Med2042 Week 2 - Hormones And Sex

Front 1

Describe the adrenal glands.

Back 1

- Essential for life (mostly due to adrenal cortex)
- hypo- or hyperfunction will result in significant morbidity and eventually death
- replacement therapies

Front 2

Describe the anatomy of the adrenal glands.

Back 2

- paired organs that sit aboce the kidneys
- pyramidal structures (2.5 x 5 x 1 cm)
- consist of an outer cortex (steroid hormone production) and inner medulla (catecholamine production)

Front 3

Describe the embryology of the adrenal glands.

Back 3

- adrenal medulla arises from neural crest cells: cortex from mesodermal cells
- the future adrenal medullary cells migrate from the neural crest and invade future adrenal cortex
- formation of fetal and definitive adrenal cortex
- adrenal glands at their relative largest just prior to birth

Front 4

Describe the cytology of the adrenal glands.

Back 4

Three distinct zones of the adrenal cortex
- Glomerulosa - outer zone (aldosterone)
- Fasciculate - middle zone (cortisol)
- Reticularis - inner zone (androgens)

Medulla - chromaffin cells (electron dense granules): each cell innervated by cholinergic, preganglionic sympathetic neurone.

Front 5

Describe the adrenal blood supply.

Back 5

- Multiple small arteries supply cortex
- Form capillary plexus that directs blood flow from cortex to medulla --> therefore medulla bathed in cortical products
- Additional direct arterial supply to medulla
- Central vein drains cortex and medulla
- Additional venous drainage of cortex

Front 6

Describe adrenal steroidogenesis.

Back 6

- Adrenals produce steroids from cholesterol or acetate
- Initial step in steroidogenesis is the transport of cholestrol across the inner mitochondrial membrane (StAR protein)
- What steroids are produced depends on what enzymes are present

Front 7

What are glucocorticoids?

Back 7

- Product of the Zona Fasciculata
- Cortisol is the endogenous glucocorticoid
- Principle stimulator is ACTH
- Other potential stimulators include cytokines and prostaglandins (PGE2)
- Act via Glucocortiboid Receptor, but may also have actions at the Mineralocorticoid Receptor

Front 8

What are the metabolic actions of glucocorticoids?

Back 8

- Carbohydrate - increase glycogen synthase, increase gluconeogenesis, decrease glucose uptake
Lipids - increase lipolysis, free fatty acids
- Protein - increase catabolism, decrease amino acid uptake, decrease fibroblast function
- Caloric Intake - increase

Front 9

What are the haematopoietic actions of glucocorticoids?

Back 9

- Decrease lymphocytes, eosinophils and monocytes
- Decrease T cell function (IL-1, IL-2, TNF)
- Decrease B cell activation
Increase apoptosis

Front 10

What are the sundry actions of glucocorticoids?

Back 10

- Bone - increase bone resorption, decrease osteoblastic function (collagen synthesis and calcium deposition)
- CNS - regulate neuronal and glial function
- CVS - actions at vascular smooth muscle, regulate vasoactive substances
- Electrolytes - increase GFR, renal K+ secretion
- Promote cellular differentiation (fetus)
- inhibit growth

Front 11

What is the link between glucocorticoids and inflammation?

Back 11

- Glucocorticoids have potent anti-inflammatory effects
- Excellent therapy in disease states
- Increased susceptibility to infection in response to therapy
- Glucocoricoid deficiency can result in uncontrolled inflammatory response (e.g. infection)

Front 12

What is aldosterone?

Back 12

- product of Zona Glomerulosa
- primary action to increase Na+ reabsorption (distal tubule and collecting ducts of the kidney), lesser extent in gut and salivary glands
- consequent increase in H2O retention and K+ and H+ secretion
- secretion stimulated by K+ and renin-angiotensin system
- essential role of ACTH

Front 13

What are mineralocorticoids?

Back 13

- aldosterone is the most important mineralocorticoid
- cortisol can also act at the mineralocorticoid receptor, but...
- an enzyme "protects" the mineralocorticoid receptor from cortisol

Front 14

Describe synthetic corticoids.

Back 14

- A wide range of synthetic glucocorticoids are available
- Differ in a number of different residues within the general steroid structure
- Will have slightly different actions in different bioassays.

Front 15

Describe replacement therapies.

Back 15

- need for glucocorticoid as well as a mineralocorticoid
- usually prednisolone and 9a flurocortisone
- staggered doses (2x am vs pm)
- great care to be taken not to overdose
- increase in dose with intercurrent illness

Front 16

What is Cushings Syndrome/disease?

Back 16

- Overexposure to glucocorticoids
- Cushings Disease described by Harvey Cushing in 1912 - adenoma of the pituitary gland causing adrenal hyperplasia
- Cushings Syndrome is due to any other cause

Front 17

What are the symptoms and signs of Cushings?

Back 17

Central weight gain
Depression/psychosis
Mentrual changes
Thin skin/easy bruising
Hair growth/acne
Muscular weakness
Hypertension
Pathological fractures
Plethora
Striae
Proximal myopathy
Glycosuria/hyperglycaemia

Front 18

What are the causes of Cushings?

Back 18

Iatrogenic
Pituitary Adenoma
Adrenal Adenoma
Ectopic Production of ACTH by tumours

Front 19

How is Cushings diagnosed?

Back 19

Clinical Assessment
Morning plasma cortisol and ACTH
24 hour urinary collection
Dexamethasone suppression tests
Imaging or selective sampling

Front 20

What is the treatment for Cushings?

Back 20

Identify the cause and treat appropriately
Surgical treatment often necessary
Medical treatments can be used to inhibit cortisol production

Front 21

What is Addisons Disease?

Back 21

- Thomas Addison first described in 1957
- Range of symptoms associated with infiltration or destruction of the adrenal gland
- Primary Hypoadrenalism

Front 22

What are teh symptoms and signs of Addisons?

Back 22

Weight loss/anorexia
Malaise
Nausea/vomiting
Depression
Abdominal pain
Syncope from postural hypotension
Salt appetite
Increased pigmentation (especially of scars, pressure areas and areas not exposed to sunlight)
Loss of body hair

Front 23

What are the causes of Addisons?

Back 23

Autoimmune disease
TB
Infarction
AIDS
Malignant infiltration
Surgical removal

Front 24

How is Addisons diagnosed?

Back 24

Random cortisol and ACTH
ACTH stimulation tests

Front 25

What is the treatment for Addisons?

Back 25

- Glucocorticoid & mineralocorticoid
- need to increase glucocorticoid when there is intercurrent infection

Adrenal Crisis
- saline and ?glucose infusion
- intravenous cortisol (hydrocortisone)

Front 26

What is congenital adrenal hyperplasia? What questions need to be asked?

Back 26

Imagine a fetus with a congenital deficiency in the activity of the enzyme 21-hydroxylase
- What steroids would the adrenal gland be capable of making?
- What would be the response of other organs (including pituitary)?
- What would happen to the child when born?

Front 27

What steroids would the adrenal gland be capable of making? (congenital adrenal hyperplasia)

Back 27

Decreased cortisol
Decreased Aldosterone
Increased pituitary drive to the adrenal (ACTH concentrations elevated)
Increased Adrenal Androgens
Virilisation

Front 28

What happens to a child with congenital adreanl hyperplasia?

Back 28

- May have ambiguous genitalia due to excessive androgen production
- No aldosterone, therefore crisis due to inability to conserve Na+

Front 29

What is Conns syndrome?

Back 29

- Hypertension due to an adrenal adenoma - excessive aldosterone secretion
- Hypernatraemia, hypokalaemia
- Rare condition - though there is emerging evidence that hyperaldosteronism may be a far more common cause of hypertension than previously thought
- Treatment - identification and removal

Front 30

What is a phaeochromocytoma?

Back 30

- Tumour of the adrenal medulla or sympathetic ganglia
- Anxiety/panic attacks, hypertension, tremor, sweating, palpitations, headache, flushing
- Diagnosis by measurement of catecholamines or their metabolites

Front 31

Describe the transport of thyroid hormones.

Back 31

- Once released, transported in blood bound to protein
- Of total 99.7% of T3, and 99.9% of T4 is protein bound
- Principal binding proteins are TBG (thyronine-binding globulin), Albumin and TBPA (thyroxine-binding pre-albumin)

Front 32

What factors affect thyroid transport?

Back 32

- Pregnancy, Estrogen treatment, Oral Contraceptives can increase TBG
- Liver disease, major illness, nephrotic syndrome can decrease TBG
- Some drugs (anti-epileptics and anti-inflammatories) can interfere with thyroid hormone binding to TBG

Front 33

Describe the peripheral deiodination of thyroid hormone.

Back 33

- 85% of thyroid hormone released is T4.
- T3 is much more biologically active and there is extensive peripheral deiodination of T4
- Deiodination of outer ring gives T3; deiodination of inner ring gives reverse T3 (rT3)
- Separate deiodinases regulate these reactions: therefore have activating or deactivating functions

Front 34

Describe thyroid hormone receptors.

Back 34

- A member of the class of steroid/thyroid/retinoic acid receptors
- These receptors bind to DNA and when activated modulate gene transciption
- They are therefore transcription-activation factors
- Interact with a range of other nuclear proteins and may increase or decrease transcription of genes
- Thyroid hormone receptor distinctive because it appears that it is constantly bound to DNA

Front 35

What is the action of thyroid hormone?

Back 35

- Virtually all cells have thyroid hormone receptors and many genes are regulated.
- beta adrenergic receptors are up-regulated
- Critical role in regulation of development of the CNS (Cretinism, Guthrie tests)
- Regulation of Basal Metabolic rate

Front 36

What are the effects of thyroid hormone?

Back 36

- Increase O2 consumption and heat production
- Increase cardiac output
- Increase gluconeogenesis and glycogenolysis
- Increase neuromuscular transmission
- Increase gut motility
- Increase CNS activity

Front 37

How is TSH secretion regulated?

Back 37

1. Exposure to cold
2. Circadian rhythm (max between 0000 and 0400 irrespective of sleep state)
3. Regulated by changes in caloric intake (starvation vs excess)

Front 38

What are the signs and symptoms of hyperthyroidism?

Back 38

- Weight loss, sweating, tremor, goitre
- Agitated & nervous, fatigability, heat intolerance
- Tachycardia - atrial fibrillation
- Muscle weakness, decreased muscle mass
- Diarrhoea, shortness of breath, infertility amenorrhoea

Front 39

What is graves disease?

Back 39

- Autoimmune disease associated with the generation of an antibody known as TSAb or Long-Acting Thyroid Stimulator (LATS)
- Very much more common in women than men
- Eye signs prominent

Front 40

What are the signs and symptoms of Hypothyroidism

Back 40

- Weight gain, coarse skin, dry hair, hoarse voice, "puffy" appearance
- Feels cold, lethargic/depressed
- Changed tendon reflexes (slow relaxation); muscle weakness
- Decreased cardiac output; bradycardia
- Menstrual irregularities

Front 41

What is the biochemical assessment of thyroid function?

Back 41

- Must be based on clinical assessment
- TSH is an excellent first-line test
> If normal - probably no problem
> If elevated - ? hypothyroid
> If decreased - ? hyperthyroid
- Free T4 a great "second-line" test

Front 42

What are steroids?

Back 42

Steroids are 4-ringed lipids derived from cholesterol. They have profound effects on all tisues of the body in development, the maintenance of homeostasis and in reproductive functions.

Front 43

What types of steroids are there?

Back 43

Cholesterol
Progestagens
Corticosteroids
Androgens
Estrogens

Front 44

Where do steroids come from?

Back 44

Progestagens
- Ovarian follicle
- Corpus Luteum
- Placenta

Corticosteroids
- Adrenal cortex (gluco- & mineralocorticoids)

Androgens
- Testis (Leydig cells)
- Ovary
- Adrenal cortex

Estrogens
- Ovarian follicle
- Placenta
- Fat

Front 45

How are steroids made?

Back 45

- From acetate or cholesterol (uptake via LDL)
- Inside mitochondria. Cholesterol entry depends on STAR (Steroid acute regulatory protein)
- The particular steroids secreted by a cell depends on the enzymes it possesses. All steroids in the pathway are secreted.

Front 46

How are steroids transported?

Back 46

Hormones often travel through the blood bound to a specific binding protein. The bond is weak enough to allow the complex to dissociate, releasing free hormone. Only he free hormone can exit the capillaries to reach the target cells.

The binding protein protects the hormone from renal filtration and enzymic attack, so prolongs its plasma half-life. It also buffers the free hormone concentration from sudden changes.

As well as the high affinity, low capacity, specific BPs, other plasma proteins (e.g. albumin) may bind hormones with lower affinity and higher capacity.

Front 47

How do steroids act on target cells?

Back 47

Steroid hormone receptors
- Being small and lipid-soluble, these hormones diffuse into the target cell.
- They bind to receptors in the cytosol or nucleus
- The receptor/ligand complex enters the nucleus
- It binds to chromosomal DNA and activates the transcription of mRNA leading to new protein synthesis (i.e. it acts as a transcription factor)

Front 48

How are steroids removed from the circulation?

Back 48

The essential strategy the body uses to eliminate steroids is to render them water-soluble, thus permitting renal excretion.

Steroid metabolism
- Most steroids rapidly & extensively metabolised in kidneys and liver
- Only free, not bound, circulating steroid metabolised
- Metabolised to water soluble conjugates (sulphate and glucuronate added at pom.3&17)
- Metabolites do not bind receptors & are cleared through urine and faeces
- Placenta sulphates maternal steroids before they pass to the fetus and fetus sulphates its steroids which may subsequently be used by the mother (E3)
- Progesterone metabolites may act as a fetal anaesthetic