PowerPoint Presentation

Hypopituitarism

Ibrahim Salti MD, PhD, FRCPC,FACP

May 15, 2015Learning objectives Differentiate between hypothalamic vs. pituitary hypopituitarism

Review the causes of hypopituitarism

Cover the sequel of anterior pituitary hormones deficiencies

Summarize the age-related changes in gonadotropic hormone and GH Describe central and nephrogenic diabetes insipidus

HYPOPITUITARISMDEFINTION: A wide spectrum. Partial or total deficiency of pituitary hormones

CLASSIFICATION:

I. Hypothalamic hypopituitarism: defect is in one or more of the hypothalamic hormones

II. Pituitary hypopituitarism: defect is in one or more of the pituitary hormones

Hypothalamic hypopituitarismPossible sites of lesions: hypothalamic Or pituitary stalk Hypothalamic hypopituitarismSpecial Features: Often includes ADH deficiency Loss of DOPAMINE inhibition leads to hyper-prolactinemiaCauses of hypothalamic hypopituitarismTRAUMA: esp. stalk injuryPOST-SURGICAL DAMAGEPOST-RADIATION DAMAGE: may be occult and slowly progressiveHYPOTHALAMIC NEOPLASMS : primary or metastaticGRANULOMATOUS DISORDERS e.g. SarcoidosisINFILTRATIVE DISORDERS e.g. Hemochromatosis, Histiocytosis XHEREDITARY: Genetic deficiency of one or more of hypothalamic hormones. May be familial May be associated with other somatic abnormalities e.g. anosmia in Kallmanns syndrome8. MISC CAUSES: e.g. vascular, birth trauma, aging

Post radiation damage with the progress of treatment of leukemia most are cured but years later they come with hypopituarism since there is cranial irradiation parts to the treatment.

Neoplasms are rare and could be metastatic.

Indliltrative where iron or lipid can be deposited.

The deficiency could be genetic born without gnrh.

Anosmia : loss of sense of smaell.

Aging could involve some form of hypothalamic damage.6Pituitary hypopituitarismSite of lesions

Pituitary hypopituitarismIn contrast to hypothalamic hypopituitarism: Usually not expected to result in ADH deficiency

Prolactin deficiency is expectedAnterior pituitary has a different vascular supply so no problem in adh reaching the circulation.Prolactin deficiency expected.8Causes of pituitary hypopituitarismPOST-SURGICAL DAMAGEPOST-RADIATION DAMAGE: may be occult and slowly progressiveISCHEMIC NECROSIS esp. after post-partum hemorrhage, (Sheehans syndrome)Pituitary apoplexy: hemorrhage in a pituitary tumor ischemia of the rest of the pituitary 5. LARGE PITUITARY TUMORS causing deficiencies in the rest of the pituitary 6. GRANULOMATOUS DISORDERS e.g. Eosinophylic granuloma7. MISC CAUSES: e.g. hemochromatosis, hypophysitis

Sheehans syndrome: hemorrhage after delivery resulting in necrosis of anterior pituitary now rareAcute form of hypopituitarism : apoplexy.Hypophysitis is an inflammation in the pituitary of autoimmune origin.9Hypopituitarism in Patients with Large Pituitary TumorsPrevalence of Hormone deficits Hormone % Deficient

GH94FSH/ LH88TSH60PRL20 ACTH 10

Child with short stature : first rule out gh deficiency.

10Hypopituitarism in Patients with Large Pituitary AdenomasPostulated mechanismsIncreased intra sellar pressureMechanical compression of portal vessels/ pituitary stalk and/ orAreas of focal ischemic necrosis

Arafah BM, et al JCEM 2000; 85:1789-1793Mechanical compression of vascular supply and lead to areas of necrosis.11Hypopituitarism in Patients with Pituitary Adenomas-ContinuedReversible in 30-60 % of patientsReversibility depends on presence of viable pituitary tissue

Arafah BM, et al JCEM 2000; 85:1789-179312SEQUELAE OF HYPOPITUITARISMTARGET ENDOCRINE ORGAN DEFICIENCIES :

GROWTH HORMONE DEFICIENCY

PROLACTIN DEFICIENCY

ADH DEFICIENCY

Look for problem in thyroid gonad13Terminology for endocrine hypo-functional states Primary : means the deficiency is in the endocrine gland

Secondary : means the deficiency is in the pituitary

Tertiary : means the deficiency is in the hypothalamus or stalk 14TARGET ORGAN DEFICIENCY IN HYPOPITUITARISMTSH DEFICIENCY leading to secondary or tertiary hypothyroidism

FSH & LH DEFICIENCY leading to secondary or tertiary hypogonadism

ACTH DEFICIENCY leading to secondary or tertiary adrenocortical failure

15FSH & LH DEFICIENCY HYPOGONADOTROPIC HYPOGONADSIM In pre-puberty: leads to sexual infantilism & lack of puberty. In adults: Loss of secondary sex characteristics & infertility in both males and females Menstrual irregularity/amenorrhea, in females Impotence, loss of libido, oligo-azospermia in males

Body hair breast size lost in adults (amenorrhea, loss of libido, azoospermia, infertility in males)16Male hypogonadism with aging Andropause: evidence from many cross sectional studies e.g. Age group Percent with s. testosterone < 300 ng/dl 20-40y 1% 40-60y 7% 60-80y 22% 80-100y 36% Vermulen et al JCEM 1991;73:221-224

17Andropause: evidence from other cross sectional studies e.g.. A study on 379 males aged 60-83 y. Serum Test Percent of sample < 350 ng / dl 36 % < 300 19 % < 250 8%

Tenover, Endoc Metabolic Clin N Amer 1994; 23:877-892

Aging is associated with a gradual but substantial decline in: Serum testosterone & esp. in serum free testosterone

Andropause

TESTOSTERONE & FREE TESTOSTERONE WITH AGING20Manifestations of androgen deficiency in the elderly male- Erectile dysfunction, decreased libido - Decreased stamina & muscle strength- Osteoporosis & decreased lean mass- Increased fat mass- Decreased sense of well being, increased irritability & depression

Erectile dysfunction or impotence.Androgens are part of our needs to maintain good muscle mass and strength.Decreased sense of well being, increased irritability and depress.21

Partial Hypogonadism of Aging in Males Mechanisms of Andropause:

Most studies suggest a combination of Decreased FSH & LH secretionDecreased testicular response to FSH-LHIncreased SHBG resulting in decreased free testosterone

24Partial Hypogonadism of Aging in Males Most guidelines advocate androgen replacement therapy in elderly males with clearly low levels of serum testosterone ( < 200 ng/dL , normal being 300-1000)

Androgens are worrying for prostate cancer. When severe enough however, treatment is advised.25SEQUELAE OF HYPOPITUITARISMTARGET ORGAN DEFICIENCY

GROWTH HORMONE DEFICIENCY

PROLACTIN DEFICIENCY

ADH DEFICIENCY

DWARFISM AS A RESULT OF PREPUBERTAL GH DEFICIENCYNORMAL,AGE 8 Y OLDGH DEFICIENTAGE 8 Y27MANIFESTATIONS OF GROWTH HORMONE DEFICIENCY

In children: Dwarfism: usually severe

In adults: Occult metabolic abnormalities e.g. Loss of anabolic effects of GH Impaired response to hypoglycemia GH deficiency apparently common in aging

28

Birth Childhood Puberty Adulthood Old Age

Growth hormone secretion at different ages 29Effect of aging on GH

Igf-1 a product of gh hormone reaches a peak around puberty then gradually declines with aging.30Changes in serum IGF-I with increasing age

AGE RELATED CHANGES IN GHSOMATOPAUSE

GH & IGF-1 levels increase gradually to reach their peak with puberty

After the age of 40 y, GH levels (basal & after stimuli) fall gradually with age due to decreased GHRH secretion and in response of pituitary somatotropes: - There is a corresponding age-related ~ 50% fall in IGF-132SOMATOPAUSE-consequences 1. A decrease in lean body mass & bone density & an increase in fat mass

2. Decreased physical fitness

The above are partly reversed by GH treatment

Hence the increasing use of GH as an anti-aging treatment

One of the reasons why elderly males may have osteoporosis.

33SEQUELAE OF HYPOPITUITARISMTARGET ORGAN DEFICIENCY

GROWTH HORMONE DEFICIENCY

PROLACTIN DEFICIENCY

ADH DEFICIENCY

PROLACTIN DEFICIENCY- Common in pituitary hypopituitarism- Unlike hypothalamic hypopituitarism in which hyper-prolactinemia is common

CONSEQUENCES:

- Failure of lactation after childbirth e.g. in Sheehans syndrome

- No discernible abnormalities in males with prolactin deficiency

35The empty sella syndromePrimary empty sella A radiologic diagnosis Normal pituitary is pushed down to the floor of sella turcica Little or no pituitary hormonal deficits

Secondary empty sella Due to infarction, surgery or irradiation of a pituitary tumor Usually associated with severe hypopitutarism

36Primary empty sella

In the empty sella syndrome the pituitary has been pushed down by increased csf pressure but even at this stage the loss of function is really minimal.37Dynamic Tests of Pituitary FunctionTRH stimulation test *GHRH stimulation test *CRH stimulation test* GnRH stimulation test*Provocative tests for GH: insulininduced hypoglycemia, arginine, exercise, sleep, L-DOPA Provocative tests for ACTH: insulin-hypoglycemia CRH stimulation ===============================================* Denotes tests that can distinguish hypothalamic from pituitary hypopituitarism.

38CRH TESTProcedure:

Measure ACTH & Cortisol at 0, 30 & 60 minutes after 100 ug IV bolus of CRH ( If not available may use DDAVP instead )

Expected response: 2-4 X increase in ACTH at 30 min Peak cortisol > 20 ug/dL and an increase over baseline GH of > 10 ug/dL

Adh can be used instead39CRH TEST-INTERPRETATION:

EXAGGERATED RESPONSE:

Cushings disease ( ACTH secreting pituitary adenoma ) Other causes: Hypothyroidism Interferon-alpha Acute & chronic illness Alcohol withdrawal

CRH TEST-INTERPRETATION:

BLUNTED RESPONSE: Other (non pituitary causes) of Cushings syndrome Glucocorticoid therapy

Renal Failure

INSULIN HYPOGLYCEMIA

Procedure :

Measure ACTH , Cortisol and Growth Hormone at 0, 30 , 60, 90 & 120 minutes after 0.05-0.1 u/kg IV bolus of insulin

Expected response: 3-5 X increase in ACTH at 30 min Peak cortisol > 20 ug/dL and an increase of 10 ug/dL Peak GH > 10 ng/mL

Precaution: watch for profound hypoglycemia

Simulate stress. Make them hypoglycemic42

GH & CORTISOL RESPONSES TO HYPOGLYCEMIAINSULIN HYPOGLYCEMIAInterpretation

BLUNTED ACTH & CORTISOL RESPONSES :

ALL CAUSES OF CUSHINGS SYNDROME ( suppression by cortisol of CRH)

Both hypothalamic and pituitary hypopituitarism

Exaggerated ACTH and absent cortisol in: Primary adrenal insufficiency

Normal Response of GH to Glucose Insulin hypoglycemia testInterpretation

Blunted GH Response:

Hypothalamic or Pituitary GH deficiency

Hypothyroidism or hyperthyroidism

Glucocorticoid excess

Obesity

Renal failure

Aging

LABORATORY ASSESMENT OF GH SECRETIONGHRH Stimulation testInsulin-induced hypoglycemiaArginine stiumulation testMeasurement of GH during sleepClonidine stimulation testL-DOPA stimulation testExercise testMeasurement of IGF-1

1. TESTS FOR GH DEFICIENCYGHRH Test

Procedure :

Measure GH at 0, 30 & 60minutes after 100 ug IV bolus of GHRH

Expected responses 5-10 X increase in GH over basal levels

GHRH STIMULATION TESTRESPONSE IS DOSE RELATED GHRH TESTInterpretation

Blunted GH Response:

Pituitary GH deficiency

Delayed in hypothalamic causes of GH deficiency

Hypothyroidism

Cushings disease & glucocorticoid therapy

Estrogens in men ObesityAlcohol abuseHyperglycemia

GHRH TESTInterpretation

Exaggerated GH Response:

Renal failure

Propranolol

Dopamine agonists

LABORATORY ASSESMENT OF GH SECRETIONGHRH Stimulation testInsulin-induced hypoglycemiaArginine stimulation testMeasurement of GH during sleepClonidine stimulation testL-DOPA stimulation testExercise testMeasurement of IGF-1

1. TEST FOR GH DEFICIENCYArginine Test

Procedure :

Measure GH at 0, 30 , 60, 90 & 120 minutes after 0.5 g/kg of arginine Infusion over 30 min

Expected response Peak > 10 ng/ml or an increase of 5 ng/ml over basal levelArginine testInterpretation

Blunted GH Response:

Pituitary and hypothalamic GH deficiency

Hypothyroidism or hyperthyroidism

Cushings disease & glucocorticoid therapyHyperglycemiaObesityAging

Arginine testInterpretation

Exaggerated GH Response:

Estrogens in menPropranololIndomethacin

LABORATORY ASSESMENT OF GH SECRETIONGHRH Stimulation testInsulin-induced hypoglycemiaArginine stiumulation testMeasurement of GH during sleepClonidine stimulation testL-DOPA stimulation testExercise testMeasurement of IGF-1

1. TEST FOR GH DEFICIENCY

GnRH TEST

Procedure :

Measure FSH & LH at 0, 30 & 60minutes after 100 ug IV bolus of GnRH

Expected response: LH : 2-3 X increase over basal-More in luteal phase FSH: Minimal increase GnRH TESTInterpretation

Blunted response of FSH & LH:

Pituitary hypogonadismHypothalamic hypogonadism ( improves after repeated testing ) Renal failureHeavy exerciseBlind individualsPrepubertyOral estrogens ( oral contraceptives)Persons with elevated prolactin

GnRH TESTInterpretation

Exaggerated response of FSH and LH:

Primary hypogonadism including menopauseRenal Failure

TRH TEST

Procedure :

Measure Prolactin and TSH at 0, 30 & 60minutes after 400-500 ug IV bolus of TRH

Expected responses Prolactin :Men 3-5 X increase over basal- Women 5-8 X increase over basal TSH: 2-4 X increase at peak

Caution may cause flushing or hypertensionTRH TESTInterpretation

Blunted Prolactin Response:

Pituitary hypopituitarism

Almost all patients with prolactinoma

Most patients with other causes of hyperprolactinemiaHyperthyroidism

Dopamine agonistsAlcoholObesityRenal failureSevere illness, aging

TRH TESTInterpretation

Exaggerated Prolactin Response:

Hypothalamic hypopituitarism

Hypothyroidism

Dopamine antagonists

TRH TEST FOR PROLACTIN TRH TESTInterpretation

Blunted TSH Response:

Pituitary hypopituitarism

Hyperthyroidism

Acute illness

Alcohol abuse

Chronic renal failure

Aging esp. males

Propranolol, somatostatin, glucocorticoids, dopamine agonists

TRH TESTInterpretation

Exaggerated TSH Response:

Primary hypothyroidism

Estrogens

Dopamine antagonists

Theophylline

Lithium

TRH STIMULATION TEST SEQUELAE OF HYPOPITUITARISMTARGET ORGAN DEFICIENCY

GROWTH HORMONE DEFICIENCY

PROLACTIN DEFICIENCY

ADH DEFICIENCY

ADH DEFICIENCY Results in central diabetes insipidus

Rare in pituitary hypopituitarism Common in hypothalamic hypopituitarism (esp. in pituitary stalk injury).

DIABETES INSIPIDUSCENTRAL ( ADH deficiency ) a- Hypothalamic hypopituitarism b- Idiopathic NEPHROGENIC ( Resistance to ADH ) a. Hereditary: defective ADH receptor b. Acquired - Hypercalcemia - Hypokalemia - Renal tubular dysfunction e.g. Lithium toxicityDIABETES INSIPIDUSMANIFESTATIONSPolyuria up to 4-6 liters per day PolydipsiaUrinary hypo-osmolality despite plasma hyper-osmolalityAbnormal response to water deprivationResponse to ADH or its analogues only in Central DI Hyper-secretion of pituitary hormonesCompensatory ( adaptive ) due to loss of negative feedback

Amplified physiologic response

Autonomous hypersecretion

Compensatory (adaptive) hyper-secretion of pituitary hormones due to loss of negative feed-back inhibition Examples:

1. Hyper-secretion of TSH in primary hypothyroidism - A very sensitive test of primary hypothyroidism - May lead to thyroid enlargement e.g. in in-born defects of enzymes of the thyroid hormone biosynthetic pathway 2. Hyper-secretion of FSH & LH in menopause or other forms of primary gonadal failure - May be related to menopausal flushes3. Hypersecretion of ACTH & MSH in primary adrenocortical failure - Leads to skin and mucous membrane hyper-pigmentation

Hyper-secretion of pituitary hormonesCompensatory ( adaptive ) due to loss of negative feedback

Amplified physiologic response

Autonomous hypersecretion

Examples of hyper-secretion of pituitary hormones as an amplified physiologic responseHyperprolactinemia of pregnancy Prolactin may rise 10 fold by the 3rd trimester Pituitary enlarges & shows lactotrope hyperplasia

2. Growth hormone hypersecretion in starvation e.g. in anorexia nervosa

Syndrome of Inappropriate ADH Secretion SIADHSDEFINTION:-ADH hypersecretion despite plasma hypo-osmolalitiy Urinary hyper-osmolalitySyndrome of Inappropriate ADH Secretion SIADHSMANIFESTATIONHypo-osmolality ( hyponatremia) Asymptomatic when mild CNS dysfunction when severe Little or no edema Syndrome of Inappropriate ADH Secretion CAUSES 1. Neoplastic e.g. ectopic ADH secretion by lung tumors 2. CNS disorders3. Heart Failure4. Hypothyroidism 5. Adrenocotical insufficiency6. Drug induced Syndrome of Inappropriate ADH SecretionMECHANISM ADH secretion by non-osmotic stimuli over-rides the normal osmotic regulation of ADHHyper-secretion of pituitary hormonesCompensatory ( adaptive ) due to loss of negative feedback

Amplified physiologic response

Autonomous hypersecretion Usually Due to Pituitary Tumors

Recommended ReadingHarrisons Principles of Internal Medicine18th Edition Chapters 339 and 340