Strand 12- Hormones and Homeostasis

what are the main endocrine glands

• hypothalamus/pituitary

• thyroid

• parathyroid

• pancreas

• adrenal

• ovaries/testicles

hypothalamic-pituitary axis

• brain:

  • hypothalamus

  • pituitary gland

pituitary gland

• controls most (not all) glands in the body

• most difficult part of endocrinology→ full attention is required

lobes of the pituitary gland

• anterior pituitary→ produces various hormones

• posterior pituitary→ stores various hormones

hormones produced in the anterior pituitary

• growth hormone (GH)→ skeletal growth

• Adrenocorticotrophic hormone (ACTH)→ stimulates adrenals to produce steroids

• gonatrotrophins (FSH and LH)→ stimulate testicles/ovaries to produce sex hormones

• thyroid stimulating hormone/thyroptrophin (TSH)→ stimulates thryroid to produce thyroid hormones

• Prolactin (PRL)→ stimulates breast milk production

posterior pituitary

• stores hormones produced in hypothalamus

• ADH→ stimulates water reabsorption by kidneys

• Oxytocin→ helps uterine contractions during labour

How is pituitary controlled

• Anterior PG under control of hypothalamus:

  • corticotrophin releasing hormone (CRH)→ stimulates ACTH secretion

  • growth hormone releasing hormone (GHRH)→ stimulates GH secretion

  • thyroptropin releasing hormone (TRH)→ stimulates TSH stimulation

  • Gonadotrophin releasing hormone (TRH)→ stimulates FSH and LH secretion

  • Prolactin release inhibited until childbirth

how are pituitary hormones switched off

• negative feedback:

  • cortisol switches off ACTH and CRH

  • growth hormone switches off GH and GHRH

  • thyroid hormones switch off TSH and TRH

  • sex hormones switch off FSH/LH and GnRH

glands not controlled by the pituitary

• adrenal medulla→ produces adrenaline and noradrenaline

• parathyroid (PTH) → produces parathyroid hormone→ controls calcium levels

• pancreas→ controls sugar levels

• Gut hormones

thyroid gland structure

• composed of:

  • midline isthmus (just below cricoid cartilage)

  • right lobe

  • left lobe

thyroid gland

• thyroid cells are arranged in follicles and produce thyroid hormones

• also contains C cells, producing calcitonin→ calcium metabolism

• thyroid hormones interact with receptors in various organs→ regulate gene expression and aspects of organ function

control of thyroid hormone secretion

1. hypothalamus secretes TRH

2. Stimulates APG to secrete TSH

3. Stimulates thyroid to produce thyroid hormones

4. thyroid hormones inhibit TRH and TSH secretion

types of hyperthyroidism

• primary hyperthyroidism→ thyroid pathology causing thyroid hormone production

• secondary hyperthyroidism→ pituitary pathology causing increased TSH synthesis and consequently higher thyroid hormone production

calcium metabolism and organs involved

• mainly controlled by 4 parathyroid glands sitting behind thyroid

• kidneys→ calcium excretion and production of active vitamin D

• gut→ absorption of calcium

• bone→ storage of calcium

• thyroid→ C cells

structure of adrenal glands

• Adrenal cortex:

  • corticosteroids (cortisol)

  • androgens (male hormones)

  • mineralocorticoid (aldosterone)

• Adrenal medulla:

  • catecholamines (adrenaline, noradrenaline, dopamine)

extent of control of pituitary glands on adrenal hormones

• catecholamine secretion not controlled by pituitary→ related to blood pressure

• mineralocorticoid secretion not controlled by pituitary→ related to renin-angiotensin system→ controls blood pressure)

ovaries

• situated on pelvis side of uterus

• ovaries contain follicles (each contain oocyte) at different stage of maturation during reproductive life

control of female hormone secretion

1. hypothalamus secrets GnRH

2. Stimulates production of FSH and LH in pituitary

3. Stimulates ovaries to make inhibin, oestradiol, progesterone:

   1. inhibin inhibits pituitary secretion→ FSH, LH

   2. oestradiol inhibits FSH, LH and GnRH

testes

• composed of:

  • interstitial/ leydig cells→ produce testosterone

  • seminiferous tubules→ made of germ cells producing sperm

  • sertoli cells→ help in sperm production and produce inhibin

control of male hormone production

1. hypothalamus secretes GnRH

2. stimulates pituitary to produce FSH and LH

3. stimulates testis to produce inhibin and testerosterone:

   1. inhibin inhibits pituitary secreting FSH and LH

   2. testosterone inhibits hypothalamus and pituitary

clinical abnormalities of glands

• hormonal over-secretion:

  • primary

  • secondary

• hormonal under-secretion:

  • primary

  • secondary

• tumour/nodules in glands without gland without affecting hormone secretion

types of tests for hormonal abnormalities

• static tests

• stimulation tests

• suppression tests

static tests

• diagnose abnormalities of thyroid and sex glands:

  • primary hyperthyroidism:

    • test for T4 and T4

    • TSH

  • Primary hyperthyroidism→ T3 and T4 elevated, TSH suppressed

stimulation tests

• for suspected hormonal under-secretion where static test is not enough

• e.g. giving ACTH to test for adrenal insufficiency (synacthen test):

  • if infividual fails to respond to stimulation test, gland failure is diagnosed

• other e.g.s: glucagon stimulation and insulin stress test for pituitary failure

supression tests

• for some hormonal over-secretion

• e.g. giving steroids and testing for endogenous steroid production

• giving glucose and testing GH secretion

diseases of the endocrine glands

• over-secretion (usually benign tumours)

• under-secretion gland destruction due to:

  • inflammation

  • infarction

• tumours/nodules with normal hormone production

prolactin oversecretion

• usually due to pituitary tumour secreting prolactin (prolactinoma)

• clinical presentation:

  • galactorrhoea (breast milk production)

  • amenorrhoea in women, sexual dysfunction in men

  • large tumours→ headaches and visual field problems

diagnosis of prolactinoma

• static test

• pituitary MRI

causes of raised prolactin

• sexual intercourse

• nipple stimulation

• stress

• large number of drugs e.g. antipsychotics and antidepressants

• non-functioning pituitary tumour→ compressing hypothalamus, interfering with inhibitory effect on prolactin secretion

growth hormone oversecretion

• in childhood/adolescent:

  • excessive growth spurt and increased feet and hand size

  • untreated→ gigantism

• in adults:

  • affects skin, soft tissue and skeleton

  • acromegalic face

  • wide and large hands/feet

  • increased sweating

diagnosis of excess growth hormone

• requires suppression test

• glucose given, followed by GH measurements at different time points:

  • in healthy individuals, glucose suppresses GH production and plasma levels of hormones fall

• imagine necessary to confirm presence of pituitary tumour

causes of cushing’s syndrome

• pituitary secreting ACTH tumour (Cushing’s disease)

• adrenal tumours secreting cortisol

• cancers producing ACTH (such as lung cancers)

clinical presentation of Cushing’s

• growth arrest in children

• typical facial appearance:

  • round (moon-like) face

  • acne

  • hirsuitism

• Fat redistribution:

  • truncal obesity

  • thin extremities

• Skin abnormalities:

  • thin skin, easy bruising

  • striae on abdomen

• complications:

  • hypertension

  • diabetes mellitus

  • high risk of infection

  • poor wound healing

tests for Cushing’s

• static tests not enough→ suppression tests required

• dexamethasone suppression test used to confirm failure of suppression of endogenous cortisol production

thyroid hormone overproduction

• could be due to primary or secondary hyperthyroidism

• primary→ very common

• secondary→ very rare

causes of hyperthyroidism

• graves disease→ autoimmune condition

• toxic nodule or toxic MNG

• thyroiditis

• drug induced

• rarities

symptoms of hyperthyroidism

• hyperactivity, irritability, insomnia

• heat intolerance and increased sweating

• palpitations

• weight loss despite overeating

signs of hyperthyroidism

• signs of thyrotoxicosis:

  • hand tremor

  • increased sweating

  • fast pulse

• enlarged thyroid:

  • smooth→ Grave’s disease

  • nodular→ toxic nodules

  • tender→ thyroid inflammation

extrathyroidal signs

• thyroid eye disease

  • swelling around eyes

  • protrusion of eyeball→ proptosis

  • paralysis of eye muscles

investigations for hyperthyroidism

• thyroid blood test:

  • raised thyroid hormone

  • supressed TSH

• static test is enough

• antibody testing (TSHR-Ab) confirms autoimmune nature of condition

growth hormone deficiency

• children→ failure of growth

• adults→ tiredness, depression

testing for growth hormone deficiency

• stimulation test required

  • glucagon stimulation test

  • insulin stress test→ lowers blood glucose, stressing body and forcing growth hormone secretion

treatment of growth hormone deficiency

• growth hormone replacement:

  • injections

  • expensive

steroid undersecretion

• may be due to:

  • adrenal failure

  • pituitary failure

• clinical presentation:

  • failure to grow in children

  • severe tiredness

  • dizziness due to low b.p

  • abdominal pain, vomiting, diarrhoea

testing for steroid undersecretion

• stimulation test:

  • synacthen test (giving ACTH) if primary adrenal failure suspected

  • GST or IST if secondary adrenal insufficiency is suspected

• for adrenal failure, cortisol should be given before results of investigations are available

hypothyroidism

• very common in older ladies

• primary hypothyroidism→ thyroid failure

  • usually autoimmune

  • can be drug induced

• secondary hypothyroidism→ failure to produce TSH

  • usually part of complete pituitary failure
    

diagnosis and treatment of hypothyroidism

• diagnosis→ static test

• treatment→ thyroid hormone replacement

sex hormone deficiency

• primary:

  • males→ testicular failure

  • females→ ovarian failure

• secondary:

  • pituitary failure

presentation of sex hormone deficiency

• males:

  • erectile dysfunction

  • reduced libido

• females:

  • menstrual abnormalities (amenorrhoea)

diagnosis and treatment of sex hormone deficiency

• diagnosis:

  • static tests for testosterone, oestradiol, FSH, LH

• treatment:

  • hormone replacement therapy

  • pituitary hormone replacement

pituitary failure

• may be due to:

  • large tumour

  • infarction

• usually involves multiple hormones and combination of static and stimulatory tests required to make diagnosis

pituitary independent endocrine abnormalities

• increased parathyroid hormone production may be due to:

  • primary hyperparathyroidism

  • cancers

  • drugs

homeostasis

• state of steady internal physical and chemical conditions maintained by living systems

• condition of optimal functioning for organism

negative feedback loop

• mechanism that reduces effect of change and helps maintain balance in a system

• occurs when the output of a system used to reduce or regulate its own activity

components of negative feedback loop

• receptors/sensors→ detects change

• control centres→ compares change to normal and initiates response

• effectors→ acts to revert change back to normal

normal blood glucose levels

4-6nM

response to high blood sugar

1. blood sugar too high

2. beta cells release insulin:

   1. glucose taken up by various tissues

   2. liver reduces gluconeogenesis

3. blood sugar levels fall

repsonse to low blood sugar

1. alpha cells release glucagon

2. liver increases production of glucose

3. blood sugar levels rise

response to high body temperature

1. hypothalamus detects raise in temp of blood

2. signals to skin to vasodilate and sweat→ heat is lost

3. body temperature falls

response to low body temperature

1. hypothalamus detects fall in blood temperature

2. signals to skeletal muscles to shiver to generate heat

3. skin vasoconstricts to reduce heat loss

4. temperature rises

blood gases

• O₂ and CO₂ have separate and different negative feedback loops

• CO₂levels control breathing:

  • if CO₂ rises by 10%, resp. rate doubles

  • O₂ levels don’t influence breathing until arterial O₂ drops by 40%

response to hypercapnia (high CO₂)

1. detected by central chemoreceptors

2. brain stem sends signals to diaphragm and intercostal muscles

3. person breathes deeper and more rapidly

4. more CO₂ exhaled

5. CO₂ levels fall

carbonic acid/bicarbonate system

• more CO₂ =more acidic blood

response to respiratory alkalosis

1. respiratory alkalosis caused by low CO₂ 

2. Respiratory compensation:

   1. inhibition of arterial and CSF chemoreceptors=decreased resp. rate

3. renal compensation:

   1. H⁺ ions made and HCO₃^-  ions secreted

4. other buffer systems release H⁺ ions

5. combined effects increase CO₂, Increased H⁺, decreased HCO₃^-

6. plasma pH returns to normal

response to respiratory acidosis

1. respiratory acidosis due to increased CO₂ conc.

2. Respiratory compensation:

   1. stimulation of arterial and CSF chemoreceptors= increased resp. rate

3. renal compensation:

   1. H⁺ secreted and HCO₃^- generated

4. other buffer systems accept H⁺ ions

5. combined effects decreased H⁺ and increased HCO₃^-

6. plasma pH returns to normal

responses to hypoxia

1. detected by peripheral (carotid body) chemoreceptors

2. brain stem sends signals to diaphragm and intercostal muscles

3. rapid, shallow breaths

4. more oxygen is breathed in absorbed into blood stream

5. O₂ levels rise

ways of increasing blood pressure

• vasoconstriction

• increased cardiac output

• RAAS activation

• EPO production (bone marrow produces more rbc)

immediate response to low blood pressure

1. falling blood pressure=baroreceptors inhibited 

2. vasomotor center stimulated→ vasoconstriction occurs

3. cardioacceleratory centers stimulated, cardioinhibitory centers inhibted→ increased cardiac output

4. blood pressure rises

renin-angiotensin-aldosterone system

1. blood flow through kidneys (renal perfusion) decreases→ renin released

2. renin causes angiotensin (made in liver) to be converted to angiotensin I

3. surface of pulmonary and renal endothelium releases ACE

4. ACE causes angiotensin I to be converted to angiotensin II

5. brings about effects raising blood pressure

effects of RASS

• sympathetic activity

• tubular Na⁺ and Cl^- reabsorption and K⁺ excretion→ water retention

• vasoconstriction

• increased ADH secretion→ water retention

immediate response to high blood pressure

1. rising blood pressure= baroreceptors stimulated

2. cardioinhibitory centers stimulated cardioacceleratory centers inhibited→ decreased cardiac output

3. vasomotor centers inhibit→ vasodilation

4. homeostasis restored

blood pressure too high-long term response

1. natriuretic peptides released by the heart

2. responses to ANP and BNP cause effects which reduce blood volume

3. homeostasis is restored

responses to ANP and BNP

• increased Na⁺ loss in urine

• increased water loss in urine

• reduced thirst

• inhibition of ADH, aldosterone, epinephrine and norepinephrine release

• peripheral vasodilation

ways to decrease blood pressure

• vasodilation

• decreased cardiac output

• ANP/BNP release

response to high levels of calcium

1. parafollicular C cells of the thyroid release calcitonin:

   1. calcium deposited in bones

   2. more calcium excreted in urine

   3. less calcium absorbed from food

2. calcium levels fall

response to low levels of calcium

• parathyroid glands release parathyroid hormone:

  • calcium released from bones

  • more calcium reabsorbed by kidneys

  • kidneys activate vitamin D→ more calcium absorbed from gut

• calcium levels rise

kidney anatomy

functions of the kidney

• fluid balance

• electrolyte homeostasis

• endocrine functions:

  • EPO production

  • Vitamin D activation

• pH regulation

• Blood filtration

• blood pressure control

glomerular filtration

• blood enters glomerulus via afferent arteriole

• passes through glomerulus, where it is filtered due to blood pressure→ plasma forced through barrier

• blood exits through efferent arteriole

serum and urine osmolality

• osmolality→ concentration of dissolved particles in a fluid

• normal serum osmolality→ 275-295 mOsm/kg

• mostly determined by sodium, glucose and urea

• fluctuates based on hydrations status and is tightly regulated by ADH and other homeostatic mechanisms

anatomy of a nephron

sodium reabsorption

hormones acting on the kidney

• antidiuretic hormone→ increases water reabsorption via aquaporins in collecting ducts

• aldosterone→ influences retention of sodium, excretion of potassium: controls BP and water retention

EPO

• erythroppoietin

• hormone produced in kidney

• stimulates erythropoiesis→ RBC production

vitamin D

• important role in calcium homeostasis

• step in metabolic activity occurs in kidney

components of the U&E

• sodium

• potassium

• urea

• creatinine

• chloride

• bicarbonate

sodium

• main extracellular cations and determines effective extracellular fluid osmolality

• osmolality/tonicity gradients→ osmotic pressure gradients

• serum sodium→ concentration determined by total body water

potassium

• primarily intracellular cation

• cellular uptake mediated by sodium/potassium ATPase

• excretion is mostly renal

urea

• produce din liver as waste product of protein breakdown

• serum urea raised in:

  • kidney failure

  • upper GI bleeding

  • dehydration

• uraemic symptoms:

  • pruritus

  • encephalopathy

  • gout

creatinine

• waste product of muscle metabolism

• higher in those with greater skeletal muscle mass

• excreted almost entirely by kidney

• serum creatinine can be used as proxy for kidney’s ability to filter creatinine from blood

bicarbonate

• determined by CO₂, bicarbonate and other factors

• bicarbonate is basic

• kidney can adjust bicarbonate to maintain normal pH

GFR

• sum of filtration in all glomeruli

• inulin clearance is gold standard way of measuring GFR:

  • inulin freely filtered, not reabsorbed and not secreted by kidneys

issues with GFR

• impractical due to injection/infusion and multiple measurements

• expensive

• time consuming

• not widely available

eGFR

• estimated glomerular filtration rate

• creatinine used as surrogate marker of renal function

  • can be used to calculate eGFR using factors e.g. age, gender, ethnicity

• normal eGFR >90mL/min/1.73m²

muscle mass and eGFR

• high muscle mass→ high baseline Cr→ false low eGFR

• low muscle mass→ low baseline Cr→ false high eGFR

diet and eGFR

• creatinine found in meat/supplements

• can transiently raise serum creatinine

tubular secretion and eGFR

• some drugs block tubular secretion of creatinine

• creatinine rises→ eGFR falls, but actual GFR is unchanged

acute kidney injury

• decrease in renal excretory function

• occurs over hours to days

• can result in failure to maintain fluid, electrolyte and acid-base balance

oliguria

• decreased urine output

• <0.5ml/kg/hour (<20/30ml/hour for most adults)

anuria

absence of urine output