The Endocrine System Flashcards by Deleted Deleted

HORMONES RELEASED BY THE ENDOCRINE SYSTEM ARE RELEASED INTO THE BLOOD.

TRUE OR FALSE?

True

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WHAT IS NEGATIVE FEEDBACK?

Once set point is reached, production/release of hormones are stopped

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CLASSES OF HORMONES

1. Amines/Amino acids- tyrosine

Thyroid hormones; bind to thyroid receptors (nuclear receptors= regulate gene transcription)

Adrenaline/noradrenaline= bind to G-protein coupled receptors to bring about intracellular signaling via cyclic AMP

2. Peptides/proteins

E.G insulin, made up of 135 amino acids, works by binding to the receptor tyrosine kinase, which in turn activates intracellular signaling via a phosphorylation cascade to bring about its effects.

3. Steroid hormones

Sex hormones, e.g. Oestrogen

Glucocorticoids

These all work by activating _ receptors which effectively work as transcription factors, regulating gene transcription

Nuclear

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WHAT ARE THE THREE CLASSES OF HORMONE?

Amines/Amino Acids

Peptides/Proteins

Steroid Hormones

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HOW DOES ADRENALINE BRING ABOUT ITS EFFECT?

Binds to G-protein coupled receptors to bring about intracellular signaling via cyclic AMP

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THE ENDOCRINE SYSTEM

Hypothalamus and pituitary release hormones that control thyroid, adrenal and gonads.

Heart releases ANP which is a hormone involved in _ balance.

Thymosin’s function in the _ system.

Melatonin is involved in regulating sleep and waking cycles.

Sodium

Immune

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ENDOCRINE GLANDS

oMajor morhphological feature is that glands are ductless (cf. salivary glands)

oRichly vascularized (good _ supply).

oSecrete messengers directly into circulation

oMay be primary glands (e.g. pituitary, thyroid, adrenals)

oOther organs may have secondary endocrine function (e.g. brain (hypothalamus), heart, kidney, GI tract)

Blood

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CELL-TO-CELL SIGNALLING

Intracrine= producing products that signal within cell

Autocrine= release products that act back on itself

Paracrine= Release things that affect neighbouring cells

Endocrine= products are secreted into the blood stream and can travel a distance to their target cells

Neuroendocrine= modified nerve cells that can secrete hormones into circulation directly.

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ENDOCRINE FUNCTIONS

Endocrine organs release hormones that are important in four broad areas:

oReproduction

o Growth and development

o Maintenance of internal environment

o Regulation of energy

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ENDOCRINE ORGANS RELEASE HORMONES THAT ARE IMPORTANT IN WHICH FOUR AREAS?

oReproduction

o Growth and development

o Maintenance of internal environment

o Regulation of energy

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HORMONES

oProduced by _ and released directly into circulation

oPresent in low concentrations (10^-7 - 10^-12 M)

oBind to specific, high affinity recognition sites or receptors on/in target cells

oSingle hormone may have different tissue-specific effects

oSingle function may be regulated by different hormones

Glands

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AMINE HORMONES

oCatecholamines derived from tyrosine

•adrenaline, noradrenaline

oThyroid Hormones also derived from tyrosine

•thyroxine, triiodothyronine

oIndoleamines derived from tryptophan

•Melatonin

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ADRENAL CATECHOLAMINE SYNTHESIS

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THYROID HORMONE SYNTHESIS

Thyroid hormones synthesised from tyrosine and iodine (iodine is essential).

T4- relates to the number of iodine residues.

In adrenal gland= converted to adrenaline and noradrenaline

Thyroid gland- iodinated in a cell specific pathway

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STEROID HORMONES

Coloured bits= tetra planar ring structure= common to all of these molecules as they are all synthesised from the same precursor molecule (cholesterol)

Steroids= lipophilic so they can enter and leave cells easily, but need to be transported in the blood stream bound to other proteins as they are lipophilic

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STEROID HORMONE SYNTHESIS

Starts with a hormone binding (for example) to a G-protein couple receptor.
Causes adenyl cyclase to produce cyclic AMP
Cyclic AMP phosphorylates protein kinase A
This causes PKA to phosphorylate other proteins (cholesterol esterase in this case)
CE enters cells in the form of LDL (low density lipoprotein)
Cholesterol esterase frees the cholesterol from the protein- cholesterol then transported into mitochondria and the enzymes required for steroid hormone synthesis are located here.
Some modifications go on in the SER
Steroid hormone produced and released into cytoplasm, can then diffuse straight out of cell into circulation (due to being lipophilic)

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DESCRIBE THE PROCESS OF SYNTHESISING A STEROID HORMONE

Starts with a hormone binding (for example) to a G-protein couple receptor.
Causes adenyl cyclase to produce cyclic AMP
Cyclic AMP phosphorylates protein kinase A
This causes PKA to phosphorylate other proteins (cholesterol esterase in this case)
CE enters cells in the form of LDL (low density lipoprotein)
Cholesterol esterase frees the cholesterol from the protein- cholesterol then transported into mitochondria and the enzymes required for steroid hormone synthesis are located here.
Some modifications go on in the SER
Steroid hormone produced and released into cytoplasm, can then diffuse straight out of cell into circulation (due to being lipophilic)

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PEPTIDE AND PROTEIN HORMONES

PEPTIDES

Short amino acid chains e.g.

ADH (9 AA)
Oxytocin (9 AA)

Polypeptides e.g.

Insulin (135 AA)
Prolactin (198 AA)

Proteins

Thyroid stimulating hormone

Follicle stimulating hormone

Growth hormone

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PEPTIDE AND PROTEIN HORMONES: SYNTHESIS

Release by exocytosis as prohormone or hormone into blood stream.

Proteins and peptides are packaged/stored in secretory vesicles- capable of being released straight away on demand.

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HORMONE RECEPTORS

The ability of a cell to respond to a hormone depends upon the presence of receptors for that hormone on or in the target cell.

The number of receptors for a hormone can increase (up-regulation) or decrease (down-regulation).

May be:

oCell surface receptors

oIntracellular receptors

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CELL-SURFACE RECEPTORS

Cell surface receptors- G-protein coupled receptors mostly

Tyrosine kinase receptors- binding of ligand causes a phosphorylation of the receptor intracellularly that recruits a signalling cascade that brings about the cellular response

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INTRACELLULAR RECEPTORS

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HORMONE RELEASE

Hypothalamus and pituitary regulates- regulatory hormone released from hypothalamic neurone in response to stimulus, which acts on the endocrine cells in the anterior pituitary and causes hormone 1 to be released, which reaches the target endocrine organ and causes a second hormone to be released, gets into circulation and to the target cells= response

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ENDOCRINE COMMUNICATION

Messages disseminated from glands to effector via circulation
Relatively slow transfer of information
Can be long lasting
All cells contacted, specificity conferred by receptors
Slow maintenance of cellular homeostasis

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_ENDOCRINE DISORDERS_ Hypo-secretion= too little secretion of hormone (typically when part of endocrine grand has been destroyed or degenerated. E.g. T1 diabetes- make antibodies that destroy the glands in the pancreas. Hyper-secretion= too much secretion (e.g.pancreatic endocrine tumour) Hypo-responsive= not responding enough, e.g. insulin resistant T2 diabetes Hyper-responsive= responding too much to hormone – antibodies can bind to and activate receptors so they’re constantly turned on, even in the absence of the appropriate hormone signal.

**_COMMON ENDOCRINE PROBLEMS_**

WHAT ARE NORMAL BLOOD GLUCOSE LEVELS?

4.5mM-5.5mM

**_OVERVIEW OF BLOOD GLUCOSE CONTROL_** Glucose comes from food; carbs are digested--\> glucose, gets into blood stream, BG might get up to 8mM at this point. \_ cells in pancreas detect this= insulin is secreted to lower BG, acts on the liver, muscle and adipose to trigger glucose uptake (and storage as glycogen in the liver). GLUT4 proteins allow this glucose uptake= returns BG to normal Alpha cells in pancreas produce _ when BG levels are too low= glucagon stimulates glycogen to break down into glucose (\_) and also stimulates gluconeogenesis= liberates glucose into the blood stream to return BG levels back up to normal

Beta Glucagon Glycogenolysis

WHAT HAPPENS TO RETURN BLOOD GLUCOSE LEVELS TO NORMAL WHEN THEY ARE TOO HIGH?

Beta cells in pancreas detect this= insulin is secreted to lower BG, acts on the liver, muscle and adipose to trigger glucose uptake (and storage as glycogen in the liver). GLUT4 proteins allow this glucose uptake= returns BG to normal

WHAT HAPPENS TO RETURN BLOOD GLUCOSE LEVELS TO NORMAL WHEN THEY ARE TOO LOW?

Alpha cells in pancreas produce glucagon when BG levels are too low= glucagon stimulates glycogen to break down into glucose (glycogenolysis) and also stimulates gluconeogenesis= liberates glucose into the blood stream to return BG levels back up to normal

REMEMBER: ## Footnote Insulin- Anabolic Glucagon- Catabolic They have opposite effects; insulin can inhibit glucagon, and glucagon can inhibit insulin. They are counter-regulatory hormones.

THE PANCREAS IS 99% ENDOCRINE FUNCTION. TRUE OR FALSE?

FALSE It is 99% exocrine function

**_THE PANCREAS_**

WHAT TYPE OF SIGNALLING DO ALPHA AND BETA CELLS SHOW?

Paracrine signalling

WHAT CAN THE BODY USE AS AN ALTERNATE ENERGY SOURCE IN A FASTED STATE?

Ketones

**_GLUCOSE BALANCE_**

**_HORMONE SECRETION FROM THE ISLETS_** beta-cells produce and release insulin -stimulates glucose utilization and uptake alpha-cells produce and release glucagon -increases breakdown of glycogen and glucose release delta-cells produce and release somatostatin -suppresses GI motility, and release of insulin and glucagon

**_STRUCTURE OF INSULIN_** C-peptide is cleaved to release the active parts (A and B chain)

**_INSULIN IS SECRETED IN RESPONSE TO A RISE IN BG LEVELS_** 1. Beta cells secrete insulin; the cells couple sensing of glucose to release of insulin (high BG, conc gradient so glucose enters cells and is converted into glucose-6-phosphate which then enters the mitochondria). Glycolysis then happens in mitochondria so ATP is produced. 2. K+ channel detects ATP to ADP ratio (it goes up); this inhibits the potassium channel in the membrane so K+ can’t leave the cell, so they stay in the cell and their positive charge causes a build up of + charge/depolarisation. 3. Depolarisation is sensed so voltage-gated calcium ion channels open so calcium moves into the cell, causes vesicles containing insulin to fuse with the membrane and release insulin= calcium-dependent exocytosis.

DESCRIBE THE PROCESS BY WHICH INSULIN IS SECRETED

1. Beta cells secrete insulin; the cells couple sensing of glucose to release of insulin (high BG, conc gradient so glucose enters cells and is converted into glucose-6-phosphate which then enters the mitochondria). Glycolysis then happens in mitochondria so ATP is produced. 2. K+ channel detects ATP to ADP ratio (it goes up); this inhibits the potassium channel in the membrane so K+ can’t leave the cell, so they stay in the cell and their positive charge causes a build up of + charge/depolarisation. 3. Depolarisation is sensed so voltage-gated calcium ion channels open so calcium moves into the cell, causes vesicles containing insulin to fuse with the membrane and release insulin= calcium-dependent exocytosis.

**_INSULIN SECRETION_** Insulin is secreted in two phases Following a glucose load/meal, plasma insulin levels rise rapidly (beta cells are releasing stored insulin). Second wave of release is newly synthesised insulin. Release of insulin is tightly coupled with BG concentration.

**_THE INSULIN RECEPTOR_** Insulin binding: - Dimerization - “receptor tyrosine kinase” autophosphorylation - Effects on intracellular kinases/phosphatases - Effects on key enzymes Beta subunits are intracellular, Alpha are extracellular Insulin binds to extracellular part

**_ACTIONS OF INSULIN_** **_Carbohydrate metabolism_** * Facilitates glucose entry into muscle, adipose (GLUT) * Stimulates the liver to store glucose as glycogen =Decreases concentration of glucose in the blood **_Lipid metabolism_** * Promotes synthesis of fatty acids in the liver (when glycogen saturated) leading to increase in lipoproteins in circulation to release FAs (triglyceride synthesis in adipocytes) * Inhibits breakdown of fat in adipose tissue * Promotes glycerol synthesis from glucose and increase triglyceride synthesis

**_STIMULATION OF GLUCOSE UPTAKE BY INSULIN_**

**_INSULIN ON MUSCLE_** Insulin-sensitizing drugs increase glucose utilization by skeletal muscle.

**_INSULIN ON LIVER_** Glucokinase converts glucose to glucose-6-phosphate Glucose, lactic acid, amino acid and fatty acid uptake also stimulated by insulin

**_INSULIN ON ADIPOSE TISSUE_** Triglycerides can be stored= need fatty acids and glycerol to make them therefore insulin also stimulates the uptake of glycerol

**_SUMMARY OF INSULIN AND BLOOD GLUCOSE_**

**_GLUCAGON ON BLOOD GLUCOSE_**

**_HYPOGLYCAEMIA_** oBlood glucose \< 3 mM (normal 4-6 mmol/L) oUptake of glucose by glucose-dependent tissue not adequate to maintain tissue function CNS very sensitive –impaired vision –slurred speech –staggered walk –mood change –confusion –coma –death Overactivity of the ANS- * palpitations * sweats * shakiness * hunger

WHAT IS HYPERGLYCAEMIA?

A fasting blood glucose of \>7mmol/L

**_THE MUSCULOSKELETAL SYSTEM_** •Comprises the skeleton, muscles and accessory tissues which together allow locomotion and articulation –bone, cartilage, joints, ligaments, tendons, nerve fibres and blood vessels The skeleton is comprised of two main tissue types •Bone – compact (exterior) and trabecular (interior) –long, short (usually cuboidal), flat (slightly curved) and irregular –encased within a fibrous periosteum •Cartilage – hyaline, fibro and elastic –sometimes encased within a fibrous perichondrium –hyaline: growth plate, joint surfaces and temporary scaffold –fibrocartilage: intervertebral discs; menisci (pads) in joint spaces -no perichondrium –elastic: external ear, epiglottis and larynx

**_SKELETAL CHARACTERISTICS: BONE AND CARITLAGE_** Cartilage doesn’t have a blood supply Chondroblasts/chondrocytes maintain the cartilage matrix

**_ANATOMY OF THE SKELETON_**

WHAT ARE THE FOUR TYPES OF BONE?

Short Long Irregular Flat

**_BONE TYPES_** Short bones= provide support and stability, have very little/no movement- hands and feet Flat bone= either serve as points of attachment from muscles or protect internal organs Irregular bone= tend to have a complex shape, these support the spinal cord and protect it from compressive forces. ALSO HAVE LONG BONES

**_ANATOMY OF A LONG BONE_** Proximal epiphysis- attached closest to the body Epiphyseal line- it is known as an epiphyseal plate when people are still growing, becomes a ‘line’ once someone has stopped growing.

**_MICROANATOMY OF A LONG BONE_** Concentric lamellae- rings- consists of osteocytes; the osteon have a canal in the middle which is where the blood vessels are located.

**_ENLARGED VIEW OF TRABECULAR (SPONGY) BONE_** No blood vessels or central canal- trabecular contain lamellae that are all parallel to each other. Lacuna have osteocytes within them Due to there being no blood supply to the spongy bone, bone has to obtain nutrients from pores in the bone surface.

**_THE CELLS OF BONE_** Osteogenic- undifferentiated, have high mitotic activity -Differentiate into osteoblasts= the bone cell responsible for forming new bone (found in growing portions of bones). Osteoblasts don’t divide, they synthesise organic compounds that then calcify etc… then differentiates into a cell called an osteocyte. Osteocytes are the primary cell in mature bone (the most common type of bone cell)- all located within lacuna, surrounded by bone tissue. They are responsible for maintaining mineral concentration of bone matrix. Osteoclasts are cells that are responsible for degrading bone- bones are constantly breaking down and being reformed. They are a form of macrophage. Can secrete acid and enzymes to dissolve the bone.

**_BONE DEVELOPMENT (OSSIFICATION)_** ## Footnote •Skeleton develops from the embryonic mesenchyme –loosely packed, unspecialised cells in a gel-like matrix –derived from the embryonic mesoderm •Mesenchymal cells migrate and form condensations –cellular aggregates; prefigure sites of bone development •Intramembranous ossification –bone forms directly within the condensation •Endochondral ossification –a cartilage template (anlage) forms within the condensation –the cartilage anlage is subsequently replaced by bone

WHAT TYPE OF OSSIFICATION DO MOST BONES UNDERGO?

Endochondral

**_INTRAMEMBRANOUS OSSIFICATION_** Ossification commences in week 6 of gestation. Mesenchymal cells start aggregating and differentiating into osteoblasts- form ossification centre. Osteoblasts release osteoid. Mesenchymal cells continue differentiating (only occurs in ossification centre)- results in osteoblasts becoming trapped in this centre, they then differentiate into osteocytes. After a few days, the osteoid begins to harden and calcify= bone. Periosteum develops from mesenchyme condensing. Compact bone gets deposited in layers.

**_ENDOCHONDRAL OSSIFICATION (MAJORITY OF BONES)_**

**_POST-NATAL GROWTH IN LENGTH: THE EPIPHYSEAL PLATE_** (a) Location of the epiphyseal plate in a long bone. (b) As the chondrocytes of the epiphyseal plate divide and align in columns, the cartilage expands toward the epiphysis, and the bone elongates. At the same time, the older cartilage is _ and then replaced by bone, which is remodeled, resulting in expansion of the medullary cavity of the diaphysis. The net result is an epiphyseal plate that remains uniform in thickness through time but is constantly moving toward the epiphysis, resulting in _ of the bone. (c) Photomicrograph of an epiphyseal plate, demonstrating chondrocyte division and enlargement and the areas of calcification and ossification.

Calcified Elongation

**_MAINTENANCE OF ADULT BONE: REMODELLING_** 1 – 2 million active, asynchronous BMU in the adult skeleton at any one time. 2-3% cortical bone replaced per annum vs 10% of trabecular bone (higher activity, in part, helps reflects the greater contribution made by trabecular bone to mineral homeostasis). Remodelling deficit approximates to zero, when averaged across the whole skeleton, in health between the ages of 25 and 45.

**_BONE REGENERATION: FRACTURE HEALING_** 1. White blood cells will remove any dead cells or germs that have entered, osteoclasts remove dead bone fragments. 2. Blood clot replaced by fibral cartilage.

**_JOINTS_** ## Footnote * Occur at the joins between two or more bones * Classified according to the range of motion they exhibit and the types of tissue that holds the bone together –synovial joints, fibrous joints, cartilaginous joints •The largest and most important class are synovial –synovial joints are diarthroses (allow free movement) •There are six subtypes of synovial joint –planar, hinge, pivot, condyloid, saddle, ball and socket

WHAT IS THE LARGEST AND MOST IMPORTANT CLASSIFICATION OF JOINT?

Synovial

WHAT ARE THE SIX SUB-TYPES OF SYNOVIAL JOINT?

Planar Hinge Pivot Condyloid Saddle Ball and Socket

**_JOINT MOVEMENT_** ## Footnote •Three main axis that movement are occurring along –X-axis for up and down movement –Y-axis for side to side movement –Z-axis for 3 dimensional movement * Uniaxial joints only move along a single axis * Biaxial joints move about 2 distinct axis * Polyaxial joints move through all 3 axis

**_SIMPLIFIED STRUCTURE OF A SYNOVIAL JOINT_** All subtypes are of a similar structure • articular (hyaline) cartilage covering the ends of the bones - smooth, lubricating surface; resists compression • bi-layered joint capsule: outer fibrous and inner elastic - fibrous layer attaches to the periosteum of the articulating bone - inner synovial membrane; site of production of the synovial fluid • a joint cavity filled with viscous synovial fluid - non-Newtonian properties (viscosity increases with applied force)

**_CHANGES IN JOINT STRUCTURE FROM AGEING AND DISEASE_**

WHAT IS EXTRACELLULAR Ca²⁺REQUIRED FOR?

oNerve function oMuscle contraction oCoagulation oSkeletal mineralization oActivation of most cell types (signaling pathways)

HOW MUCH CALCIUM IS IN THE BODY OF A YOUNG ADULT?

1100g

**_CALCIUM METABOLISM IN THE ADULT HUMAN_**

WHAT THREE HORMONES REGULATE CALCIUM HOMEOSTASIS?

Calcitriol Calcitonin Parathyroid hormone

**_PARATHYROID HORMONE (PTH)_** •Single chain polypeptide (84 aa) with a molecular weight of 9500 –Derived from the larger precursor peptides pre-proPTH and proPTH * Produced by the chief cells of the parathyroid gland (x4) * Normal plasma level PTH (1-84) 10-55 pg/ml; t_1/2 10 min **_REGULATION OF PTH SECRETION_** Minute to minute: •Ca²⁺ acting via the G protein coupled calcium sensing receptor (CaSR) ↓ in ionized (free) plasma Ca²⁺ causes an ↑ in PTH secretion Long-term: •1,25(OH)₂D₃ acts directly on the PTG to decrease preproPTH mRNA

**_ACTIONS OF PARATHYROID HORMONE_** Increases plasma Ca²⁺ (and decreases plasma PO₄^3-) via several actions: **_Kidney_** - Stimulates Ca²⁺ reabsorption in the distal tubule - Inhibits PO₄^3- reabsorption in the proximal tubule - Increases activity of 1alpha-hydroxylase and decreases 24-hydroxylase (net effect is a gradual increase in renal production of 1,25(OH)₂D₃) **_Bone_** - Stimulates rapid efflux of Ca²⁺ from freely exchangeable calcium pool (an effect on osteocytes and bone-lining cells) - Increases the number and activity of osteoclasts via action on osteoblasts --\> gradual increase in bone resorption (Ca2+ and PO43- release) **_(GI Tract)_** -Stimulates absorption of Ca²⁺ and PO₄^3- Effect is delayed (≥ 24 hr) & indirect (increased renal production 1,25(OH)₂D₃)

**_REGULATION OF CALCIUM BY PARATHYROID HORMONE_**

**_1 ALPHA, 25 DIHYDROXYVITAMIN D₃- CALCITRIOL_** ## Footnote oAbbreviated to 1,25 (OH)₂D₃ oActive metabolite of vitamin D₃ (cholecalciferol) oA secosteroid (open B ring) oProduced in the kidney by 1alpha-hydroxylation of 25(OH)D₃ oNormal plasma level= 0.03 ng/ml (100 pmol/L) Bulk bound to vitamin D-binding protein (a-globulin) transcalciferin Only the free fraction is active; t_1/2 3-6 hr Interacts with a nuclear receptor - member of the nuclear receptor superfamily

**_METABOLISM OF 1ALPHA, 25-DIHYDROXYVITAMIN D₃_**

**_REGULATION OF 1,25(OH)₂D₃PRODUCTION_**

**_ACTIONS OF 1,25(OH)₂D₃_** Increases plasma Ca²⁺: •GI Tract (Main) - Stimulates absorption of Ca²⁺ (principally in the duodenum) - Stimulates absorption of PO₄^3- (jejunum and ileum) •Bone –Increases the number and activity of osteoclasts -Leads to an increase in bone resorption and hence Ca²⁺ and PO₄^3- release •Kidney – Facilitates Ca²⁺ reabsorption (DCT)

**_ENDOCRINE REGULATION OF Ca²⁺HOMEOSTASIS: THE IMPORTANCE OF FEEDBACK LOOPS_**

**_CALCITONIN (CT)_** ## Footnote oSingle chain polypeptide (32 aa) with a molecular weight of 3500. oSecreted by the parafollicular ‘C’ cells of the _ gland oSecretion is regulated by Ca²⁺ (increase Ca²⁺ --\> increase in CT secretion) and gastrin (increases) oActions lead to fall in plasma Ca²⁺ – opposite effect to PTH oActs on bone to decrease release of Ca²⁺ and PO₄^3- - Decreases rapid efflux across the bone membrane - Acts directly on osteoclasts to inhibit bone reabsorption oActs on the kidney to decrease tubular reabsorption of Ca²⁺ and PO₄^3- oNo significant effect on Ca²⁺ absorption in the small intestine _THE EXACT PHYSIOLOGICAL ROLE OF CT IN ADULT HUMANS IS UNCERTAIN_ * May protect against postprandial hypercalcaemia * May protect the female skeleton during pregnancy and \_. * In pathological states may act to prevent excessive bone destruction

Thyroid Lactation

WHAT IS THE SECRETION OF CALCITONIN (CT) REGULATED BY?

Ca²⁺and gastrin (Increase in Ca leads to increase in CT secretion)

WHAT IS CALCITONIN SECRETED BY?

Parafollicular 'C' cells of the thyroid gland

**_ENDOCRINE REGULATION OF Ca²⁺ HOMEOSTASIS: OVERVIEW_**

**_DISORDERS OF CALCIUM METABOLISM_** oHypercalcaemia –Associated with XS parathyroid hormone –e.g. tumour of parathyroid gland –Affects bones, kidneys, GI tract as well as neurological symptoms oHypocalcaemia –Lack of parathyroid hormone effect e.g. PTH resistance –Lack of vitamin D effect e.g. intake, drug interaction –Symptoms related to neuromuscular excitability –Long term lack of vitamin D affects bone growth –Examples: osteomalacia, rickets, osteoporosis

**_ENDOCRINE REGULATION OF Ca²⁺HOMEOSTASIS- SUMMARY_** The sensitivity of PTH secretion to changes in blood ionised calcium levels, the rapid onset of its actions in target tissues and its short half-life in the circulation allow for the rapid correction of short-term deviations from the homeostatic set-point. By contrast, the role of the vitamin D endocrine component assumes greater importance when the challenge to calcium homeostasis is of greater magnitude and longer duration.

**_THE HYPOTHALAMIC-PITUITARY AXIS_** * The hypothalamus is located at the base of the brain (“stimulus”) * Relatively small structure receiving massive inputs from many other areas of brain. * Secretes many _ to control widespread homeostatic functions * Uses the _ gland as an output organ (initiates “response”) – aka hypophysis

Hormones Pituitary

**_HYPOTHALAMUS AND PITUITARY GLANDS_**

**_DIVERSE FUNCTIONS OF HYPOTHALAMIC NUCLEI_**

**_CONNECTIONS OF THE HYPOTHALAMUS_** ## Footnote Cells in periventricular zone: oSuprachiasmatic neurones - receive retinal innervation and synchronize circadian rhythms in the light-dark cycle oSend output to sympathetic and parasympathetic output neurones in spinal cord to control activity of ANS oNeurosecretory cells responsible for release of regulatory hormones to control pituitary gland.

**_ENDOCRINE FUNCTIONS OF THE HYPOTHALAMUS_**

**_HYPOTHALAMIC REGULATORY HORMONES_** **Releasing factors** ØCRF - corticotropin releasing factor ØTRH - thyrotropin releasing hormone ØGHRH - growth hormone releasing hormone ØGnRH - gonadotropin releasing hormone ØPRF - prolactin releasing factor **Inhibiting factors** ØGHIH - Growth hormone inhibiting hormone ØPIH - prolactin inhibiting hormone ØMSH-IH - melanocyte stimulating hormone inhibiting hormone

WHAT ARE SOME EXAMPLES OF HYPOTHALAMIC INHIBITING FACTORS?

ØGHIH - Growth hormone inhibiting hormone ØPIH - prolactin inhibiting hormone ØMSH-IH - melanocyte stimulating hormone inhibiting hormone

WHAT ARE SOME EXAMPLES OF HYPOTHALAMIC RELEASING FACTORS?

ØCRF - corticotropin releasing factor ØTRH - thyrotropin releasing hormone ØGHRH - growth hormone releasing hormone ØGnRH - gonadotropin releasing hormone ØPRF - prolactin releasing factor

**_ANTERIOR PITUITARY HORMONES_** **Four trophic hormones** oThyroid Stimulating Hormone oAdrenoCorticoTrophic Hormone oFollicle Stimulating Hormone oLuteinizing Hormone **Two primary hormones** oGrowth Hormone oPRoLactin

WHAT ARE THE FOUR TROPHIC HORMONES OF THE ANTERIOR PITUITARY?

oThyroid Stimulating Hormone oAdrenoCorticoTrophic Hormone oFollicle Stimulating Hormone oLuteinizing Hormone

WHAT ARE THE TWO PRIMARY HORMONES OF THE ENTERIOR PITUITARY?

oGrowth Hormone oPRoLactin

**_HORMONE SECRETION BY THE ANTERIOR PITUITARY_**

**_HYPOTHALAMIC PITUITARY AXIS_**

**_FEEDBACK CONTROL OF PITUITARY AXIS_**

**_EFFECTS OF GROWTH HORMONES (A.K.A SOMATOTROPHIN, SOMATOTROPIN)_** oIncrease cell size, number and differentiation oStimulate protein synthesis oStimulate fat utilization oAlter carbohydrate metabolism

WHAT ARE THE FOUR EFFECTS OF GROWTH HORMONES?

oIncrease cell size, number and differentiation oStimulate protein synthesis oStimulate fat utilization oAlter carbohydrate metabolism

WHAT IS A GROWTH HORMONE?

A polypeptide hormone that acts at a receptor tyrosine kinase

**_EFFECTS OF GH/SOMATOMEDINS ON PROTEIN SYNTHESIS_**

**_SOMATOMEDINS_** oSmall proteins produced by the liver in response to GH (insulin-like growth factors) oAt least 4 produced - somatomedin C is most important oLong half life (20 hrs) compared to GH (\<20 mins)

WHAT ARE SOMATOMEDINS?

Small proteins produced by the liver in response to GH (insulin-like growth factors)

**_GROWTH HORMONE (GH) SECRETION_** ## Footnote oReleased in response to growth hormone-releasing hormone (GHRH) oRelease decreased by growth hormone-inhibiting hormone (GHIH or somatostatin) oBoth released from ventromedial hypothalamus oGH is regulated by a short feedback loop oControlled by many factors: sleep, exercise, stress

WHEN WOULD GROWTH HORMONE BE RELEASED?

In response to growth hormone-releasing hormone (GHRH)

WHEN WOULD THE RELEASE OF GROWTH HORMONE BE DECREASED?

By the presence of growth hormone-inhibiting hormone (GHIH or somatostatin)

WHERE ARE GHRH AND GHIH RELEASED FROM?

From the ventromedial hypothalamus

**_WHY IS GROWTH HORMONE IMPORTANT IN THE HEALTHY BODY?_** ## Footnote **Deficit** oDwarfism - may be - general anterior pituitary dysfunction - - specific GH deficit - normal GH but hereditary somatomedin deficit oAccelerated aging - loss of growth hormone after adolescence -decreased protein synthesis **Excess GH** –Gigantism – early life pituitary tumour –Acromegaly- pituitary tumour after adolescence

WHAT THREE THINGS CAN CAUSE DWARFISM?

- General anterior pituitary dysfunction - - Specific GH deficit - Normal GH but hereditary somatomedin deficit

**_ACROMEGALY_** oCaused by excess production of growth hormone oMost commonly affects middle-aged oCan result in premature death oDue to slow onset, it is frequently incorrectly diagnosed oMost common symptoms are abnormal growth of hands & feet. **TREATMENT** Aim is to reduce GH production: oSurgical removal of tumour oDrug therapy oOctreotide & lanreotide (somatostatin analogues) oBromocriptine oRadiation therapy

**_THE THYROID GLAND_** Under control of the hypothalamus; produces TRH, which stimulates the _ to produce TSH, which then stimulates the thyroid to produce thyroidhormones (Thyroxine and Tri iodothyronine). Thyroidhormones bind to _ receptors to regulate gene transcription- often affects metabolism and affects basal metabolic rate (BMR), also affects body weight and _ metabolism (which therefore also affects growth). C cells in thyroid= Produce Calcitonin. Dose dependent; low doses are anabolic, high doses are catabolic.

Pituitary Nuclear Protein

WHAT CONTROLS THE THYROID GLAND?

The hypothalamus; produces TRH, which stimulates the pituitary to produce TSH, which then stimulates the thyroid to produce thyroidhormones (Thyroxine and Tri iodothyronine).

**_THYROID HORMONE SYNTHESIS_** Iodine required to make thyroid hormones T₄= Number represents how many iodines are in the molecule 1. Cells actively accumulate iodide and iodinate tyrosine residues to form T₃ and T₄ 2. Iodinated thyroglobulin enters lumen by exocytosis 3. Stored thyroglobulin re-enters follicle cells by endocytosis 4. Lysosomal enzymes release T₃ and T₄ 5. Most (~90%) are “bound” by binding proteins in plasma - “Free” fraction of T₃ and T₄ can enter target tissues

**_SYNTHESIS AND RELEASE OF THYROID HORMONES_** Inside cell, peroxidases at surface of cell are able to iodinate the tyrosine residues in the thyroglobulin under the influence of peroxidase= get T₃ and T₄ etc in the storage molecule, endocytosed into epithelial cells when needed and they are digested by enzymes to release them into circulation. Un-iodinated residues are recycled back into storage. Only free hormones get inside the cells. When pituitary releases thyroid stimulating hormone (TSH), lysosomal digestion occurs.

**_REGULATION OF SECRETION_** T₃ and T₄ provide negative feedback onto TSH

**_THYROID STIMULATING HORMONE_** Thyroid hormone production absolutely requires TSH o + Iodine uptake from blood by pump mechanism o + TH synthesis by iodinase o + thyroglobulin breakdown by lysosomal proteases

**_THYROID HORMONES_** **_MAJOR HOMEOSTATIC REGULATORS_** oGrowth and development oStimulate protein, carbohydrate and lipid metabolism oRegulate energy metabolism oBody temperature oRegulation of nervous system, cardiovascular, musculo-skeletal and reproduction

**_ACTIONS OF THYROID HORMONES_** o90% of released hormone is T₄ o70-75% of both T₃/T₄ are bound by thyroid binding \_, rest by thyroid binding prealbumin. oOnly unbound T₃ (0.3%) and T₄ (0.03%) can enter target tissues. oMost of physiological effects of thyroid hormones are due to T_3.

Globulin

MOST OF THE PHYSIOLOGICAL EFFECTS OF THYROID HORMONES ARE DUE TO T_3. TRUE OR FALSE?

TRUE

**_ACTIONS OF THYROID HORMONES_** oMitochondrial receptor ++ size and number o++ _ production oNuclear receptor increases transcription and translation via TRE oEffect is generalized increase in enzyme synthesis oNearly all cells have TH receptors - widespread effects

ATP

**_THYROID HORMONE AFFECTS BMR_** T₃ and T₄ bind to receptors on nuclease= stimulates synthesis of sodium-potassium ATPase (purpose is to main electrochemical gradients for excitability).

**_TH STIMULATES PROTEIN METABOLISM_**

**_TH STIMULATES CARBOHYDRATE METABOLISM_**

**_TH STIMULATES FAT METABOLISM_**

**_PHYSIOLOGICAL EFFECTS OF TH_**

**_THYROID GLAND: FOLLICLE STRUCTURE_**

**_HYPOTHYROIDISM IN ADULTS_** oCharacterized by an _ in TSH & a _ in T₄ oMany grossly hypothyroid patients are too lethargic to complain of anything!! oCaused by autoimmune disease, iodine deficiency, altered H-P activity oCan occur with gland enlargement – swelling of the thyroid aka “goitre”

Increase Decrease

**_HYPERTHYROIDISM (THYROTOXICOSIS)_** o Gland increased in size and increased rate of secretion o Secretion rates 5-6 times normal o Largely autoimmune disease – Graves disease - antibodies bind to TSH receptors and continually activate them o May also be caused by thyroid adenoma secreting large quantities of TH

WHAT CAN CAUSE HYPOTHYROIDISM?

Autoimmune disease, iodine deficiency, altered H-P activity

WHERE DOES THE ADRENAL GLAND SIT?

On top of the kidneys

**_THE ADRENAL GLAND_** Sits on top of \_. Produces 3 different classes of hormones: Catecholamines are produced from the adrenal \_. Adrenaline aka epinephrine aka noradrenaline (also produced by the adrenal medulla). Work by binding to alpha and beta _ receptors. Aldosterone is produced by the adrenal cortex. It is a mineralocorticoid= affects _ reabsorption (and then water follows), so the overall affect of aldosterone is to increase blood volume. Aldosterone works via mineralocorticoid receptors, which regulates gene transcription. -Glucocorticoids: e.g. cortisol, via glucocorticoid receptors, regulates gene transcription--\> mobilize glucose into blood stream (coordinated response to stress)

Kidneys Medulla Adrenergic Sodium

WHERE ARE CATECHOLAMINES PRODUCED?

Adrenal medulla

WHERE IS ALDOSTERONE PRODUCED, AND WHAT DOES IT DO?

Adrenal Cortex Affects sodium reabsorption (and then water follows), so the overall affect of aldosterone is to increase blood volume. Aldosterone works via mineralocorticoid receptors, which regulates gene transcription

**_THE MAJOR ENDOCRINE ORGANS_** Adrenal glands: Central role in mediating response to acute and chronic stress Stress can be trauma of any type – infection, intense cold or heat, prolonged exercise, sleep deprivation, fright, emotional stress etc. In a physiological sense the response of the body to all these different stressors is the same – increased _ secretion – although the pathways activated are clearly all very different Acute stress – YOUR experience – after a fright is increased heart rate, hair standing on end, respiration effects that mimic effects of the autonomic nervous system. Chronic stress – YOUR experience – prolonged stress can cause weight loss and muscle weakness because of effects of adrenal hormones on metabolism

Adrenal

**_HISTOLOGY OF THE ADRENAL GLAND_** Central medulla region – actually derived embryologically from neural crest cells and is a modified sympathetic ganglion – it secretes the catecholamines, adrenaline and noradrenaline. Outer cortex region – has 3 different zones that each produce different steroid hormones: ZG- mineralocorticoid – ALDOSTERONE ZF – glucocorticoid or corticosteroid – CORTISOL ZR – androgen precursors – DEHYDROEPIANDOSTERONE Secretions of each of these are regulated by different mechanisms.

**_HORMONES OF THE ADRENAL MEDULLA_**

**_REGULATION OF SECRETION_** The adrenal medulla is a part of the _ division of the autonomic nervous system. Can be considered as a specialised group of postganglionic neurons (- axons). Secretion is controlled by sympathetic preganglionic nerve fibres. Activation of the sympathetic nervous system during stress is a major stimulus for the release of adrenal medullary hormones; the so called “fight-or-flight response”.

Sympathetic

WHAT SECTION OF THE AUTONOMIC NERVOUS SYSTEM IS THE ADRENAL MEDULLA PART OF?

The sympathetic division

**_EFFECTS OF MEDULLARY CATECHOLAMINES_** •Virtually the same as direct activation of sympathetic nerves except: - last much longer (minutes) - effects generalized to all cells with alpha and/or beta-receptors (GPCRs) •Major physiological effect is on _ output and cellular metabolism due to greater effect of AD than NA at beta-receptors

Cardiac

**_ACTIONS OF ADRENAL CATECHOLAMINES_** Plasma adrenaline often exceeds the threshold for its metabolic and cardiovascular effect. In contrast, under normal circumstances the threshold for noradrenaline is rarely, if ever, exceeded.

**_SYNTHESIS OF STEROIDS IN THE ADRENAL CORTEX_**

**_ACTIONS OF ALDOSTERONE_** Stimulates the reabsorption of Na+ /excretion of K+ in the cortical collecting ducts. Decreases the ratio of [Na+] to [K+] in sweat and saliva Increases the reabsorption of Na+ in the colon and excretion of K+ in the \_. Overall effect of aldosterone is to retain Na+ in the body at the expense of K+. Net effect is an _ in plasma volume and hence cardiovascular pressure.

Increase Faeces

WHAT IS THE OVERALL EFFECT OF ALDOSTERONE/WHAT DOES IT CAUSE TO HAPPEN?

Stimulates the reabsorption of Na+ /excretion of K+ in the cortical collecting ducts. Decreases the ratio of [Na+] to [K+] in sweat and saliva Increases the reabsorption of Na+ in the colon and excretion of K+ in the \_. Overall effect of aldosterone is to retain Na+ in the body at the expense of K+.

**_ALDOSTERONE STRUCTURE_**

**_THE RENIN-ANGIOTENSIN SYSTEM_** Stretch sensitive cells in afferent arterioles supplying blood to kidneys; detect BP changes, renin produced when BP\_, travels in circulation to liver so angiotensinogen is converted to Angiotensin 1, travels to the lungs where Angiotensin I-\> Angiotensin II. This then stimulates adrenal gland to produce _ to increase sodium retention, also causes increase in \_.

Drops/decreases Aldosterone Vasoconstriction

WHEN IS RENIN PRODUCED BY THE RENIN-ANGIOTENSIN SYSTEM?

When blood pressure drops

WHEN BLOOD PRESSURE DROPS, WHAT HAPPENS? (IN TERMS OF THE RENIN-ANGIOTENSIN SYSTEM)

Stretch sensitive cells in afferent arterioles supplying blood to kidneys; detect BP changes, renin produced when BP drops, travels in circulation to liver so angiotensinogen is converted to Angiotensin 1, travels to the lungs where Angiotensin I-\> Angiotensin II. This then stimulates adrenal gland to produce aldosterone to increase sodium retention, also causes increase in vasoconstriction.

WHAT THREE TYPES OF DRUGS ARE USED TO AFFECT ALDOSTERONE ACTION?

Aldosterone antagonist (e.g. Spironolactone) ACE inhibitors (e.g. Captopril, Enalapril; used as anti-hypertensives and for cardiac failure). ATII antagonist (e.g. Losartan; similar to ACE inhibitors, used in hypertension)

HOW ARE MOST ADRENAL GLUCOCORTICOIDS TRANSPORTED AROUND THE BODY, AND WHY ARE THEY TRANSPORTED THIS WAY?

Travel in the plasma bound to proteins. ## Footnote Highly lipophilic= allows them to cross cell membranes, but they aren’t ‘happy’ in a hydrophobic environment such as the blood (hence why the are transported bound to proteins).

**_CORTICOSTERONE STRUCTURE_**

**_CORTISOL STRUCTURE_**

**_REGULATION OF GLUCOCORTICOID SECRETION_** Hypothalamus in response to stress triggers release of CRH, acts on pituitary which releases ACTH, which acts on adrenal glands to produce cortisol. Circulates in blood supply and produces its tissue actions. Negative feedback loop= cortisol switches off pituitary production of ACTH, also switches of hypothalamic production of CRH.

**_CRH-ACTH CORTISOL SEQUENCE_**

**_CIRCADIAN RHYTHM IN CORTISOL SECRETION_** The fluctuations in cortisol secretion are caused by fluctuations in ACTH secretion from the pituitary gland.

WHAT DOES CORTISOL STIMULATE?

Gluconeogenesis

**_CORTISOL ON LIVER_**

WHAT IS ADDISON'S DISEASE?

Cortisol deficiency

**_CORTICOSTEROIDS_** Cause rise in plasma _ levels (release from liver and increased gluconeogenesis). -This causes increase in proteolysis, which in turn can bring about muscle wasting and skin thinning. Cause fat redistribution (as in Cushing syndrome)- moon face, buffalo hump. Cause increased breakdown of \_, leading to a rise in plasma fatty acid levels. **Suppress inflammation and immune responses**

Glucose Triglycerides

**_CUSHING'S DISEASE- CORTISOL EXCESS_**

WHAT ARE THE GONADS IN FEMALES?

The ovaries

WHAT ARE THE GONADS IN MALES?

The testes

**_THE REPRODUCTIVE SYSTEM_** Gonads; produce sperm cells, also produce sex steroid hormones. Gonads in females= \_ - Produce ova (eggs) - Oestrogen is a common sex hormone in females, main examples are oestrone, oestrodiol etc (oestrogen receptors) - Progesterone is also a very common hormone, binds to progesterone receptors. Gonads in males= testes -Produce sperm, also produce _ (sex hormone). Main example is testosterone, most common example of an active form of testosterone in the body is dihydrotestosterone (DHT); bind to androgen receptors. All of the receptors are nuclear receptors; regulate gene transcription. Hormonal control comes from hypothalamus --\> pituitary --\> gonads. -Hypothalamus produces ‘\_’ (GnRH)- this is switched on at puberty, as is LH (luteinizing hormone) and FSH (Follicle Stimulating Hormone), which are both produced by the pituitary.

Ovaries Androgens Gonadotrophin Releasing Hormone

WHAT HORMONE, PRODUCED BY THE HYPOTHALAMUS, IS SWITCHED ON AT PUBERTY?

Gonadotrophin Releasing Hormone (GnRH)

WHICH TWO HORMONES, PRODUCED BY THE PITUITARY, ARE SWITCHED ON AT PUBERTY?

LH (Luteinizing Hormone) FSH (Follicle Stimulating Hormone)

**_ANATOMY OF THE MALE REPRODUCTIVE SYSTEM_** Testes- site of sperm production --\> Epididymis--\> Vas deferens (then seminal vesicle adds secretions) --\> Ejaculatory duct. TURN OVER TOO

WHERE SPECIFICALLY IN THE TESTES IS THE SITE OF SPERM PRODUCTION AND HORMONE SYNTHESIS?

Seminiferous tubules

WHAT IS A SERTOLI CELL?

Where sperm are derived from

**_SPERMATOGENESIS_** **TURN OVER**

Sertoli cell- where sperm are derived from. Action of FSH and testosterone that drives production of sperm.

**_SYNTHESIS OF ANDROGENS_**

**_ACTIONS OF ANDROGENS_**

**_HORMONAL CONTROL OF THE TESTES_**

**_ANATOMY OF THE FEMALE REPRODUCTIVE SYSTEM_** TURN OVER TOO

Eggs develop in follicle, egg is then released and the follicle degenerates to form the corpus luteum. If egg doesn’t implant in wall, the uterus lining is shed and this leads to menstrual bleeding.

WHERE DOES AN EGG DEVELOP?

In the follicle

**_OVARIAN FUNCTIONS_** oOogenesis- development of new eggs. oMaturation of the oocyte oOvulation- releasing the egg oSecretion of the female sex steroid hormones

WHAT ARE THE FOUR FUNCTIONS OF THE OVARIES?

oOogenesis- development of new eggs. oMaturation of the oocyte oOvulation- releasing the egg oSecretion of the female sex steroid hormones

WHEN DOES MENOPAUSE OCCUR?

When you have no eggs left

**_OOGENESIS_** oOvum production oOccurs monthly in ovarian follicles oPart of ovarian cycle - Follicular phase (preovulatory) - Luteal phase (postovulator)

WHAT IS AN OOCYTE?

A new egg

**_THE OVARIAN CYCLE 1_** Step 1; follicle cells develop into granulosa cells, which produce oestrogen. Follicle cells also develop into thecal cells; responsible for hormone production. The “follicular phase”: Maturation of primary follicles is under the control of follicle stimulating hormone

**_THE OVARIAN CYCLE 2_** Follicle that is left behind after egg release degenerates into corpus luteum; starts producing \_, which prepares for implantation of egg into womb. If egg doesn’t implant, the corpus luteum degenerates further into corpus albicans and progesterone stops being produced. The “luteal phase”: Ovulation & corpus luteum formation is under the control of luteinizing hormone

Progesterone

WHAT HAPPENS DURING THE 'FOLLICULAR PHASE' OF THE OVARIAN CYCLE?

Maturation of primary follicles is under the control of follicle stimulating hormone.

WHAT HAPPENS DURING THE 'LUTEAL PHASE' OF THE OVARIAN CYCLE?

Ovulation & corpus luteum formation is under the control of luteinizing hormone. Follicle that is left behind after egg release degenerates into corpus luteum; starts producing progesterone, which prepares for implantation of egg into womb. If egg doesn’t implant, the corpus luteum degenerates further into corpus albicans and progesterone stops being produced.

**_OVARIAN FOLLICLE DEVELOPMENT_**

**_FUNCTIONS OF THE UTERUS_** oMuscular organ oMechanical protection oNutritional support oWaste removal for the developing embryo and fetus oUterine cycle involves changes in the uterine wall

WHAT ARE THE FUNCTIONS OF THE UTERUS?

oMuscular organ oMechanical protection oNutritional support oWaste removal for the developing embryo and fetus (Uterine cycle involves changes in the uterine wall)

**_THE UTERINE WALL_** Uterine wall consists of three layers **Myometrium** – outer muscular layer **Endometrium** – a thin, inner, glandular mucosa [**Perimetrium** – an incomplete serosa continuous with the peritoneum]

WHAT ARE THE THREE LAYERS OF THE UTERINE WALL?

Uterine wall consists of three layers Myometrium – outer muscular layer Endometrium – a thin, inner, glandular mucosa [Perimetrium – an incomplete serosa continuous with the peritoneum]

**_THE UTERINE CYCLE_** * Repeating series of changes in the endometrium * Continues from menarche to menopause **–Menses** •Degeneration of the endometrium = Menstruation **–Proliferative phase** •Restoration of the endometrium **–Secretory phase** •Endometrial glands enlarge and accelerate their rates of secretion

WHAT DOES PROGESTERONE DO IN TERMS OF THE UTERINE CYCLE?

Progesterone makes the uterus lining ready to implant the fertilized egg.

WHAT ARE THE THREE STAGES OF THE UTERINE CYCLE?

**–Menses** •Degeneration of the endometrium = Menstruation **–Proliferative phase** •Restoration of the endometrium **–Secretory phase** •Endometrial glands enlarge and accelerate their rates of secretion

**_HORMONES OF THE FEMALE REPRODUCTIVE CYCLE_** **FSH** oStimulates follicular development **LH** oMaintains structure and secretory function of corpus luteum **Oestrogens** oHave multiple functions **Progesterones/ Progestogens** oStimulate endometrial growth and secretion

WHAT DOES FSH DO?

Stimulates follicular development

WHAT DOES LH DO?

Maintains structure and secretory function of corpus luteum

WHAT DO PROGESTERONES DO?

Stimulate endometrial growth and secretion

**_HORMONAL CONTROL OF OVARIAN FUNCTIONS_** Follicle development and oestrogen synthesis during the early and middle follicular phases.

**_GONADOTROPHIN RELEASING HORMONE_** Functioning of gonads is controlled by hypothalamus & _ pituitary, under the influence of higher brain centres in cortex. This leads to the establishment of pulsatile GnRH release ( frequency 60-90 mins) and a consequent increase in pulsatile gonadotrophin secretion from the pituitary at puberty.

WHAT IS THE FUNCTIONING OF GONADS CONTROLLED BY?

The hypothalamus and anterior pituitary

**_HORMONAL REGULATION OF THE FEMALE REPRODUCTIVE CYCLE_** ## Footnote **TURN OVER TOO**

**_OESTROGENS/PROGESTOGENS_**

**_SEX HORMONES ACT THROUGH NUCLEAR RECEPTORS_** Common properties: oHave ligand-binding (hormone-binding) and DNA-binding domains oTranslocate to nucleus once hormone bound oBind to hormone-response elements (recognition elements) in specific gene sequences oDimerization important for function oAndrogen receptors (AR), Estrogen receptors (ER), Progesterone receptors (PR)

WHAT ARE SOME COMMON PROPERTIES OF SEX HORMONES THAT ACT THROUGH NUCLEAR RECEPTORS?

Common properties: oHave ligand-binding (hormone-binding) and DNA-binding domains oTranslocate to nucleus once hormone bound oBind to hormone-response elements (recognition elements) in specific gene sequences oDimerization important for function oAndrogen receptors (AR), Estrogen receptors (ER), Progesterone receptors (PR)

**_OESTROGEN RECEPTORS_** oThe receptor changes conformation due to the dissociation of heat shock proteins after oestrogen binds oThe receptor undergoes dimerization in order for increased affinity to DNA. oThis oestrogen-receptor complex can now bind to specific DNA sites, called oestrogen response/ recognition elements (EREs).

**_PROGESTERONE RECEPTORS_** oNuclear receptors regulating gene transcription. oThere is a single gene that encodes the progesterone receptor – PR; bind to PREs oTwo isoforms – PR-A and PR-B - Identical ligand binding - PR-B mediates the stimulatory effects of progesterone

**_ACTIONS OF OESTROGENS_**

**_ACTIONS OF PROGESTERONES_** oProduced in luteal phase, decreases GnRH production oInduction of secretory activity in oestrogen-primed endometrium o Increases the viscosity cervical mucous oPromotes glandular breast development o Increases basal body temperature

PROGESTERONE DECREASES GnRH PRODUCTION. TRUE OR FALSE?

True

**_OESTROGEN PREPARATIONS_** Natural oestrogens oOestradiol/ Oestrone oOestriol Synthetic oestrogens oMestranol oEthinylestradiol oDiethylstilbestrol Availability: oral, transdermal, intramuscular, implantable, topical

WHAT ARE SOME NATURAL OESTROGENS?

oOestradiol/ Oestrone oOestriol

WHAT ARE SOME SYNTHETIC OESTROGENS?

oMestranol oEthinylestradiol oDiethylstilbestrol

**_SERMS (SELECTIVE ESTROGEN RECEPTOR MODULATORS)_** Selectivity is possible because: oER-alpha and/or ER-beta show differential tissue expression oConformation dependent binding to DNA and transcription factors. oTissue dependent responses ranging between pro-oestrogenic, partially oestrogenic and anti-oestrogenic effects oRole in treatment of certain cancers e.g. tamoxifen in breast cancer.

**_PROGESTOGEN PREPARATIONS_** Natural progestogens oHydroxyprogesterone oMedroxyprogesterone oDydrogesterone Testosterone derivatives oNorgestrel oDesogestrel oEthynodiol

WHAT ARE SOME EXAMPLES OF NATURAL PROGESTOGENS?

oHydroxyprogesterone oMedroxyprogesterone oDydrogesterone

WHAT ARE SOME EXAMPLES OF PROGESTOGENS THAT ARE TESTOSTERONE DERIVATIVES?

oNorgestrel oDesogestrel oEthynodiol

**_MENOPAUSE_** oMenopause normally occurs 45-55 yrs. oMenstruation becomes irregular & then ceases. oCaused by “ovarian failure” - very few functional primordial _ are left in ovaries oGonadotropins secreted in greater amounts, because of loss of negative feedback.

Follicles

**_PHASES OF MENOPAUSE_** oPerimenopause Fluctuation in hormone levels Can last 2-8 years oMenopause Oestrogen levels drop 1 year after cessation of menstrual cycle oPostmenopause Oestrogen levels continue to drop Miscellaneous health concerns begin

WHAT ARE THE THREE PHASES OF MENOPAUSE?

oPerimenopause Fluctuation in hormone levels Can last 2-8 years oMenopause Oestrogen levels drop 1 year after cessation of menstrual cycle oPostmenopause Oestrogen levels continue to drop Miscellaneous health concerns begin

**_SYMPTOMS OF MENOPAUSE_** ALL ARE MAINLY ASSOCIATED WITH THE DECREASE IN OESTROGEN LEVELS oHot flushes of skin oNight sweats oPalpitations oIncreased irritability oMood change oVaginal atrophy oDevelopment of osteoporosis ( risk hip & spine fractures)

**_OSTEOPOROSIS_** oOestrogen acts to maintain bone mineral density oThere is a positive relation between maintenance of bone mass and HRT with oestrogen oDecrease rates of wrist, non-vertebral, vertebral, and hip fractures oRaloxifene – SERM that functions like oestrogen to maintain bone density

WHAT IS RALOXIFENE?

SERM that functions like oestrogen to maintain bone density

**_HORMONE REPLACEMENT THERAPY (HRT)_** oGenerally use “natural” oestrogen rather than more potent synthetic derivatives oOestrogens + progestogens in women with an intact uterus oOral, transdermal patch, vaginally, subcutaneous implant oHRT long-term can reduce post-menopausal osteoporosis & vasomotor symptoms. oOestrogens _ LDL cholesterol levels but evidence mixed about the decreased risk of coronary heart disease

Decrease

**_HRT- THE EFFECTS OF OESTROGEN TREATMENT_**

**_CONTRACEPTION_** oBarrier methods -Caps, diaphragms, condoms oIntra-uterine devices (IUD) “coil” oOral contraceptives - Combined hormonal contraceptives - Progestogen-only contaceptives - Emergency contraception

WHAT ARE THE THREE MAIN 'CATEGORIES' OF CONTRACEPTION?

Barrier Methods IUD Oral Contraceptives

**_COMBINED OESTROGEN/PROGESTOGEN PREPARATION FOR ORAL CONTRACEPTION (COCs)_** “The Pill”, low dose synthetic oestrogen/progestogen combinations are regarded as very effective, easy to use & relatively safe contraceptives -Taken 21/28 days **Oestrogens** suppresses ovulation by inhibiting LH/FSH release, thus mimicking normal negative feedback effect of oestrogen at pituitary & hypothalamic level **Progestogens** induces thickening of cervical mucus & thins endometrium

HOW DO OESTROGENS WORK IN COCs?

Oestrogens suppresses ovulation by inhibiting LH/FSH release, thus mimicking normal negative feedback effect of oestrogen at pituitary & hypothalamic level

HOW DO PROGESTOGENS WORK IN COCs?

Progestogens induces thickening of cervical mucus & thins endometrium

**_SIDE EFFECTS WITH COCs_** **Mild side effects are mostly related to the oestrogen content:** oNausea, vomiting oWeight gain (Na+/ fluid retention) oMild hypertension oBreast tenderness **Rare toxicity includes:** oVenous thromboembolism (oestrogen coagulation) oCerebral haemorrhage/ embolism/stroke, myocardial infarction (especially in heavy smokers & 35+) oIncreased risk of breast/cervical cancer oAmenorrhoea following withdrawal can last several months

**_PROGESTOGEN-ONLY CONTRACEPTIVE (POC)_** oPOC less reliable than COC – “mini pills” oTaken continuously, effects include: - Cervical mucus becomes thick & sticky, thus hostile to \_. - Endometrium changes so making implantation less likely. - Weak negative feedback inhibition of LH release & ovulation - POC’s in some women can completely suppress gonadotrophin secretion & ovulation resulting in amenorrhoea.

Sperm

**_POSTCOITAL ORAL CONTRACEPTION ('EMERGENCY CONTRACEPTION')_** e.g. levonorgestrel, ulipristal oPregnancy can be prevented by short-term administration of a high dose of progestogen - the “morning after pill”, “plan-B” oUsed within 72 h of unprotected intercourse it is 98% effective oUlipristal is a PR modulator - effective within 5 days oSide effects: nausea, vomiting ( can affect absorption), cardiovascular and metabolic effects, breast tenderness

**_MENSTRUAL DISORDERS_** ## Footnote **Dysmenorrhoea** Painful periods, abdominal cramps **Menorrhagia** Heavy periods, excessive blood loss **Premenstrual Syndrome** Physical, pyschological and behavioural symptoms **Endometriosis** Where the same epithelial cells that line the walls of the uterus are found outside of the uterus (long-term condition)

WHAT ARE THE FOUR TYPES OF MENSTRUAL DISORDERS?

Dysmenorrhoea Menorrhagia Premenstrual Syndrome Endometriosis

**_ANTIPROGESTOGENS_** •Mifepristone – PR antagonist -Used in combination with a prostaglandin - gameprost •“Medical abortion” - an alternative to surgical termination of pregnancy

**_UTERINE WALL CONTRACTIONS- PROSTAGLANDINS_**

**_UTERINE WALL CONTRACTIONS- PARTURITION_**

**_UTERINE WALL CONTRACTIONS SUMMARY_** oOxytocin and prostaglandins stimulate contractions -Induce labour oProgestogens relax uterine wall and maintain cervical length - Habitual miscarriage - Premature labour oBeta2-adrenoceptor agonists inhibit contractions of the pregnant uterus