Kaset Pituitary

Pituitary Disorders

Kaset Chimplee M.D.

HYPOTHALAMUS

ANTERIOR PITUITARY

TARGET GLAND

Peripheral Hormones

+ Trophic Hormones

- Inhibitory Hormones

Releasing Factors +

HypothalamicAnteriorPituitary

Target GlandPeripheral Hormones

TRH

TSH

Thyroid

T3, T4

GHRH+Somatostatin-

GH

Liver

IGF-1

GnRH

LH, FSH

OvaryTestisSex steroidhormones

CRH

ACTH

AdrenalGlandCortisol

Hypothalamic

AnteriorPituitary

Target tissue

Prolactin

Dopamine

Breast

TSH

Hypothalamic

Posterior Pituitary

Peripheral Target Gland

Vasopressin

Vasopressin

Kidney,Blood vessels

Oxytocin

Oxytocin

Uterus,Breast

PITUITARY DISORDERS• Hypopituitarism

• Pituitary Tumors• Empty Sella Syndromes• - Disease of Posterior Pituitary DI, SIADH

Clinical Manifestations of Pituitary Disorders• Hormone Hypersecretions

• Hypopituitarisms

• Local Mass Effects

Hypopituitarism• Definition: Diminished secretion of one or more

pituitary hormones• Can be caused by either anterior pituitary gland destruction or secondary to hypothalamic disorders• Usually slow and insidious disorder• Pituitary lesion may result in single or multiple hormone losses

Etiology of Hypopituitarism• Congenital: - Septo optic dyspla

- sia, Prader Willi S.• Tumors: - Pituitary secretory or

nonsecretory adenoma -Hypothalamus Cranioph

aryngioma, pinealoma etc• Immunological - Lymphocytichypophysitis• Infiltrative - Hemochromatsis,

Histiocytosis, Sarcoidosis Metastasis CA(breast and

bronchus)• Infectious - TB, Mycoses, Syphilis• Physical trauma - Head traum

a, Surgery, Radiation• Vascular - Sheehan’s syndrome , apoplexy, carotid aneurysm

Symptoms of Hypopituitarism• TSH Deficiency: lethargy, constipation, cold intolerance bradycardia, wt. gain, poor appetite, dry skin, delayed reflex relaxation• ACTH Deficiency: lethargy, weakness, nausia, vomitting dehydration, orthostatic hypotension, coma if untreated• GH Deficiency: - Infancy&Childhood growth retardation short stature and fasting hypoglycemia - : Adult increased abdominal adiposity, reduced strength& -exercise capacity, impaired psychosocial well being

Symptoms of Hypopituitarism cont’• Gonadotropin Deficiency: Childhood: failure to enter pube

rty, eunuchoid proportions Girl- delayed breast developm

ent, pubic&axillary hair Boy- phallus and testis remain

small, sparse body hair Adult: Women- breast atrophy, l

oss pubic&axillary hair,

secondary amenorrhea Men- testicular atrophy, d

ecreased libido,

impotence, loss of body hair• ADH Deficiency: DI with polyur

ia, polydipsia and nocturia

Diagnosis• Clinical: depend on specific hormones that are lacking• Hormonal reserve evaluation: TSH: TFT: FT4 and/or FT3, TSH (may be WNL or ) ACTH: ACTH stimulation test - Insulin induced hypoglycemic test GH: - Insulin induced hypoglycemic test Stimulation tests: arginine, clonidine, prpanolol,

- L dopa, GHRH-IGF BP3

Diagnosis• Hormonal reserve evaluation cont’: Gonadotropins (LH and FSH): - Female serum LH, FSH and estradiol(+HCG, prolactin) - Male serum LH, FSH and testosterone Prolactin: serum prolactin ADH: Water deprivation test, vasopressin test

Treatment of hypopituitarism• Correct causes:• Adequate replacement of hormones:

TSH deficiency: - - Levothyroxine 0.05 0.15 mg/d ACTH deficiency: - -Prednisolone 5 7.5mg/d

- - Cortisone acetate 20 37.5 mg/d Gonadotropins deficiency: Male: Testosterone IM

Female: Estrogen, progesterone HMG IM or GHRH infusion for infertility

Treatment of hypopituitarism cont’• Adequate replacement of hormones cont’:

GH deficiency: - hGH 0.3 1 mg/d Prolactin deficiency: replacement not necessary

ADH deficiency: - DDAVP intanasal 1 3 times/d Chlorpropamde, clorfribrate, carbamazepine (some residual releasible ADH)

Pituitary Tumors• Incidence: 1.85 / 1000,000 / year• - Autopsy: 20 25%• -Prolactinoma 30 40% -Gonadotropinoma 10 20% -GH secreting adenoma 2 17% ACTH secreting adenoma 10% TSH secreting adenoma <1%

Clinical manifestations of pituitary tumors• Endocrine manifestations: - Hypersecretion - Hypopituitarism• Mass effects:

Optic nerve- bitemporal hemianopia, central scotoma Carvernous sinus- opthalmoplegia, ptosis, diplopia

Hypothalamus- DI, ANS dysfunction, sleep disorder appetite and thirst disorderOthers- headache, hydrocephalous, dementia, psychosis

Prolactinoma• Most common secretory pituitary tumor• Clinical manifestations: Female- amennorhea, galactorrhea, infertility - estrogen deficiency: hot flushes, vaginal dryness - weight gain, hirsutism Male- loss of libido, impotence

- -often delayed diagnosis macro prolactinoma visual impairment, headache, hypopituitarism

Approach to nipple discharge

fa t s ta in

fo llow yearlyP R L , G H (if in d ica ted )

n orm a l

trea tas in d icated

n orm a l p ro lac tinab n orm a l TS H

M ac road en om ap ro lac tin > 2 0 0 n g /m l

M ic road en om aN on sec re to ry p itu ita ry

ad en om ap ro lac tin < 1 0 0 n g /m l

N orm a l TS HP ro lac t in e leva te

M R I

G alac to rrh each eck :p ro lac t in ,TS H , h C G

N on g a lac to rrh ea l d isc h arg e

N ip p le d isch arg e

GAP VIPTRH

PRLrp

Sucking

Serotonin(+)

Prolactinoma• Prolactin secreting pituitary adenoma

(lactrotrophs)– microadenoma ( < 10 mm in tumor size )– macroadenoma ( > 1 0 mm in tumor si

ze )

• Most common secreting pituitary tumor

Complication

• 1. Mass effects of the tumor• 2. Hormonal effects

Mass effects of the tumor

• 1. Microadenoma :– nn nnnnnn nnnnnnnnnnnnn– nnnnnnnn nnnnn nnnn nnnnn nnnn nnnnnn nnnnnn

nnnnn• 2. Macroadenoma :

– n nnnnn nnnnnn nnnnnnnnnnn n()– homonemous hemianopia (optic tract comp

n)– nn nnnnn n nnnnnnnnn nnnnn nnnnnnnnn n,,, 1,2( )– nnnn nnnnnnnnn n()– n nnn n nnn nnnnnnnnnn n nnnnnnnnnnn nn nnn,, ,, (

mal pituitary tissue )

Hormonal Effects

G on ad al in su ffic ien cy

d im in is h p u lsa tile L H , F S H re lease

a lte ra t ion inp itu ita ry L H R H sec re tion

in c rease en d og en ou s op ia te ton e

P ro lac t in om a

Hormonal Effects

• Chronic hyperprolactinmia decrease bon e density in both men and women

• Menopause with hyperprolactinemia dec rease bone deasity than menopause wit

h normal prolactin level

Diagnosis of prolactinoma

• 1. Prolactin level more than 200 ng /l

• 2. Presence of macroadenoma more

than 10 mm in tumor size

•1.+2. : most likely a prolactinoma

Diagnosis of prolactinoma

• Prolactin level less than200 n ----- g / l +l ar ge pi t ui t ar y t umor : >m

echanical effects from stalk compression

• Prolactin level less than200 n ------- g /l + microadenoma : > prolactin

secreting microadenoma

Diagnosis of prolactinoma

Microadenoma

Macroadenoma

Pituitary Apoplexy

Pituitary Apoplexy

Treatment of prolactinoma• Medical: - bromocriptine 2.5 15 mg/d orally - : other dopamine agonists eg. Pergolide,

carbergolide, lisulide• Transphenoidal surgery: rarely curative indicated in: persistent VF defects despite bromocriptine

: intolerant of dopamine agonists : relieve symptom in tumor with large cystic or hemorrhge• Radiotherapy: peristent tumor after surgery or med.Rx

Cushing’s disease - * 2540women > men , age years * solitary monoclonal corticotroph adenoma * 1usually intracellular microadenoma (< cm) - *macroadenoma extrasellar extension/invasion *midlife, gradual progress * hypokalemia, virilization, extremely high cortisol

10excretion (> fold normal) : very uncommon * invasive pituitary adenoma : slightly younger age * Nelson’s syndrome : hyperpigmentation + high A

CCC CCCCCC CCCCC CCCCCCCCC CCCCCCCCCCCC C

Acromegaly• GH excess: - children gigantism

- adult acromegaly• Insidious and chronic debilitating• Shortened life expectancy: increased death from cardiovascular disease, cerebrovascular disease, respiratory disease, malignancy• - Almost always due to GH secreting pituitary adenoma - Others: Ectopic GH pncreatic, breast, lung tumors

- Ectopic GHRH pancreatic tumors, carcinoids

Clinical Features of Acromegaly• Somatic: Acral change- enlarged hand and feet

Musculoskeletal- arthralgia, prognathism, malocclusion of teeth, poximal myopathy

Skin changes- sweationg, oily skin GI- polyps, carcinoma, CVS- cardiomegaly, HT Viseromegaly- thyroid, liver, tongue

Clinical Features of Acromegaly cont’

• -Endocrine metabolic:Reproductive- menstrual abnormalities, galactorrhea, decreased libido

CHO metabolisms- IGT, diabetes mellitus Lipid changes- hypertriglyceridemia

Others- hypercaciuria, elevation of serum P

Diagnosis of Acromegaly• Clinical features:old pictures may be helpful• Thickness of heel pad(M:>21,F:>18mm)• Glucose suppressed GH concentrations: normal <2ug/L, acromegaly usually >10ug/L• - Increased IGF 1 level• CT or MRT: 90% of tumor size>1cm.• If no pituitary mass is detected, extrapituitary sauce of GH or GHRH should be sought

Treatment of Acromegaly• Objectives: - return GH/IGF 1 to normal, decreased tumor size, preserve pituitary functions• GH < 2 ug/L representing cure• Transhenoidal surgery: initial therapy of choice Medical Rx: - Octrotide effective, requires chronic therapy

- Bromocriptine less effective Radiotherapy : effective but need time,high incidence of

hypopituitarism

- Gonadotropin Secreting pituitary tumors• Rare and reported mainly in men• Majority are large at presentation, mostly secrete FSH• Usually presents with S/S of mass effects• Men may present with low or normal testosterone and sperm count• Should be DDx from menopause or 1’ hypogonadism• Surgical removal usually 1’ treatment, may required subsequent radiotherapy

- Thyrotropin Secreting pituitary tumors• Extremely rare• Presenting with hyperthyroidism, goiter, and in appropriate elevate TSH• -Usually plurihormonal: co secrete GH, PRL, alpha

subunit• Treatment by surgery with or without radiotherapy• Octreotide has been found to be useful• May required I131 to control thyrotoxicosis

Empty Sella Syndrome• Occurs when the arachnoid membranes herniate through incompetent diaphragmatic sella, partially filling with CSF and copressing pituitary gland• Etiology: - Primary usually obese women, HT, ICP

- Secondary following surgery or XRT, post pituitary infarction

• usually asymptomatic, endocrine function usually WNL• Diagnosis is confirmed by CT or MRI

Adenohypophysis : Anterior pituitary gland

Neurohypophysis : Posterior pituitary gland

ADH ( Arginine Vasopressin ) ArginineVasopressin

Peptide hormone

CHROMOSOME 20

MAGNOCELLULAR NEURON

Actions of ADH• Increase water reabsorption in collecting du

ct• Stimulate ACTH secretion• Physiologic Antipyretics : lower core body t

emperature• Improve memory by hippocampal action• Modulating baroreceptor mediated controlle

d of blood pressure

ADH acts on V2 receptors

AQP2

AQP3-4

Regulations of ADH secretion

Regulations of ADH secretion

Neurogenic, also known as central, hypothalamic, pituitary or neurohypophyseal is caused by a deficiency of the

antidiuretic hormone, vasopressin.

Nephrogenic , also known as - vasopressin resistant is caused by insensitivity of the kidneys to the effect of the

antidiuretic hormone, vasopressin.

Dipsogenic , a form of primary polydipsia is caused by abnormal thirst and the excessive intake of water or other

liquids

Water Diuresis

Clinical Approach to Polyurea

p rim ary p o lyd ip s ia C D I o r N D I

S tan d ard wa te r d ep riva tion tes t

p u re wa ter d iu res isC osm < 3 .0 m l/m in

F E osm < 3 %

m ix so lu te -wa terC osm > 3 .3 m l/m in

F E osm > 3 %

U osm /P osm < 0 .9 U osm /P osm > 0 .9P u re so lu te d iu res is

Y esP O L Y U R E A

N O- U R G E N C Y O F U R IN A TIO N

- IN C O N TIN E N C E

> 3 0 0 0 m l /2 4 H r

Approach to solute or mix diuresis

Typ e o f s o lu te

g lu cose d iu res is u rea,m an n ito l d iu res is

2 (U N a+ U K )/U osm < 0 .4org an ic s o lu te

U N a+ U K > > U C ld ru g an ionke ton u ria

b ica rb on a tu ria

U N a+ U K < U C ld iu re tic

N aC l loadrecovery from A R F ob s tru c tion

2 (U n a+ U K )/U osm > 0 .6e lec tro lyte d iu res is

S o lu te d iu res is

Questions in Diabetes Insipidus• Question : What is osmolal clearance and how can we ca

lculate ?• Answer : conceptsurine volume

= free water volume + specific volume with solute excretion= CH2O + Cosm

if Uosm = Posm ----> no free waterurine volume = Cosm

ifUosm > Posm ----> negative free water clearance (total water reabsorbtion)

urine volume = Cosm - CH2O

Questions in Diabetes Insipidus

• Answer : (continue)If

Posm > Uosm ----> positive free water clearance

urine volume = Cosm + CH2OUosm x Uvol = Posm x Cosm

Cosm = Uosm x Uvol Posm

Questions in Diabetes Insipidus• Question : How can we calculate FEosm ?• Answer : FE osm = (Cosm / GFR) x 100 , GFR

= (Ucr/Pcr) x Vif > 3% ----> mixif < 3% ----> pure

• Question : Mention drugs that caused Nephrogenic DI ?• Answer : Lithium , Amphotericin B , domeclocycline

, Streptozocin , Methoxyflurane

Questions in Diabetes Insipidus• Question : Describe phase after Hypothalamic trau

ma or injury ?

• Answer : phase I ----> polyurea (1-2 day after event)

phase II ----> antidiuresis (5-7 day)

phase III ----> polyurea (permanent or recovery as long as 6 month

phase IV ----> recovery

Questions in Diabetes Insipidus

• Question : In water deprivation test why we stop the process when bodyweight decrease from 3-5% of baseline ?

• Answer : To eliminate the effect of hypovolemia on ADH secretion.

Questions in Diabetes Insipidus

pre posm pre pNa post uosm/posm post uos

m/posm+ ADH post pADH

Normal NL NL 1> 1 10

PPD/DDI 1 1 10> (< %)

CCDI 1 1 50> (> %) -

PCDI 1 -1 1050> ( %)

CNDI 1 1 10< (< %)PNDI 1 1 10> (< %)

Questions in Diabetes Insipidus

• Question 21 : How can we initiate therapy with desmopressin ?

• Answer : Start with low dose such as 1 puff or 0.1 ml (10 ug) at bed time

• The second dose can prescribed for the morning or the noon.

• Patients with volume depletion : isotonic saline infusion until hemodynamically stable

Syndrome of Inappropriate ADH secretion (SIADH)

Definition : sustained endogenous production of ADH resulted in excess water conservation- Hyponatremia,Volume expansion- Increased GFR- Tubular sodium wasting- decreased tubular absorption of creatinine and uric acid- No edema

Patterns of ADH secretion in SIADHPattern Characteristics Frequency

Type A Erratic ADH secretion20% Type B Reset osmostat 3 5 % Type C ADH leak with selective 35%

loss of ADH suppression Type D - ADH dissociated diuresis1 0 %

Major causes of SIADH Malignant neoplasia carcinoma: bronchogenic, pancreatic

lymphoma and leukemia, thymoma and mesothelioma Central nervous system disordrers :

Trauma, Tumors, Infection, Porphyria Pulmonary disorders:

TB, pneumonia, abscess, fungal infections, positive pressure ventilator

Drugs: chlorfribate, carbarmazepine, chlorpropamide,

cyclophosphamide, morphine, amitryptylline

Diagnosis of SIADH Essential reuirements

• - decreased effective osmolality Posm<275mOsm/kgH2O• - Inappropriate urinary concentrations Uosm>100• - Euvolemia absence clinical signs of hypovolemia• Elevated urinary sodium excretion with normal salt and water intake• Absence of other potential causes of euvolemic hypoosmolality; hypothyroidism, hypocortisolism

and recent antidiuretic use

Diagnosis of SIADH con’t Supplemental criteria

• Abnormal water load test(inability to excrete at least 90% of a 20ml/kg water load within 1 hr and or failure to dilute Uosm to <1 0 0 mOsm/kgH2 O• Inappropriately elevated AVP relative to Posm• No significant correction of plasma osmolality with volume expansion but improvement after fluid restriction

Clinical manifestations of SIADH• Symptoms and signs of the disease that causes SIADH• Hyponatremic encephalopathy

- headache, nausea- disorientation, confusion- obtundation, seizure- cerebral edema, respiratory arrest

Treatment of SIADH• Correct the ethiologic causes• Fluid restriction: depend on urine out put and - insensible loss , generally < U output 500cc/d with relatively high NaCl intake• Pharmacologic therapy:

- demeclocycline- lithium carbonate- AVP V2 receptor antagonist

HYPOTHALAMIC DYSFUNCTION• Common etiology: craniopha

ryngioma, pinealoma, dermoid , epidermoid tumor

• Symptoms: Hypothalamic distur- bances disorders of

- Thirst Polyuria, Polydipsia

- Appetite Hyperphagia and Obesity

Temperature regulationsBehaviorsConsciousness