Hypothalamus and pituitary

EXTRA

Lipid lowering drugs

1 stattins 2 fibrates (ppar alpha) 3 PCSk9 inhibotrs 4. exetimibde 5 orlistat 6 cod oiver oil Surgeries for obesity.. Gastric bypass lipot No need to know histopathology classification of fatty disease Metabolos syndrome nothing to do with LDL Diet helps with diabetis and metabolic but in dislioidemia not much so important place for pharm Sim.. Atovva... Rosuvastatin Fenobdribates Glizofribrates Fibrates etc Muscle pain can withdraw statin. Statin induced nyopathy and renal failure Statin especially acute stage of MI high dosages Fibrates cn be used if only Tag high as more effect on this or as second choice Can use combination but more incidence of ttansmainase increase and nyopathy Other anti lipid drugs see pharmacology? Simvastatin low ... And atorvastatin middle and high in Sri Lanka doses........ Saliva dry and out and whether sleep dry throat Only way to increase HDL is by exercise... Statin might reduce HDL also But low HDL is an independent risk factor

1 Mass lesions •benign tumors craniopharyngiomas, •malignant tumors •metastasize from lung and breast carcinomas. •2 Hypothalamic radiation •3 Infiltrative lesions sarcoidosis and Langerhans cell histiocytosis •4 Infections tuberculous meningitis. •5 Traumatic brain injury 1 Mass lesions •benign tumors craniopharyngiomas, •malignant tumors •metastasize from lung and breast carcinomas. •2 Hypothalamic radiation •3 Infiltrative lesions sarcoidosis and Langerhans cell histiocytosis •4 Infections tuberculous meningitis. •5 Traumatic brain injury

HYPOPITUITARISM - INTRO AND NOT PARTICULAR HORMONAL DISORDERS

SHEEHANS

ASSESSMENT OF PITUITARY FUNCTION

CAUSES OF HYPOPITUITARISM

•

A pituitary tumor or treatment of the tumor 76 percent

•

An extra pituitary tumor ( eg , craniopharyngioma) 13 percent

•

Infiltrative lesions: malignancies, lymphocytic, granulomatous plasmacytic hypophysitis

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Infections : Tuberculosis

•

Haemochromatosis

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Sarcoidosis 1 percent

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Traumatic brain injury

•

Sheehan's syndrome 0.5 percent

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Pituitary apoplexy

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OTHER CAUSES OF PITUITARY INFARCTION

SHEEHANS

•

Prolonged Hypotension of any cause

•

Following snakes bites and hemorrhage into pituitary

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SHEEHAN’S SYNDROME

Infarction of the Pituitary gland usually following a post partum

hemorrhage

•1

failure of lactation

•2

amenorrhea

•3 l

ethargy, anorexia, weight loss,

Presentation

*severe cases within a few weeks or months after delivery in **milder forms delayed for many years

Deficiency identified

growth hormone, prolactin, gonadotropin TSH ACTH ADH deficiency is rare

Later the pituitary becomes small and atrophic in a the normal sized sella ( Empty sella syndrome)

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ASSESSMENT OF PITUITARY FUNCTION

Direct measurement of pituitary hormone ( TSH, ACTH, FSH, LH )

Dynamic tests of pituitary function •Insulin induced hypoglycemia test •Arginine GHRH •Glucagon stimulation test

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INSULIN HYPOGLYCEMIA TEST

Insulin induced hypoglycemia •administering 0.1 unit of insulin per kg of body weight •measuring serum (or blood) glucose and growth hormone before and 15, 30, 60, 90 and 120 minutes after the injection. •Adequate hypoglycemia should be achieved ( <35mg /dl •If GH (<5.1 ng/mL [<5.1 mcg/L]) hormone deficiency is present. •This test should be done only under strict medical supervision. •Same test can be used for study adrenal insufficiency •contraindicated in elderly patients and in patients with seizure disorders and ischemic heart disease.

Symptoms of hypoglycemia

Autonomic symptoms •sweating •tachycardia •palpitations

2 Neuroglycopenic symptoms •light headedness •Focal neurological deficits •confusion •dysarthria •unconsciousness ---------------------------------GLUCAGON STIMULATION TESTAdminister 1 mg of glucagon •measure growth hormone every 30 minutes for 4 hours. •Growth hormone peaks around 120 to 180 minutes •Deficient if peak value is <3ng /mL (<3 mcg/L). ----------------------------------------ARGININE-GHRH

Arginine GHRH •growth hormone releasing hormone, 1 mcg/kg body weight, •followed immediately by an intravenous infusion of arginine HCl , 0.5 g/kg body weight (to a maximum of 30 g) over 30 minutes. •Serum growth hormone measured at 30, 0, 30, 60, 90, and 120 minutes. If peak GH level is <4.1 ng/mL (<4.1 mcg/L) pituitary insufficiency is present

HYPOSECRETION OF GROWTH HORMONE

Children

Short stature Pituitary dwarfism 2 Adults Reduction in bone mineral density

Actions of GROWTH HORMONE

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Small protein with 191 Amino acids •Increases rate of protein synthesis •Increased fat utilization for energy •Promotes linear growth •Stimulates osteoblastic activity •Promotes bone mineralization •Effects of growth hormone mediated through Somatomedins ( insulin like growth factor ) produced in the liver

Diurnal variation

What does dwarfirsm cause? Causes •Pituitary dwarfism •Cretinism •Achondroplasia

PREVENTION

TREATMENT

Physiological replacement therapy by recombinant human growth hormone

•B

To assess adequacy of growth hormone treatment •1 Growth chart monitoring • 2 Measurement of serum IGF 1 ( Somatomedian HYPOSECRETION OF ACTH

Causesprimary adrenal insufficiency ( a primary adrenal disorder resulting in deficiency of cortisol •secondary adrenal insufficiency (a pituitary disorder resulting in deficiency of corticotropin (ACTH) secretion) •tertiary adrenal insufficiency ( hypothalamic disorder resulting in deficiency of corticotropin releasing hormone (CRH) and secondarily of ACTH)Clinical Presentation •severe deficiency death due to vascular collapse •moderate deficiency postural hypotension and tachycardia. •Mild, chronic deficiency lassitude, fatigue, anorexia, weight loss, decreased libido, hypoglycemia, and eosinophilia. ACTH deficiency does not cause deficiency of aldosterone •No salt wasting, No hyperkalemia, No hyperpigmentation.To assay adrenal function a) early morning 8.00 a.m. serum cortisol is measured b) 24 hour urinary free cortisol is assayed

HYPOSECRETION OF FSH & LH

And TSH

And management of hypopituitary disorders

Hypogonadotropic hypogonadism (secondary hypogonadism) in both women and men. •Women

decreased estradiol secretion Amenorrhea •Infertility •Hot flushes •MenTesticular atrophy •Loss of libido •infertilityHypothyroidism symptoms are due to resulting hypothyroidism and include •fatigue •cold intolerance •decreased appetite •constipation •facial puffiness •dry skin •bradycardia •delayed relaxation the deep tendon reflexes •anemia •Menstrual irregularities oligomenorrhoea or heavy menstrual bleedingMANAGEMENTReplacement of individual target hormones in physiological doses for life •1 Thyroxine •2 Cortisol •3 Androgens / estrogens 3.1 MalesA Fertility not required Testosterone replacement is indicated in men who havesecondary hypogonadism •B Fertility required gonadotropins if pituitary disease is present •or gonadotropin releasing hormone (GnRH) if hypothalamic disease is present 3.2 Females •A Fertility not required ( pre menopausal ) estrogen progestin replacement therapy. •B Fertility required Ref to specialized clinic

HYPERSECRETION-PROLACTIN

CAUSES

1 Physiological hypersecretion

Lactation pregnancy stress

2 Pathological

Prolactin secreting adenoma Prolactinoma ( lactotroph adenoma )

Decreased dopaminergic inhibition of prolactin secretion •B1 Tumors of the hypothalamus, both benign ( eg , craniopharyngiomas) and malignant eg , metastatic breast carcinoma) •B2 Infiltrative diseases of the hypothalamus ( eg , sarcoidosis) •B3 Section of the hypothalamic pituitary stalk ( eg , due to head trauma or surgery) •B4 Adenomas of the pituitary other than lactotroph adenomas

Clinical presentation

•(prolactinoma)

A 42 year old man presents with decreased libido, erectile

dysfunction, and headaches. He reports no weight change,

gynecomastia, fatigue, or other symptoms. He takes no

medications. Testicular size is decreased on examination. His

prolactin level is 648 μg per liter (normal value, <15). Magnetic

resonance imaging (MRI) reveals a sellar mass (2.5 by 1.5 by 2.0 cm)

that is 5 mm below the optic chiasm and that extends bilaterally into

the cavernous sinuses.

HYPERPROLACTINAEMIA

•

May be due to MICROADENOMA / MACROADENOMA

Indications for intervention in hyperprolactinemia

Treatment

Dopamine agonists are the primary therapy for both microadenomas that require treatment and macroprolactinomas.

•2

cabergoline had fewer side effects and was more effective at normalizing prolactin levels Adverse effect cardiac valve disease

Other options •Trans sphenoidal surgery

PREGNANCY AND PROLACTINOMA

May enlarge during pregnancy •Prolactin levels increase •Routine screening for visual field defects •Commence on bromocriptine if visual field defects enhance

HYPERSECRETION GROWTH HORMONE

Hypersecretion During growth => Gigantism Post growth => Acromegaly

CLINICAL FEATURES OF PRESENTATION

•1

ACROMELIC FEATURES see previous slide •2Metabolic features •Diabetes •Increased bone mineral density •3Hypertension •4Cardiac failure •5Carpal tunnel syndrome due median nerve compression •6 Due to mass effect •Headache •Visual field defects Classically bitemporal hemianopia due to compression of the optic chiasma

MASS EFFECT - ANT PITUITARY DISORDERS

MACROADENOMA

Hyperprolactinaemia •Mass effect •Dopamine agonists achieve both goals to some extent

POST PITUITARY PHYSIOLOGY AND DYSFUNCTION

There are 2 main subtypes of vasopressin receptors.

V1 vascular receptors

vasoconstriction vascular smooth muscle. kidney, myometrium, spleen.

V2 renal receptors distal tubal and collecting ducts that activate adenylyl cyclase to increase cyclic adenosine monophosphate (AMP). This mobilizes aquaporin channels, collecting duct cells The V2 renal receptors are therefore responsible for the antidiuretic effects of vasopressin.

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THE AXES OF VOLUME REGULATION

Renin angiotensin aldosterone (RAA) axis Hypothalamic Pituitary ADH axis Two hormones are involved with the regulation intravascular volume Aldosterone : Reabsorbs salt and water in isotonic proportions ADH : Reabsorbs water only

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VOLUME DEPLETION

In the presence of volume depletion 3 mechanisms come into play.

Increased thirst

Secretion of renin by the juxtaglomerular cells which promotes the conversion of

angiotensinogen (inactive form ) produced by the liver to angiotensin 1. Angiotensin 1 is converted to angiotensin 2 by angiotensin converting enzyme. Angiotensin 2 promotes the secretion of Aldosterone by the adrenal cortex which promotes reabsorption of Na and Water there by attempting to restore the volume status back to normal.

Increased secretion of ADH which promotes reabsorption of water by making the DCT of the nephron permeable to water

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HYPOSECRETION ADH

TARGET ORGAN COLLECTING DUCTS

ADH is secreted if either circulating volume is low or if the tonicity is high or if both of the above are present. •In central diabetes insipidus the supraoptic and para ventricular nuclei of the hypothalamus fails to secrete adequate amounts of ADH when necessary. •These patients cannot concentrate their urine and present with polyuria. If they do not have access to water the resultant polyuria will result in volume depletion and hypernatremia.CENTRAL DICauses •brain tumor *brain injury *[brain surgery •TuberculosisSymptoms •Extreme thirst with polydipsia •Producing large amounts of diluted urine •Frequent need to get up to urinate during the night •Preference for cold drinksManagement •Synthetic ADH also called DDAVP given as a nasal spray, tablets or injection -----------------------------------------

HYPERSECRETION ADH

TARGET ORGAN RENAL TUBULE

PhysiologicalHypersecretion of ADH when there is a volume deficit or if there is hypernatremia, can be considered a normal response where the increased ADH secretion is a physiological response to correct the volume deficit and / or hypernatremiaPathologicalHowever there are certain instances when the volume and tonicity is normal, and yet there is persistent secretion of ADH. This is known as the Syndrome of Inappropriate secretion of ADH ( SIADH). In this instance persistent hypersecretion of ADH gives rise to a diseased state resulting in hyponatremia. ( Will be discussed in more detail in a later lecture on thirst axis and water regulation )SYNDROME OF INAPPROPRIATE SECRETION OF ADH (SIADH) ManagementFluid restriction Oral Salt Cautious use of Hypertonic saline Administration of a vasopressin receptor antagonist ( tolvaptan , mozavaptan, satavaptan , and lixivaptan) ADD BASED ON KUMAR AND CLARK AND TUTORIALS