The Endocrine System Flashcards
HORMONES RELEASED BY THE ENDOCRINE SYSTEM ARE RELEASED INTO THE BLOOD.
TRUE OR FALSE?
True
WHAT IS NEGATIVE FEEDBACK?
Once set point is reached, production/release of hormones are stopped
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
WHAT ARE THE THREE CLASSES OF HORMONE?
Amines/Amino Acids
Peptides/Proteins
Steroid Hormones
HOW DOES ADRENALINE BRING ABOUT ITS EFFECT?
Binds to G-protein coupled receptors to bring about intracellular signaling via cyclic AMP
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
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
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.
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
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
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
AMINE HORMONES
oCatecholamines derived from tyrosine
•adrenaline, noradrenaline
oThyroid Hormones also derived from tyrosine
•thyroxine, triiodothyronine
oIndoleamines derived from tryptophan
•Melatonin
ADRENAL CATECHOLAMINE SYNTHESIS
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
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
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)
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)
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
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.
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
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
INTRACELLULAR RECEPTORS
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
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
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:
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
- 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.
- 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.
- 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
- 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.
- 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.
- 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)
•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
- White blood cells will remove any dead cells or germs that have entered, osteoclasts remove dead bone fragments.
- Blood clot replaced by fibral cartilage.
JOINTS
- 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
•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; t1/2 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 PO43-) via several actions:
Kidney
- Stimulates Ca2+ reabsorption in the distal tubule
- Inhibits PO43- 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 PO43-
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
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; t1/2 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)2D3 PRODUCTION
ACTIONS OF 1,25(OH)2D3
Increases plasma Ca2+:
•GI Tract (Main)
- Stimulates absorption of Ca2+ (principally in the duodenum)
- Stimulates absorption of PO43- (jejunum and ileum)
•Bone
–Increases the number and activity of osteoclasts
-Leads to an increase in bone resorption and hence Ca2+ and PO43- release
•Kidney
– Facilitates Ca2+ reabsorption (DCT)
ENDOCRINE REGULATION OF Ca2+ HOMEOSTASIS: THE IMPORTANCE OF FEEDBACK LOOPS
CALCITONIN (CT)
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 PO43-
- 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 PO43-
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
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
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?
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
- Cells actively accumulate iodide and iodinate tyrosine residues to form T3 and T4
- Iodinated thyroglobulin enters lumen by exocytosis
- Stored thyroglobulin re-enters follicle cells by endocytosis
- Lysosomal enzymes release T3 and T4
- 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 T3.
Globulin
MOST OF THE PHYSIOLOGICAL EFFECTS OF THYROID HORMONES ARE DUE TO T3.
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.
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.
Anterior
WHAT IS THE FUNCTIONING OF GONADS CONTROLLED BY?
The hypothalamus and anterior pituitary
HORMONAL REGULATION OF THE FEMALE REPRODUCTIVE CYCLE
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
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
