Endo/Repro 1 Flashcards
Endocrine system
- a system of hormone glands secreting substances into the bloodstream that influence remote tissues
- also unexpected sources, eg heart -> ANP, adipose tissue -> leptin, skin -> vitamin D
Often in odd arrangement, layers inside and out
- eg adrenal medulla in cortex
- C cells inside thyroid
- pancreatic islet cells inside exocrine pancreas
Movement of bioregulators
INTERNAL
- hormones + neurotransmitters
- via haemolymph or blood stream
EXTERNAL
- pheromones
- via water (fish) or air
Pheromonal signals
Origins of endocrine system
- from unicellular organisms, move towards high pheromone concentration
- become multicellular organisms
A chemical signal transmitted between individuals of the same species
- still present in complex multicellular organisms
Uses of endocrine system
Survival - find optimal chemical and physical environment - find sustenance - optimise conditions for reproduction - facilitate successful evolution Competition - steroids have antimicrobial effects - host hormones can inhibit parasite growth
Controls of the endocrine system
Circadian rhythm - internal clocks
Diurnal rhythm - external cues (driven mainly by vision, dark/light)
Ultradian rhythm - hour to hour fluctuations
Influenced by:
- senses
- autonomic input
Underactive endocrine system causes
- inherited metabolic fault, eg enzymes missing
- destruction of glandular tissue, physical or autoimmune
- abnormal hormone production
- excessive binding protein
- receptor not responding or absent
- inappropriately high feedback
Overactive endocrine system causes
- autoimmune attack inducing overactivity
- intrinsic receptor overactivity
- reduced inhibition (eg tumour blocking feedback response)
- neoplastic formation of a functional adenoma
- persistent feedback stimulation leading to autonomy
Anatomy of hypothalamus
Part of diencephalon
On either side of third ventricle below thalamus
Connected to pituitary by pituitary stalk (infundibulum) through dura mater layer
Nuclei arranged in three zones - periventricular, medial, lateral
Endocrine nuclei in periventricular and medial zones - contain neurosecretory cells to secrete hormones (transduce from neural to hormonal signal)
- pulsatile firing, so discrete package of hormone released, controlled by synaptic input
Neural connections of hypothalamus
Descending to - hippocampus, amygdala, septal nuclei
Ascending from - locus ceruleus, dorsal vagal complex, midbrain raphe, midbrain ventral tegmentum
Extensive intrahypothalamic connections
Circumventricular organs
Lie on midline, along 3rd and 4th ventricle
Leaky, reduced BBB - route for large molecules into brain
Release molecules to hypothalamus; for appetite (leptin), fever (cytokines), drinking (angiotensin)
(includes median eminence)
Embryological development of pituitary
At 4-5 weeks
Downgrowth from floor of diencephalon
= neural tissue
Upgrowth from roof of oral cavity
= glandular tissue
- stalk will regress, attaches to infundibulum process instead
- sphenoid bone develops around
- > leaves pituitary gland in sella turcica, indent in bone - means if tumour can only grow up as bone below
- > dura mater layer over top of pituitary, around stalk, diaphragm sella
- > sharp processes on either side of stalk, in head injury can damage pituitary stalk
Empty sella syndrome
Where there is no development of dura mater (diaphragm sella) over top of pituitary gland
- > CSF gets into sella turcica, increase in pressure, flattens pituitary against walls (may appear absent)
- > can be normal, or hypopituitarism - underproduction of one or more pituitary hormones
Anatomy of pituitary gland
= hypophysis
Posterior pituitary (from neural downgrowth) - median eminence (top) - infundibulum (stalk) - posterior/neural lobe = pars nervosa
Anterior pituitary
(from glandular upgrowth)
- pars tuberalis (either side of infundibulum)
- anterior lobe = pars distalis
— intermediate lobe = pars intermedia — present only in foetus, poorly vascularised, direct hypothalamic innervation
Blood supply to pituitary gland
Very well vascularised
From internal carotid artery
Posterior pituitary
- inferior hypophyseal artery into posterior lobe
- efferent vein
Anterior pituitary
- superior hypophyseal artery into primary portal plexus in median eminence
- continues as long portal vessel down
- into secondary plexus in anterior lobe
Veins drain to systemic blood via cavernous sinus, superior/inferior petrosal sinuses, jugular bulb and vein
- if need to take blood close to pituitary outflow, use inferior petrosal sinus, as close as you can get in humans
Nerve supply to pituitary gland
MAGNOCELLULAR HYPOTHALAMIC NEUROSECRETORY NEURONES
- large cell bodies, originating in paraventricular or supraoptic nuclei
- directly innervate posterior pituitary
- made, and released in same place directly into blood draining from pituitary
PARVOCELLULAR HYPOTHALAMIC NEUROSECRETORY NEURONES
- small neurones in paraventricular nucleus
- indirectly control anterior pituitary
- originate in paraventricular, arcuate and periventricular nuclei
- axons terminate in median eminence, blood to anterior pituitary and can affect pituitary function
Cells in anterior lobe (pars distalis) of pituitary gland
(labile tissue, changes proportions of cell type easily eg in pregnancy, but makes it susceptible to tumour formation)
SOMATOTROPH -> growth hormone (GH)
LACTOTROPH -> prolactin (PRL)
GONADOTROPH -> leutinising hormone (LH), follicle-stimulating hormone (FSH)
THYROTROPH -> thyroid-stimulating hormone (TSH)
CORTICOTROPH -> adrenocorticotrophic hormone (ACTH)
+ in foetus, in pars intermedia, melanotrophs -> Melanocyte-stimulating hormone (MSH)
Corticotrophin-related peptide hormones
Made in anterior pituitary gland
- single small peptides, derived from common precursor POMC (pro-opiomelanocortin)
- can be cleaved at many points, specific enzymes to make products found in different regions
- adrenocorticotrophic hormone (ACTH) - in corticotroph cells
- alpha-melanocyte-stimulating hormone
- beta-lipocortin
- beta-endorphin
Glycoprotein hormones
Made in anterior pituitary gland
- made of two peptides, alpha is always similar, beta differs for each hormone and confers specificity (binds to specific receptor)
- hormones are glycosylated before being secreted, carbohydrate and sialic acid added (amount determines stability)
- follicle-stimulating hormone (FSH)
- leutinising hormone (LH)
- thyrotrophin (TSH)
Somatomammotrophin hormones
Made in anterior pituitary
- single peptide chain, no carbohydrate, 2-3 disulphide bonds
- prolactin (PRL)
- growth hormone (GH)
Hypothalamic hormones - neuropophysial hormones
- made in magnocellular neurosecretory cells
- transported to and released from posterior pituitary
OXYTOCIN
-> milk ejection, expulsion of foetus
VASOPRESSIN
-> antidiuresis and ABP regulation
- made in supraoptic and paraventricular nuclei of hypothalamus
- 9 amino acid structure
Hypothalamic hormones - hypophysiotrophic hormones
- made in parvocellular neurosecretory cells
- transported to median eminence, released into portal circulation (so control anterior pituitary function)
THYROTROPHIN-RELEASING HORMONE (TRH) GONADOTROPHIN-RELEASING HORMONE (GnRH) SOMATOSTATIN (SS) GROWTH HORMONE RELEASING HORMONE (GHRH) PROLACTIN-INHIBITING HORMONE (DOPAMINE) CORTICOTROPHIN-RELEASING HORMONE (CRH)
All cause release or inhibition of anterior pituitary hormone release
- pulsatile release, so makes pituitary pulsatile release
- all have now been artificially synthesised
Corticotrophin-releasing hormone
Hypophysiotrophic hormone
Synthesised in paraventricular nucleus
41 amino acids
Stimulates synthesis and release of ACTH from pituitary corticotroph cells
-> signals to adrenal glands, produce cortisol (negative feedback)
Thyrotrophin-releasing hormone
Hypophysiotrophic hormone
Synthesised in paraventricular nucleus
3 amino acids
Stimulates synthesis and release of TSH from pituitary thyrotroph cells
(in high levels, stimulates release of prolactin)
-> signals to thyroid gland, produce T3 and T4 (negative feedback)
Gonadotrophin-releasing hormone
Hypophysiotrophic hormone
Synthesised in arcuate nucleus
10 amino acids
Stimulates synthesis and release of LH and FSH from pituitary gonadotroph cells
-> signals to gonads (ovary/testes), release testosterone in males, progesterone/oestrogen in females (negative feedback)
Growth hormone releasing-hormone
Hypophysiotrophic hormone
Synthesised in arcuate nucleus
44 amino acids
Stimulates synthesis and release of GH from pituitary somatotroph cells
-> negative feedback back to release more GHRH
Somatostatin
Hypophysiotrophic hormone
Synthesised in periventricular nucleus
14 amino acids, in cyclical structure
Inhibits synthesis and release of GH from pituitary somatotroph cells
-> signals to liver, and others. Release insulin-like growth factor 1 (IGF-1)
Prolactin-inhibiting hormone
= dopamine Hypophysiotrophic hormone Synthesised in arcuate nucleus 1 amino acid Inhbits synthesis and release of PRL from pituitary lactotroph cells -> signals to mammary gland
Signals stimulating HPA axis
CSF signals
Circumventricular organs
Neural inputs
Blood signals
Causes of pituitary disorders
HYPERSECRETION
- functioning tumours
- drugs
HYPOSECRETION (=hypopituitarism)
- craniopharyngeoma
- non-functioning pituitary tumours (affects surrounding tissue)
- radiotherapy
- trauma
- empty sella syndrome
Hypopituitarism
GH deficient - growth retardation (children), tiredness, muscle weakness
FSH/LH deficient - hypogonadism: men - reduced body hair, low libido, impotence. women - amenorrhoea, dyspareunia, hot flushes
TSH deficient - weight gain, decreased energy, cold sensitivity, constipation, dry skin
ACTH deficient - pale, weight loss, low bp, dizziness, tiredness
ADH(AVP) deficient - thirst, polyuria
Thyroid gland
Left and right lobes, connected by isthmus
Formed from floor of pharynx
20g weight
Rich blood supply
Produces thyroid hormone from follicles
TSH is principal regulator
Well vascularised - necessary to take up eg iodide, and to release hormone
In inactive state - wide colloid filled lumen, containing precursor to thyroid hormones. Follicle epithelial cells are flattened, inactive.
In active state - little colloid, as thyroid hormone is released as it is made. Taller, columnar epithelial cells.
Thyroid hormone synthesis
1 - active transport of iodide in from blood stream - needs adequate iodine in diet, but efficiently absorbed from gut into extracellular pool, then thyroid or kidneys absorb here
2 - oxidised to iodine, released into colloid lumen
1 - amino acid uptake, conversion to thyroglobulin (hormone precursor)
2 - thyroglobulin release into colloid lumen
3 - thryoglobulin iodination
4 - reabsorption into cell
5 - digestion by lysosymes to form T3 and T4
6 - release
Thyroid hormones
98% is T4 (tetra-iodothyronine/thyroxine) - 2 DIT (dihydrotyrosine) joined
2% is T3 (tri-iodothyronine), but is 10x more potent - 1 DIT and 1 MIT (monoiodotyrosine) joined
Small amount reverse T3
T4 is prohormone, converted to T3 or rT3 by de-iodination before acting at a receptor
- > increased calorigenesis (heat production)
- > increased metabolism (energy expenditure)
- > growth and maturation
- > cardiovascular effects
Disorders of thyroid gland
(Goitre is just enlarged thyroid, not indicative of hypo or hyper thyroid state)
- hypothyroidism
- hyperthyroidism
- subclinical conditions
2% of females get, 0.2% males get (mainly hypo)
Hypothyroidism symptoms
If present early in development:
- neurological deficits
- small stature, immature appearance
- puffy hands and face
- delayed puberty
If present in adulthood:
- insidious onset
- low BMR
- cold sensitivity
- bradycardia
- slow, hoarse speech
- lethargy, slow movements
- weight gain
- constipation
- menstrual abnormalities, infertility
- dry thickened skin (myxoedema)
- slowing of mental function
(would have high TSH, low T3/4)
Causes of hypothyroidism
Chronic autoimmune thyroiditis - antibody production against thyroglobulin/thyroid tissue = Hashimoto’s thyroiditis
Thyroid irradiation
Pituitary/hypothalamus defect
Iodide deficiency
- need replacement therapy with T4 (dosage hard to optimise)
Hyperthyroidism symptoms
- nervousness, restlessness, tremors, anxiety
- high metabolic rate, raised temperature
- sweating, heat sensitivity
- tachycardia and palpitations
- increased appetite (but weight loss)
- tiredness
- more bowel movements
- decreased menses (infrequent periods)
(would have low TSH, high T4)
Causes of hyperthyroidism
Grave’s disease, diffuse toxic goitre (autoimmune disease) - identifiable by exopthalmos, bulging eyeball
Toxic multinodular goitre
Toxic adenoma in thyroid gland
Pituitary tumours (adenoma producing TSH)
- treat with antithyroid drugs (thiocarbamides) or propanolol, radioactive iodine (thyroid irradiation), surgery (only really in malignancy
Growth hormone production and release
Synthesised in anterior pituitary somatotrophs (stable population, 50% of pituitary cells)
Signal to release from pulse of Growth hormone releasing-hormone (stimulatory), and a decrease in somatostatin (inhibitory)
Released in pulses, 5-8/day, lasting 2-3 hours
Then bound to GH binding protein in blood
Negative feedback via GH and IGF1 (to increase somatostatin output)
- and IGF1 acts at pituitary to reduce GHRH effects
GH secretagogues
GHRH - stimulates GH release
Somatostatin - inhibits GH release
Ghrelin
- from specialised cells in submucosa of stomach
- released before meals, decreases after meals
- stimulates GH release, stimulates appetite
Factors affecting GH release
Age - increased in puberty, declines with age
Sleep wake cycle - surges in slow wave sleep
Gonadal steroids - stimulate release (men higher peaks)
Nutrition - increased during fasting/hypoglycaemia, increased following high protein meal, reduced by elevated free fatty acids (so low in obesity)
Stress increases
Exercise increases
GH actions
Indirect effects - via IGFs
- increases height in children (not required in utero)
- stimulates limb growth
Direct effects (mainly metabolic)
- increases muscle mass - sarcomere hyperplasia, increased protein synthesis - but NO effect on strength
- increases internal organ size
- promotes gluconeogenesis
- promotes lipolysis
- stimulates immune system
GH therapy in adulthood
No effect on strength, despite increasing muscle and decreasing fat
May lessen fatigue
Increases risk of bowel cancer
Increases death rate on ITU, despite catabolic state and low endogenous GH
(drug of abuse in athletes)
Insulin-like growth factors
IGFs, IGF1 most important
Plasma IGF1 is GH dependent, so levels are parallel
Produced in liver, and many other tissues
Transported with binding proteins, eg IGFBP3
GH deficiency in adults
Long general list of symptoms including low mood, low confidence, tiredness, struggle to concentrate, poor memory
If more than 11 of these, give IV bolus of GHRH and measure GH levels
In old age, spontaneous GH secretion falls despite normal pituitary reserves of GH
- > functional GH insufficiency
- won’t benefit from supplements, as get increased muscle mass and decreased fat, but no change in strength (and get side effects)
Acromegaly symptoms
Where there is excess growth hormone after full development reached
- coarsening of features
- growth of extremities (growth at cartilage end plates, so most apparent where many bones eg hands and feet)
- soft tissue growth - lip and nose
- snoring, obstructive apnoea
- headaches
- carpal tunnel syndrome
- arthralgia, arthritis
- spacing of teeth
- sweating
Anatomy of adrenal glands
Capsule
Cortex - yellowish, 90% (full of lipid, making steroids)
Medulla - reddish, 10%
Circumferential blood supply:
- aorta supplies via renal artery (below) and inferior phrenic artery (above)
- arteries then pierce capsule and into cortical sinusoids
- blood runs through cortex and medulla, drains into adrenal vein
Zones of adrenal glands
Zona glomerulosa - mineralcorticoids eg aldosterone
Zona fasiculata - glucocorticoids eg cortisol (and some androgens)
Zona reticularis - androgens eg dehydroepiandrosterone (DHEA) (and some glucocorticoids)
Medulla - catecholamines eg adrenaline, noradrenaline
Chromaffin cells
Modified post-ganglionic neurones
In adrenal medulla
- receive sympathetic innervation via splanchnic nerves to coeliac ganglion to chromaffin cell
- discharge hormones in packets to blood
- 80% adrenaline, 20% noradrenaline
- neurohormones, so circulate and have effect on whole body
Rapid release, as ANS has direct control over chromaffin cells
Adrenaline vs Noradrenaline
Adrenomedullary catecholamines in circulation
ADRENALINE
- 50% bound to albumin
- shorter half life (10 mins)
- 20-50 ng/ml
- all from adrenal medullary chromaffin cells
- stronger agonist
(phaeochromocytoma is tumour of adrenal medulla, extreme increase in A levels)
NORADRENALINE
- 50% bound to albumin
- longer half life (15 mins)
- 100-350 ng/ml
- mostly from postganglionic sympathetic neurones
Released in response to stress - hypoglycaemia, haemorrhage, hypoxia, pain, psychological stress
Adrenocortical steroids
Mineralcorticoids
eg aldosterone
- for sodium (water) retention and potassium excretion
- from zona glomerulosa
Glucocorticoids
eg cortisol
- for metabolic control, stress, actions on immune system
- from zona fasiculata, and some from zona reticularis
Androgens
eg dehydroepiandrosterone (DHEA)
- for libido in females
- from zona reticularis, and some from zona fasiculata
Hypothalamo-pituitary-adrenal axis
Stress (+ diurnal rhythm) -> hypothalamus -> release corticotrophin-releasing hormone and antidiuretic hormone -> anterior pituitary -> release adrenocorticotrophic hormone -> adrenal cortex -> cortisol (negative feedback to anterior pituitary and hypothalamus)
Functions of glucocorticoids
Metabolic - mainly catabolic - cause muscle weakness, skin + connective tissue breakdown, lipolysis, to release proteins for gluconeogenesis and fuel generation
Cardiovascular Immunologic (anti-inflammatory) Homeostatic Musculoskeletal (breakdown) Arousal and mood
All permissive, indirect actions
Cushings’ syndrome symptoms
Chronic glucocorticoid excess
- truncal obesity
- reddened moon face
- hypertension
- low mood
- easy bruising
- abdominal striae
- hirsuitism (hair)
- muscle wasting
- increased appetite
- osteoporosis
- thinning of skin
Causes of Cushings’ syndrome
Exogenous steroid use (most common) - suppresses HPA axis, atrophy of adrenal cortex
Pituitary tumour (= Cushings' disease) Ectopic ACTH/CRH
Adrenal adenoma/carcinoma/adrenal disease
Adrenocortical deficiency causes
Deficient production of glucocorticoids or mineralcorticoids
1 - destruction/deficiency of adrenal cortex (primary)
- Addison’s disease (autoimmune) or adrenal haemorrhage
- both glucocorticoids and mineralcorticoids low
2 - deficient pituitary ACTH (secondary)
- withdrawal from prolonged glucocorticoid therapy
- glucocorticoids low, mineralcorticoids normal
Addison’s disease symptoms
- weakness, fatigue
- anorexia, weight loss
- hyperpigmentation
- hypotension
- GI disturbances
- salt craving
- amenorrhea (loss of axillary and pubic hair)
Therapeutic uses of glucocorticoids
- replacement therapy in Addison’s disease
- acute inflammatory disease
- chronic inflammatory disease
- neoplastic disease
- immunosuppression
- emergency medicine
MANY MANY SIDE EFFECTS
Requirements for fertility treatment
Couple trying for 2 years Both aged under 40 Both BMI under 30 Both non-smoking No previous children together No prior sterilisation
-> postcode lottery
NICE recommend offer 3 rounds on the NHS (stop if reach aged 40 in this time)
DON’T offer ovarian stimulants if cause of infertility unknown
Techniques for fertility promotion
Ovarian induction
Induce spermatogenesis
IVF - stimulate ovaries to make many eggs, collect (aspirate follicles), fertilise by mixing, assess womb with ultrasound daily until correct environment, implant embryo
GIFT - put unfertilised gametes straight into fallopian tube (may be allowed in some religious groups)
ICSI - as with IVF, but inject single sperm into egg - concerns about allowing genetic conditions to perpetuate, selecting one sperm
Epididymal sperm extraction + ICSI
Testicular sperm extraction + ICSI
Surrogacy
Egg donation
Improving techniques for fertility promotion
Genetic screening
Sperm collection
Better incubation, so embryos can grow more, select best one to implant (if get to blastocyst stage, success rate doubles)
Womb transplants now possible?
Egg freshening - remove ooplasm and replace with donor’s (removes mitochondrial disease)
Roles of calcium
Mineral component of skeleton and teeth Muscular contraction Blood coagulation Enzyme activity Neuronal excitability Hormone secretion Cell adhesion
-> so if very deficient, death
Where is calcium in the body?
99% - bone, inorganic, mineralised matrix
- 9% - intracellular, in endoplasmic reticulum
- 1% - extracellular fluid
- 000002% - free in cytosol
Of that which is free in the cytosol:
50% ionised - biologically active, available for above functions
5% complexed (calcium salts)
45% protein bound
- proportions change depending on pH, dissociates from proteins at pH decreases, free amount increases
Calcium as a second messenger/regulatory ion
10,000 fold increase in calcium extracellularly vs intracellularly free in cytosol
- so when calcium channels open, calcium floods into cell
- can now act as signalling ion to activate intracellular processes (neurotransmitter release/contraction/secretion)
Calcium homeostasis
Gained from diet
Exchange between bone remodelling
Lost to urine, faeces, lactation
Balance controlled by parathyroid hormone (calcium too low), calcitonin (calcium too high), active vitamin D (calcium too low)
Parathyroid hormone
Peptide hormone
Released in response to falling levels of circulating calcium
From parathyroid glands (embedded in thyroid gland)
- PTH protein stored in secretory granules of chief cells
- high calcium inhibits secretion, low calcium allows
For minute to minute, fine regulation
BONE EFFECTS
- release from calcium salts in bone extracellular fluid - osteoblasts - immediate
- breakdown hydroxyapatite crystals - osteoclasts - long term - only indirect, via ligands released from osteoblasts
(efflux of calcium from bone)
KIDNEY EFFECTS
- increase tubular reabsorption of calcium
(decreased loss of calcium in urine)
- release of vitamin D, promotes formation of active vitamin D
(enhanced absorption of calcium from intestine)
-> increased concentration of calcium in the blood
Calcitonin
Peptide hormone
Released in response to high blood calcium
An emergency hormone (not minute to minute like PTH)
Secreted by C cells in thyroid gland (not follicular cells, between them)
- > reduce blood calcium levels
- > prevent hypercalcaemia
BONE
- inhibit bone reabsorption
KIDNEY
- reduce calcium reabsorption
Active vitamin D
Steroid, produced from cholesterol
… or percursor from diet (dairy, fortified cereals)
Produced in response to falling blood calcium, via PTH
Cholesterol
- – UV light —
- > cholecalciferol
- – liver —
- > 25-hydroxycholecalciferol
- – kidney, with PTH present —
- > active vitamin D
For longer term regulation of calcium
Increases absorption of calcium from intestine
-> protect bone
Vitamin D deficiency
Rickets in children, osteomalacia in adults
- diet deficient in vitamin D, lack of sunlight
- renal 1alpha hydroxylase (genetic cause)
Low active vitamin D Decreased calcium uptake in gut Increased PTH Increased calcium resorbed from bone (cartilage not properly mineralised, weak malformed bones)
Hyperparathyroidism
Excessive PTH secretion
PRIMARY
Unregulated parathyroid glands (eg adenomas of chief cells)
Increased PTH
-> Increased calcium resorption from bone, decreased bone density and multiple fractures
-> Increased calcium uptake in kidney
SECONDARY
Chronic renal failure -> excess PTH secretion
Reduced kidney function
-> Low calcitriol production, low Ca absorption in gut
-> Low Ca retention in kidney
–> Hypercalcaemia, increased PTH, bone deformation and fractures
Hypoparathyroidism
Inadequate PTH secretion
(eg from accidental removal of parathyroid glands during thyroid surgery)
Low PTH
- > Reduced calcitriol production, reduced Ca absorption in gut
- > Reduced bone resorption
- > Reduced Ca retention in kidney
- -> Hypocalcaemia, increased neuromuscular excitability (lowered threshold), paresthesia and tetany, abnormalities in enamel formation
Obesity
Obese phenotype is from exposing individuals with a predisposing genotype to an inappropriate environment.
(interplay between genes (poly or monogenic) and environment)
- exponential rise in risk of type II diabetes and cardiovascular disease mortality as BMI increases
Ob / Db mice experiments
ObOb mouse - no Ob gene for blood bourne hormone (leptin)
- so loses weight when parabiosis to healthy mouse
DbDb mouse - no Db gene for hormone receptor
(leptin receptor)
- so stays overweight when parabiosis to healthy mouse
Leptin
= Ob
Polypeptide hormone
Plasma concs decrease in fasting, increase in feeding (is reporter of fed state)
- secreted by adipose tissue
- signals to hypothalamus
- decreased feeding, increased thermogenesis
(rarely works in human treatment, unusual to be deficient in leptin)
Hypothalamic hormones regulated by leptin
OREXIGENIC (hunger inducing)
- neuropeptide Y (NPY)
- agouti-related peptide (AgRP)
Leptin reduces expression
ANOREXIGENIC (decreases appetite)
- melanocyte stimulating hormone (alpha MSH) - endogenous, made from POMC, ACTH
- cocaine and amphetamine-related transcript (CART)
Leptin increases expression
Male reproductive tract
Tract activity regulated by androgen
Testis covered by fibrous capsule - tunica albuginea Sperm made in seminiferous tubules Tubules converge to drain in rete testis Into efferent ductules Into duct of epididymis Into vas deferens
(need to go through epididymis in order to be fertile and motile, most fluid absorbed and head so by the time sperm is at tail, very concentrated)
Sperm first appear in the testis at puberty, as regulated by androgen
Seminiferous tubule cells
Sertoli cells - somatic cells, controlled by FSH to support germ cell development - extend full length of epithelia, bridges to support engulfed germ cells, and secrete fluid for sperm
Germ cells - start at base of epithelia, then mature and detach at lumen as sperm
Encircled by myoid cells
-> spermatogenesis
(basal and adluminal compartments, above and below the level of the blood-testis barrier)
Interstitial area cells
Leydig cells - controlled by LH to make testosterone
Lymph vessels
Macrophages
Purpose the blood-testis barrier
- maintain differences in fluid composition between fluid within and outside tubule
(tubular fluid is environment for developing germ cells and vehicle for sperm transport) - protect developing sperm from auto-immune attack from blood-bourne antibodies
(otherwise ant-sperm antibodies would attack sperm, have haploid gamete)
Steroid production by testis
STEROIDS Prostagens Androgens Oestrogens (all sex steroids - women make all the same but in different proportions) \+ Corticosteroids
Testicular androgen synthesis
5-7 mg/day testosterone - 50% potency
2 mg/day androstendione - 8% potency
70 μg/day DHT (5alpha dihydrotestosterone) - 100% potency
Testosterone is prohormone, converts to more active DHT metabolite
Testicular testosterone/DHT synthesis
LH causes conversion of cholesterol to testosterone in Leydig cell via delta 5 pathway
- testosterone then released to blood and lymph to regulate epithelial lining of reproductive duct
- mainly testosterone into Sertoli cell, converted to DHT via 5alpha reductase. DHT then released to tubular fluid
Testicular oestrogen synthesis
LH causes conversion of cholesterol to testosterone in Leydig cell via delta 5 pathway
- testosterone converted to oestradiol 17beta
- oestradiol 17beta released to blood and lymph to regulate brain, bone, vascular system
- testosterone converted to oestradiol 17beta in Sertoli cell, via aromatase. Oestradiol 17beta released to blood and lymph for fluid reabsorption, increasing concentration of sperm (NECESSARY)
Oestrogens in men
Oestradiol via aromatase enzyme in testis
+ most oestradiol from peripheral conversion of testosterone and androstenedione (in fat, breast, testes, muscle)
Functions of testosterone
PUBERTY
- induce growth and development of male reproductive tract
- induce secondary sex characteristics (DHT maintains)
- growth and fusion of long bones
ADULTS
- spermatogenesis
- libido, sex behaviour, aggression, mood
- maintain muscle mass and bone
- maintain accessory sex glands
- regulate secretion of gonadotrophins
Causes of male infertility
- obstructive azoospermia (eg following inflammation from STD)
- varicocele (swelling of veins in testicles, compresses)
- endocrine (HPT axis failure
- disorders of seminal plasma (eg poor liquefaction)
- presence of antibodies to sperm
- pathological damage of seminiferous epithelium (eg mumps, radiation)
- ejaculatory malfunction
- high scrotal temperatures
- chromosomal abnormalities
- cryptorchidism (undescended testes)
- poor diet (deficient in vitamins A/B/D)
- drugs, especially cannabis
Hypothalamo-pituitary-testicular axis
Pituitary -> FSH -> sertoli cells
Pituitary -> LH -> leydig cells
Controlled by GnRH (gonadotrophic neurone releasing hormones)
Intersex disorders of development of male reproductive tract
NO alpha reductase
- so no conversion from testosterone to DHT
- > internal male genitalia (seminal vesicles, epididymis, vas deferens), female appearing external genitalia (no penis, scrotum, prostate)
ANDROGEN INSENSITIVITY SYNDROME
= testicular feminisation syndrome
- lack of androgen receptors (partial or complete)
- XY with testes
- no internal tract, but has female genitalia and secondary sex characteristics
Semen quality
30 million sperm per ml ejaculate, 2-5ml per ejaculation usually
Seminal plasma needed: transport vehicle, buffering, nutrient supply
Infertility problems
- low sperm count - oligospermia
- low sperm motility - asthenospermia
- abnormal sperm morphology - teratospermia
- low semen volume - hypospermia
(need 4% of sperm to be normal to be considered fertile)
Spermatogenesis
MITOSIS Type A dark spermatogonia Type A light spermatogonia Type B spermatogonia Primary spermatocyte
MEIOSIS
Secondary spermatocyte
Spermatid
SPERMIOGENESIS
Spermatozooa
- here acquire acrosome (cap-like head), flagellum, midpiece, lose excess cytoplasm)
Stages of germ cell development
Distinct cell-cell associations
Each batch of epithelia initiate new wave of spermatogenisis every 16 days
So allows continuous production of sperm, not synchronised
Functions of epididymis
Storage of sperm in tail, very concentrated
Maturation - loss of cytoplasmic drop, stabilisation of cell membrane, increased energy reserve
- sperm movement through here is passive (and through testis)
- sperm can survive here about 10 days
- non-ejaculated sperm are resorbed (or lost in urine)
Accessory sex glands
Seminal vesicles (60%) Prostate gland (40%) Bulbourethral glands = Cowper's glands (pre-ejaculate to flush tract)
For producing secretions (constituents of seminal plasma)
- fructose - fuel for sperm motility
- ascorbic acid, spermine, citric acid - protection of DNA of sperm
- cholesterol, phospholipids
- prostaglandins - contraction of female reproductive tract to propel sperm up
- phosphate buffers, bicarbonate buffers - against acidity of female tract
Prostate disorders
Prostatitis
- inflammation of prostate gland
Benign prostatic hyperplasia (BPH)
- uniform, smooth, normal enlargement with ageing
Prostatic cancer
- craggy appearance
(most common male cancer)
Phases of ejaculation
Seminal emission phase
- contractions of epididymis and vas deferens
- sends sperm to ampulla
- contractions of prostate, ampulla and seminal vesicles
- send semen to upper urethra
Ejaculation phase
- contractions of smooth and striated muscle associated with urethra
Causes of erectile dysfunction
Failure to initiate
Failure to fill
Failure to store blood volume
Caused by: In older men - diabetes, atherosclerosis, drugs - psychogenic factors - alcoholism - endocrine factors - trauma/pelvic injury - spinal lesions/MS
Treat with intracorpal injection or Viagra
Monogenic disorders of human obesity
No leptin secreted, as with ObOb mice (also infertile)
No leptin receptor, as with DbDb mice
MC4R (melanocortin 4 receptor), so alpha MSF (anorexigenic hypothalamic hormone) can’t stimulate
Prohormone convertase-1 absent, so can’t make alpha MSH
All VERY rare, far more common to be polygenic (99%)
Polygenic causes of obesity
13 loci identified so far, possibly up to 100
- MC4R variants
- FTO gene
Each locus may account for ~0.1 BMI units
Also possible epigenetic changes
Anti-obesity therapies
CURRENT: behaviour, physical activity, surgery
- Orlistat/Xenical - gut and pancreatic lipase inhibitor, so reduced digestion of fats, weight loss (but steatorrhoea). Available over the counter if BMI>28
- Reductil, Acomplia both withdrawn
FUTURE:
- MC4R agonists - selectivity a problem.
- Mitochondrial uncoupling protein activators (so thermogenesis, but no ATP made)
Satiety-inducing peptides
Produced endogenously by L cells in small intestine in response to nutrient intake
- supress appetite
Glucagon-like peptide
PYY
Cholecystokinin (CCK)
Hunger-inducing peptides
Ghrelin
Orexins A and B
(major pharmacological targets, but levels reduce after bariatric surgery)
Fasting vs fed state hormones
FASTING
- high ghrelin release from stomach
- low leptin release from fat cells
- > so high AgrP, high NYP, low POMC
- > increased appetite
FED
- low ghrelin release from stomach
- high leptin release from fat cells
- > low AgrP, low NYP, high POMC
- > reduced appetite
Bypass surgery types
Roux-en-Y gastric bypass
- join top of stomach to the ileum, so bypass most of stomach, duodenum and jejunum
- reduced ghrelin expression as stomach not stimulated
- increased GLP-1 and PYY
- if BMI>40, aged over 18
Sleeve gastrectomy
- majority of stomach removed, nutrients pass straight through remaining stomach into GI tract
- reduced ghrelin expression
- increased GLP-1 and PYY
Gastric band to restrict stomach
-> reduced appetite, weight loss, improved glucose tolerance
(unsure of long term consequences for eg cardiovascular disease)
Treatment of hyperthyroidism
Drugs inhibiting T3/4 secretion High dose iodide Thyroidectomy Beta blockers Radio iodine (concentrates in and destroys follicle cells)
- amiodorone (anti-arrhythmic), lithium and interferons all also interfere with iodination
