hormones cannot be stored and are synthesized on demand - Eg; Thyroid hormones T3 Vitamin D3

> Peptide and protein hormones, adrenaline etc., are stored as pre-formed molecules in secretory vesicles. > A stimulus will cause the release of the secretory vesicles by exocytosis where the plasma membrane fuses with the vesicle membranes leading to the release of their contents to the cell exterior > Steroids on the other hand are lipophilic and are therefore not stored in cells - They are synthesized on demand from cholesterol

Transport of Hormones in the Blood; > Most peptides and protein hormones are hydrophilic and therefore circulate in the blood in the free form - Steroid hormones and thyroxine are hydrophobic and are therefore transported in the blood bound to serum proteins - Eg; thyroxine binds to thyroxine binding globulin, cortisol binds to cortisol binding protein > Each globulin is specific to it’s hormone; - Only the free circulating hormone is “active” - remainder acts as a reservoir - Therefore, hormone levels can be altered just by changes in the level of the binding proteins themselves.

Half Life T½ of Hormones; > Hormones have to be removed from circulation and this is done by the kidney, liver and occasionally lungs - The rate of clearance will determine the half-life of the hormone and this will vary with the different hormones (rate of their metabolism). - Half-life (T1/2) of a hormone is defined as the time required to reduce the circulating hormone concentration by half. > Example; If the [adrenaline] = 30 um at T=0 and is now 15um at T=30s, then the half life of adrenaline = 30 seconds

How Hormones Work; > Hormones interact with specific receptors on target cells - The receptor can be either localized the cell surface or in the nucleus - Most hydrophilic molecules act on the cell surface, but steroid hormones and thyroid hormones have their own receptors in the nucleus > Hydrophobic hormones; - Work on a longer timescale than hydrophilic hormones

Hydrophilic Hormones; >

Hormones acting at the cell surface act by generating second messengers or by tyrosine phosphorylation of specific target proteins

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They use a three-component system, consisting of RECEPTOR, G-PROTEIN and ENZYME to make intracellular messengers ~800GPCRs in the human genome and 17 G alpha proteins

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Two examples of second messenger systems which are widely used; - (1) Receptor interacts with a GTP binding proteins Gs and this protein activates adenylate cyclase.

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Adenylate cyclase catalyzes the conversion of ATP to cAMP.

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Phosphorylation regulates the function of target proteins

cAMP interacts with a specific protein kinase A (PKA) and this stimulates phosphorylation of target proteins.

Serine, threonine and tyrosine residues in proteins can be phosphorylated by ATP Phosphorylation can change the “activity” status of the protein, eg an enzyme can be ‘activated’ or ‘deactivated’ Phosphorylated proteins are dephosphorylated by enzymes called phosphatases

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(2) Receptor interacts with GTP binding proteins Gq and this protein activates the enzyme phospholipase C. - Phospholipase C catalyses the hydrolysis of a membrane lipid phosphatidylinositol (4,5) bisphosphate (PIP2) to release two second messenger; - Inositol (1,4,5) – trisphosphate (IP3)) and diacylglycerol. - IP3 is responsible for causing an increase in cytosol [Ca2+] by opening IP3 – gated channels t the endoplasmic reticulum and diacylglycerol activates protein kinase C (PKC)

> The second messengers cAMP, diacylglycerol, Ca2+ control many of the cellular functions of the cell (other second messengers are cGMP) - Receptors that activate G-proteins are often referred to as GPCRs (G-protein-coupled receptors) - These receptors have SEVEN transmembrane regions

Tyrosine Phosphorylation as a Signal Transduction Event; > Insulin receptors are single transmembrane proteins and contain tyrosine kinase activity - Insulin causes tyrosine phosphorylation of target proteins and activates the enzyme PI3K - PI3K phosphorylates PIP2 to PIP3 and this activates a protein kinase PKB (Protein kinase ) > Growth Hormone and Prolactin receptors are single membrane spanning proteins and their mode of signaling is through JAK-STAT signaling pathways - JAK (Janus kinase) is a tyrosine kinase and phosphorylates STAT (Signal Transducer and Activator of Transcription) - STAT enters the nucleus and promotes transcription of genes. > Phosphorylation of proteins regulates activity – another molecular SWITCH commonly used in cells.

Steroid Hormones and Thyroid Hormones are LipidSoluble Hormones; > These hormones circulate in the blood bound to globulins - The unbound hormone enters the cells from the blood and binds to a receptor in the nucleus. - The complex binds to DNA and activates the transcription of specific genes. - The mRNA directs the synthesis of specific proteins, enzymes etc.

Negative Feedback; > Negative Feedback is defined as a signal produces a response which feeds back on the signal generator to decrease the level of the signal - In order to regulate hormones released by this mechanism, the first hormone (Hormone A) is released from Cell A. - Hormone A acts on Cell B (eg; anterior pituitary) to trigger the release of Hormone B. - Hormone B acts on Cell A to inhibit production of Hormone A > Thus many of the hormones of the anterior pituitary which are trophic hormones and which act on other endocrine glands such as the thyroid, adrenal cortex, to stimulate production of other hormones are controlled by negative feedback.

Organisation of the Endocrine System; Hypothalamus and the Pituitary; > The pituitary is located at the roof of the mouth and is responsible for controlling many of the endocrine organs such as the thyroid, adrenals and gonads and is thus regarded as the master gland of the body. - The pituitary itself is controlled by the hypothalamus which receives inputs from the CNS > The pituitary can be subdivided into the anterior (adenohypophysis) and the posterior )neurohypophysis). - In the lower animals (reptiles, Amphibia) a third intermediary lobe is present which is responsible for the hormone melanocyte stimulating hormone (MSH).

Control of the Endocrine System; > Since the primary role of the endocrine system is one of control, it is useful to consider the possible mechanisms available for control; > Hypothalamus/Pituitary Axis; - Posterior Pituitary is an example of Neurohormone secretion

> Acronyms; - GnRH – Gonadotrophin Releasing hormone - GHRH – Growth hormone RH - TRH – Thyrotropin RH - CRH – Corticotrophin RH - FSH – Follicle Stimulating Hormone* - LH – Luteinizing Hormone* - TSH – Thyroid Stimulating Hormone* - ACTH – Adrenocorticotrophin - IGF – Insulin like Growth Factor - T3/T4 – Thyroid Hormones - *Glycoproteins Made of two subunits Alpha and Beta subunits

Anterior Pituitary; > The anterior pituitary synthesizes and secretes 6 hormones stored in these cells; - Somatotrophs – Stores Growth hormone - Lactotrophs – Stores Prolactin - Gonadotrophs – stores FSH/LH - Corticotrophs – stores ACTH - Thyrotrophs – Stores Thyroid stimulating hormone > (1) Growth Hormone (GH);

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A polypeptide hormone which is specific-specific. GH has powerful effects on growth and metabolism. - Absence results in dwarfism an excess results in gigantism - Functions; Effects of GH on two time scales; corresponding to a long term growth effect and short term effect on metabolism > (2) Prolactin; - Resembles GH in structure. Its main function is to induce mammary gland growth and milk secretion essential for lactation. - Levels of prolactin is high in pregnancy due to the increase in the size and number of prolactin-secreting cells stimulated by estrogens. - Higher prolactin levels in females compared to males generally - Prolactin has effects on salt and water balance in non-mammals as well as in controlling behavior - In birds it induces nest building activity > (3) ACTH and MSH – a polypeptide of 39 amino acids - ACTH controls the secretion of adrenal cortex hormones eg cortisol. ACTH also stimulates the growth of the adrenal gland (known as the trophic effect) - It is synthesized as part of a Proopiomelanocortin precursor coded by the POMC gene. - POMC molecule can be processed differently depending on its cellular site. - In the anterior pituitary, it is made into ACTH and beta-endorphin an opioid peptide having analgesic effects - In the intermediate lobe, processing of the POMV molecules leads to MSH formation. In reptiles and Amphibia, MSH is formed in the intermediary lobe of the pituitary - MSH acts on melanocytes to stimulate the dispersion of melanin granules, which causes skin darkening and permits the animal to blend with its environment. > (4) TSH, FSH and LH; - They are all glycoproteins composed of two subunits, beta and alpha. - The alpha subunit is the same for all three hormones. - Beta subunit confers specificity. - FSH and LH are involved in reproductive physiology - TSH stimulates the thyroid and like ACTH, it also has a “trophic” effect on the gland.

What controls the secretions of pituitary Hormones? > The hypothalamus controls the anterior pituitary. - Releasing hormones from the hypothalamus arrive directly to the pituitary via the portal veins, so that they do not get diluted out into the general circulation - TRH controls section of TSH - GHRH controls secretion of GH - CRH controls secretion of ACTH - GnRH controls secretion of LH and FSH - PRH controls release of prolactin > The hypothalamus also constrains hormones that inhibit section from the anterior pituitary; - Somatostatin inhibits growth hormone secretion - Dopamine inhibits prolactin release > The releasing hormones and the inhibitory hormones are stored in neurons in axon terminals in the hypothalamus. The neurons are in synaptic contact with a host of neurotransmitters - Noradrenergic and cholinergic fibers and neuropeptides; VIP, Angiotensin II and neurotensin.

The Posterior Pituitary; > The posterior pituitary is derived from the neural tissue and consists of the terminals of neurosecretory cells and is responsible for the section of two hormones; - Oxytocin and vasopressin - The cell body of the neurosecretory cells reside in the hypothalamus. - Synthesis of the hormones occurs in the cell body and are transported down the nerve terminal by fast axonal transport > Oxytocin; has two main functions - Lactation – stimulates ejection of milk from the mammary glands - Parturition – contraction of the smooth muscle of the uterus > Vasopressin (also known as ADH – anti-diuretic hormone);

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This acts on the kidney to permit water to be re-absorbed, making the urine concentrated and making water available to dilute the osmolarity of body fluids. > Positive Feedback; - This is a system in which the signal generator is stimulated by the response, which it induces. - This is intrinsically unstable control system but there are a few specific biological systems where such a control system is operative - During childbirth (parturition) and during lactation - In both cases oxytocin is involved

Physiology Lecture (13) Notes ENDOCRINOLOGY; Endocrinology of the Reproductive Systems ; What Makes Male and Female; > Sex differentiation under control; - Y chromosome has the SRY gene; Sex determining Region of the Y chromosome) - SRY gene dictates that a testes is made - But Endorines dictates development - Testosterone and glycoprotein hormone called Mullerin inhibiting Hormone (MIH) require for male development - In their absence, female characteristics develop

> Before 7-8 weeks of gestation, the sex of the embryo is indeterminate - All embryos acquire dual ductal systems – the Mullerian Duct and the Wolffian duct - Mullerian duct gives rise to the fallopian tubes and uterus and Wolffian duct give rise to Vas deferens and Seminal vesicles - In the female the mullerian ducts develop and the Wolffian ducts degenerate (default route) - In the male, Mullerin inhibiting hormone causes the Mullerian duct to degenerate and the testosterone differentiates the Wolffian ducts and also causes virilization of the external genitalia (requires testosterone to be converted into 5-hydrotestosterone).

Spermatogenesis; > Sperm cells are produced continually in the testes throughout life. > The structural organization of the testes is important in the control of sperm maturation. - The spermatogenic tubules consist of SERTOLI cells and germ cells - The LEYDIG cells (also known as interstitial cells) present in the interstitium contains the enzymes for the production of androgens (mainly testosterone) - The anterior pituitary is stimulated to produce both LH and FSH by GnRH from the hypothalamus.

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The secretion of GnRH is episodic resulting in the intermittent secretion of LH in 814 pulses/24hours in adult males. Pulsatile secretion of FSG also occurs but of smaller amplitude - FSH acts on Sertoli cells (also known as nurse cells) which surround the sperms during different sages of maturation - LH acts on Leydic cells and stimulates the synthesis and secretion of testosterone Testosterone maintains spermatogenesis but is unable to initiate the process Sertoli cells have to be primed by FSH - This testosterone and FSH control the rate of production of spermatozoa.

> Secretions from accessary glands; - Seminal vesicles (60%) - Prostate (20%) - Bulbo-urethal glands - All added to spermatozoa to form SEMEN - Sperm count; 100 million sperms/ml (200 million a day) - Secretions provide nutrients (fructose) - Maintain pH of 6.5 (alkaline) - LH acts on Leydig cells to produce testosterone - FSH acts on Sertoli cells to initiate spermatogenesis

> Testosterone inhibits LH secretion at the level of the pituitary and GnHR secretion from the hypothalamus via negative feedback. - Sertoli cells also produce INHIBN, a polypeptide hormone that acts on the anterior pituitary, to inhibit the release of FSH

Female Reproductive Physiology; > The ovaries have a dual function of producing germ cells and of secreting female sex hormones - Oocytes are the cells from which ova will be formed by meiotic (reduction) cell division and this is only completed after puberty under the influence of LH. - Oocytes are surround by a single layer of granulosa cells – this constitutes the primary follicle.

> Ovarian Cycle – produces mature oocyte every 28 days > Uterine Cycle – provides the environment for the fertilized ovum to develop > Release of germ cells in Cyclical; - This is reflected by the corresponding cyclic structural and functional changes throughout the female reproductive system - These hanges are dependent on two inter-related cycles; - Ovarian and Uterine (menstrual) cycle.

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Both these cycles, although variable, last approximately 28 days The menstrual cycle is controlled y the ovarian cycle via sex hormones.

The Ovary; > > > >

At birth, there are 1 million oocytes By puberty there are 100,000 – 500,000 only Each oocycte reaches maturity at intervals of 28 days Oocytes are exhausted by age 50 approx so a woman ultimately need s 500 oocytes

The Ovarian Cycle; > The hypothalamus releases Gonadotrophin releasing hormone (GnRH) - This stimulates the Ant. Pit. To secrete FSH - This acts on the ovarian follicle, to initiate maturation and become the Gaafian follicle - This will release the ovum into the fallopian tubes (OVULATION) - The developing follicle synthesizes oestrogens which acts to inhibit production of GnRH and FSH by the hypothalamus and pituitary respectively. - The fall in FSH levels and the increase in oestrogens cause the ant. Pit. To release LH - LH triggers ovulation 12 hours later by the multicomponent mechanism. - The ruptured follicle becomes the CORPUS LUTEUM, which in turns starts to produce both oestrogen and PROGESTERONE - In an infertile cycle, the corpus luteum only lasts for 10 days after which it regresses. - If pregnancy does occur, the corpus luteum is maintained for at least 3 months

Follicle Phas

> Estrogen synthesized by the developing follicle - Reaches a peak 2 days before ovulation - The estrogen peak is responsible for the surge of both LH/FSH release - hours after LH/FSH peak ovulation takes place > Estrogen secreted by follicle has two major effects; - Suppresses FSH release at low concentrations - At high concentrations it stimulates a surge of both LH and FSH

Luteal Phase; > After ovulation the corpus luteum , under the influence of LH secretes both estrogen and progesterone; - Therefore secretory endometrium develops - Inhibition of secretion of FSH/LH - Decreases in LH leads to degeneration of Corp. Lut. And a corresponding decrease in estrogen and progesterone - Endometrium beings to slough at conclusion of day 28

Uterine Cycle; > The uterus has three layers; - A thin layer in contact with the body cavity - A thick muscular layer myometrium - A mucous membrane lining the uterine cavity endometrium > During the course of the uterine cycle the endometrium undergoes cyclic structural changes which can be divided into three stages. > (1) The proliferative stage where the endometrial cells proliferate under the influence...