Growth hormones

1. Synthesis of GH

• GH aka somatotrophin
• produced by somatotropes (adenohypophysis)
• plasma half life 20-50mins

2. Structure of GH

• single polypeptide hormone
• 191 aa
• 2 disulphide linkages
• MW of 22kDa
• water soluble
• GH, prolactin, chorionic somatomammotropin have similar sequence homology

3. GH receptor

• MW of 70kDa
• GH binds to a cell surface receptor -> dimerisation of 2 GH receptors -> forms a dimeric complex -> activates tyrosine kinase and phosphrylation of the receptor and protein kinase on tyrosine residues

4. Regulation of GH secretion

GHRH from hypothalamus and GHIH from hypothalamus and D cells of pancreas.

5. Physiological and biochemical actions of GH

• Growth

• Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and supresses their ability to take up and accumulate circulating lipids.

• INDIRECT: mediated by IGF
• stimulates cartilage grwoth
• stimulates linear bone growth by its action on the epiphyseal growth plates of long bones
• Width of bone also increases

• Normal carbs, lipid, protein and mineral metabolism
• Protein synthesis: GH increases the transport of AA into muscle cells and increase protein synthesis; increases synthesis of RNA and DNA in some tissue; resemble effects of insulin
• Carb metabolism: antagonises effect of insulin;decreased tissue glucose uptake and decreased rate of glycolysis; increased glycogen synthesis in the liver; increases hepatic glucose production via gluconeogenesis; prolonged administration can lead to dm
• Lipid metabolism: promotes lipolysis- increases release of FFA and glycerol from adipose tissue; increases circulating FFA, causes increased oxidation of FFA in liver (ketogenic): encourages use of fat as fuel and conserves glucose
• energy metabolism: GH increases the availability of fatty acids, which are oxidised as energy (spares glucose and proteins)
• Its effects on tissue/ organs
• adipose tissue: GH stimulates lipolysis -> breakdown of TG releases FFA and glycerol into the blood-> reduced synthesis of TG in fat cells
• muscle: GH stimulates lipolysis -> increase FFA in blood surrounding muscle and hence they will be used as fuels, conserving glucose and spares proteins -> since glucose uptake is reduced, rate of glycolysis is reduced; GH increases transport of AA into muscle cells and increase protein synthesis
• liver: stimulate production and release of IGF; GH increases oxidation of FA to acetyl CoA, enhancing ketogenesis; increased glycerol reaching the liver from lipolysis -> gluconeogenesis; increase glycogen synthesis in liver; glycolytic pathways are suppressed
• Mineral metabolism: promotes positive calcium, magnesium and phosphate balance; retention of Na+, K+ and Cl- 
• As it binds to lactogenic receptors, it can stimulate mammary gland eg lactogenesis (prolactin like effects)

5. Abnormal secretion of GH

• Hyposecretion
• GH deficient dwarfs       : Low GH and responds to exogenous GH
• Pygmies                          : Normal GH, but low IGF-1; post GH receptor defect
• Laron type dwarfs          : High GH but low IGF-1 and IGF-2; lack functional hepatic GH receptor
• fail to increase GH levels in response to hypoglycaemia
• Hypersecretion
• most often due to pituitary tumour 
• Children- gigantism - before epiphyseal plates close
• Adults- acromegaly - acral bone growth causes protruded jaw, enlarged nose, hands, feet and skull
• fail to suppress GH levels in response to glucose administration

Pituitary tumours

1. Different types of Pit Tumours + its clinical features

• Pit adenomas
• most common
• peak incidence 35-60yo
• 3 types
• Functioning: hormone excess and cause clinical manifestation 
• Non functioning aka silent: demo of hormone production at tissue level only, without clinical manifestations of hormone excess- may cause hypopituitarism as it encroach and destroy adjacent anterior it parenchyma
• (Both functioning and non functioning pit adenomas are composed a single cell type and produce a single predominant hormone but there are exceptions eg mammosomatotroph- excess GH and prolactin produced)
• Hormone negative: absence of IHC reactivity/ ultrastructural evidence of hormone production 
• (Non functioning and hormone neg adenomas are likely to present at a later stage and hence more likely to be macroadenoma.
• incidentally diagnosed as microadenomas 
• Classification 
• by size (micro, macro and giant adenoma)
• by patho 
• ACTH cell
• GH cell
• prolactin cell
• mammosomatotroph
• TSH cell
• Gonadotroph cell adenoma)
• Pit carcinoma
• Others (mets, epithelial, neural mesenchymal)

Signs and symptoms

• Excess hormones & Mass effect
• **Mass effect: the effect of a growing mass that results in secondary pathological effects by pushing on or displacing surrounding tissue.
• Intracranial mass: headache and vomitting
• hypopituitarism: compression leading to loss of normal anterior pit hormone production
• bitemporal hermianopia
• hyperprolactinemia due to stalk effect


• **Stalk effect: pituitary stalk may become compressed due to suprasellar tumors in the pars tuberalis region, and that the resulting compression may cause hyperprolactinemia.

Morphology

• soft, well circumcised lesion
• larger lesions extend and often compress the optic chiasm and adjacent structures- invasive adenomas
• In larger adenomas, foci of haemorrhage and/ or necrosis are common
• Histology
• monomorphic
• uniform round cells
• delicate stippled chromatin -> salted pepper apperance
• mitotic activity- scanty

Types of pit tumours

• Prolactinoma
• most frequent 
• cytoplasm weakly acidophillic or chromophobe
• sparsely/ densely granulated
• Rupture of cells and intracellular Ca2+ leaks out and Ca2+ accumulates, resulting in dystrophic calcification -> pituitary stone
• this tumour is characterised by 
• efficiency (eventhough tumour is small, it will secrete hormones)
• proportionality (size of tumour affects the amount of hormone prod)
• Clinical signs and symptoms
• amenorrhea
• galactorrhea
• loss of libido
• infertility
• ** Pregnancy, high dose estrogen therapy, renal failure, hypothyroidism, hypothalamic lesions and dopamine inhibiting drugs or mass in the suprasellar compartment can disturb the normal inhibitory influence of hypothalamus on prolactin secretion -> results in hyperprolactetinemia (stalk effect)
• Growth hormone-producing adenoma
• 2nd most common type of functional pituitary adenoma 
• quite large when clinically symptomatic because the clinical manifestation of excessive GH is subtle
• acidophillic
• sparesely/ densely granulated cells
• IHC postive for GH and cytokeratin
• Diagnosed by increased GH and IGF-1; with glucose loading, there is no suppression of GH
• Corticotroph cell adenoma 
• microadenomas when diagnosed
• stain positively with PAS stains due to carboydrate content
• densely granulated and basophilic 
• IHC postive for ACTH
• Present as?
• clinically silent
• cause hypercortisolism due to stimulatory effect of ACTH on the adrenal cortex -> Cushing syndrome
• cause hypercortisolism due to excessive production of ACTH by the pit -> Cushing Disease
• large, clinically agressive corticoptroph cell adenomas may develop after surgical removal of adrenal glands for treatment of Cushing syndrome, can result in Nelson syndrome 
• No hypercortisolism as adrenal glands are absent 
• patients present with mass effects of the pit tumour
• also presents in hyperpigmentation due to increased secretion of MSH
• Gonadotroph adenomas
• difficult to recognise 
• secrete hormones inefficiently and variably, and secreted hormones do not cause a recognisable syndrome 
• only detected when tumours are so large that they cause neurologic signs and symptoms
• Thyrotroph adenomas
• Pit adenomas (very rare!) 
• local extension beyond the sella turcica
• distant mets

3. Medical and surgical management of pit tumours

• Surgery
• transphenoidal approach esp in patients with progressive mass effect eg visual loss, hyperfunction, failure of medical treatment and pituitary apoplexy
• must remove all cells. If not, can lead to recurrence
• Medical
• Prolactinoma -> dopamine agonist to reduce hyperprolactinemia & tumour size
• GH producing adenoma -> somatastation analogues but doesn't reduce tumour size
• Gamma knife
• Radiation
• esp for incomplete surgical resection, recurrent tumours, those that are unfit for surgery
• can lead to hypopituitarism, glioma or sarcoma 

Hypopituitarism

Sheehan syndrome - postpartum necrosis of the ant pit

During pregnancy, ant pit enlarges considerably as there is a physiologic increase in the size and no of prolactin secreting cells. However, this isn't accompanied by an increase in blood supply from the low-pressure portal venous system. The enlarged gland is vulnerable to ischaemic injury esp in women who xperience significant haemorrhage during parturition. 

Post pit, as it receives blood supply directly from arterial branches (superior and inferior hypophyseal arteries),  is less susceptible. 

Pituitary apoplexy

- pit undergoes haemorrhage due to increased BP

DDx to pit tumour are Suprasellar tumours:

- induce hypo/ hyper functionaing of ant pituitary

- diabetes insipidus

- 2 main types are Gliomas from chiasm (malignant) & craniopharyngiomas (benign)

4. Craniopharyngioma (malignant transformation is rare unless exposed to radiation)

• 2 types
• adamantinomatous 
• stratified squamous epitheium
• losee reticulum
• calcification
• chronic inflammation
• cholestrol rich yellow fluid -> as tumours produce lots of fats
• papillary
• solid and papillary sheets of squamous epithelum
• no keratin, no calcification, no cysts
• no reticulum

Hypothalamus & Pituitary Gland

The pituitary gland (aka hypophysis) is located below the hypothalamus, in the sella turcica. It is a fossa which can be approached through the nasal cavity and the sphenoid sinus.

1. Parts of Pituitary Gland

Anterior pituitary   - adenohypophysis
Posterior pituitary  - neurohypophysis

The hypothalamus is connected to the pit gland via pit stalk aka infundibulum.

2. Relations of the pit gland
Anterior, and superior of the gland -> optic chiasma (where 2 optic nerves of the temporal half of both eyes cross over each other and enter the optic tract.

** When pit gland enlarges, the optic chiasma will be compressed, and affect the temporal half of the vision of both eyes and result in bitemporal hemianopia.

Anterior to pituitary gland -> sphenoidal air sinus
** pit gland tumour can rupture the roof of the sphenoidal air sinus.

■■ Anteriorly: The sphenoid sinus (Fig. 11.13)
■■ Posteriorly: The dorsum sellae, the basilar artery, and the pons
■■ Superiorly: The diaphragma sellae, which has a central aperture that allows the passage of the infundibulum. The diaphragma sellae separates the anterior lobe from the optic chiasma (Fig. 11.108).
■■ Inferiorly: The body of the sphenoid, with its sphenoid air sinuses

■■ Laterally: The cavernous sinus and its contents 

Oculomotor nerve (CV III)
Trochlear nerve (CV IV)
Ophthalmic (VI) & maxillary nerve (VII) (CV V)
Abducens nerve (CV VI)
**When the pituitary gland enlarges, the oculomotor nerve will be compressed.

3. Development of the pit gland

The pituitary gland develops from a small ectodermal diverticulum (Rathke’s pouch), which grows superiorly from the roof of the stomodeum immediately anterior to the buccopharyngeal membrane and a small ectodermal diverticulum (the infundibulum), which grows inferiorly from the floor of the diencephalon of the brain. 

During the second month of development, Rathke’s pouch comes into contact with the anterior surface of the infundibulum, and its connection with the oral epithelium elongates, narrows, and finally disappears Rathke’s pouch now is a vesicle that flattens itself around the anterior and lateral suraces of the infundibulum. The cells of the anterior wall of the vesicle proliferate and form the pars anterior of the pituitary; from the vesicle’s upper part, there is a cellular extension that grows superiorly and around the stalk of the infundibulum, forming the pars tuberalis. The cells of the posterior wall of the vesicle never develop extensively; they form the pars intermedia. Some of the cells later migrate anteriorly into the pars anterior. The cavity of the vesicle is reduced to a narrow cleft, which may disappear completely. Meanwhile, the infundibulum has differentiated into the stalk and pars nervosa of the pituitary gland. 

4. Microscopic structure of the pit gland

Adenohypophysis with Pars Distalis

• chromophobe cells
• chromophil cells
• Acidophils (alpha cells)
• red staining (eosin) granules in the cytoplasm and blue nuclei 
• are somatrophs and mammotrophs
• As somatrophs, they secrete somatotropin, aka GH
• As mammotrophs, they secrete prolactin 
• Basophils (beta cells)
• less numerous
• blue staining (heamtoxylin) granules in cytoplasm
• are thyrotrophs (TSH) , gonadotrophs (LH and FSH) and corticotrophs (ACTH)

Pars intermedia

• colloid filled follicles
• basophils- Melanocyte stimulating hormone

Neurohypophysis
Pars Nervosa

• nerve fibres
• pituicytes (unmyelinated axons and supportive cells)
• axons from neurons of (both in hypothalamus)
• paraventricular nucleus - produce oxytocin - milk ejection + contraction of uterus smooth muscle during parturition
• supraoptic nucleus - anti diuretic hormone - increases permeability of CT to water
• Herring Bodies: storage sites of the neurosecretory material of the pars nervosa neurons- contain many greyish-brown storage vesicles.
• No hormone producing cells
• Unmyelinated axons- hypothalamohypophysial tract

Pars tuberalis- surrounds the stalk, highly cellular

5. Hormones secreted by the pit gland

• Anterior- adenohypophysis
• GH
• ACTH
• Prolactin
• LH and FSH
• TSH
• Posterior- neurohypophysis
• Oxytocin
• ADH

6. How does hypothalamus regulate the secretion of hormones from pit gland?

 The secretion of tropic hormones from the pituitary gland is regulated by releasing hormones from the hypothalamus, which either stimulate or inhibit the anterior pituitary gland.

7A. Hypothalamo-hypophyseal system

Hormones (Oxytocin and ADH) are produced at the paraventricular and supraoptic nuclei. They are then transported down the axons and accumulate at Herring bodies. Herring bodies has many neurosecretory granules. When released, they enter the fenestrated capillaries and pars nervosa.

7B. Hypophysial portal circulation

- axons terminate in median eminence @primary capillary plexus
- superior hypophyseal artery also meets at the primary capillary plexus
- portal veins carries hormones from primary to secondary capillary plexus
- hormones secreted by adenohypophysis goes into general circulation

8. Pit Dwarfism, gigantism, acromegaly

• Pit dwarfism: deficient in GH- short
• Gigantism: excess GH- tall (child)
• Acromegaly: excess GH (adult)

9. Consequences of pit tumour

1. can compress optic chiasma (located superior and anterior to pit gland) and result in bitemporal hemianopia
2. can compress cavernous sinus and result in paralysis of eye muscle

10. Diabetes Insipidus (Neurogenic)

Damage to hypothalamic neuron that produces ADH- decreased amounts of ADH produced -> lots of urine secreted