2 hypothalamic and pituitary disorders, part 2

Hypothalamic and

Pituitary Disorders

Part 2

Hypopituitarism: Clinical Manifestations

� If ACTH is Deficient ~

Secondary (Central) Hypoadrenalism:

Hypopituitarism: Clinical Manifestations

� If ACTH is Deficient ~

Secondary (Central) Hypoadrenalism:

• fatigue, weakness, weight loss, nausea,

vomiting, hypotension, shock

• if partial, may not have symptoms until

stressed by illness or surgery

Hypopituitarism: Clinical Manifestations

� If ACTH is Deficient ~

Secondary (Central) Hypoadrenalism:

• ↓ adrenal secretion of epinephrine

• adrenal aldosterone secretion is

relatively preserved unless ACTH is

totally absent (ACTH stimulation is

required for the initiation of

steroidogenesis, a small ACTH amount

is sufficient)

Hypopituitarism: Clinical Manifestations

� If ADH (AVP) is Deficient ~

Central (Cranial) Diabetes Insipidus (DI):

• polyuria (2-20 L/d), urinary frequency,

nocturia, enuresis, polydipsia

• it gets masked if ACTH and/or TSH are

deficient as well (free water clearance in

the kidney is dependent on a

background levels of cortisol and

T4/T3)

Hypopituitarism: Clinical Manifestations

� If ADH is Deficient ~

Cranial (Central) Diabetes Insipidus (DI):

• if fluid intake is inadequate: Symptoms

& Signs develop due to dehydration

(tachycardia, orthostatic hypotension,

dry mucous membranes and axilla,

oliguria) and due to ↑Na (lethargy,

irritability, weakness, fever, delirium,

seizures, focal deficits, coma)

Hypopituitarism

Laboratory Findings

Hypopituitarism: Lab Findings

� Fasting hypoglycemia (GH or ACTH

deficiency)

� Hyponatremia (hypothyroidism and/or

hypoadrenalism)

� Hypernatremia (in DI when fluid intake

is inadequate)

Hypopituitarism: Lab Findings � To evaluate the hypoadrenalism:

• ACTH is low or normal (8:00 am)

• Dehydroepiandrosterone (DHEA) is

often low

• An 8-9 am serum cortisol <3 mcg/dL

usually indicates adrenal insufficiency

but it may not be this low, and so what

to do? => => =>

Hypopituitarism: Lab Findings � To evaluate the hypoadrenalism:

• ACTH stimulation test (functional

atrophy of the adrenal cortex occurs

within two weeks of ACTH deficiency)

(synthetic ACTH1-24 would be given)

(natural ACTH peptide is composed of

39 amino acids)

• Random or stimulated serum cortisol

level of ≥ 20 mcg/dL rules out

hypoadrenalism

Hypopituitarism: Lab Findings

� To evaluate the hypothyroidism:

• Free T4 is low

• TSH is low, normal or very mildly

elevated

Hypopituitarism: Lab Findings

� To evaluate the hypogonadism:

• In males: low total testosterone with

low or normal serum FSH/LH

• In pre-menopausal women: if menses

are regular then it rules out

hypogonadism, otherwise there would

be low estradiol with low or normal

serum FSH/LH

Hypopituitarism: Lab Findings

� To evaluate the hypogonadism:

• In post-menopausal women: serum

LH and FSH would not be elevated as

expected (FSH normally > 30 IU/L

and LH > 20 IU/L)

Hypopituitarism: Lab Findings

� To evaluate the GH Deficiency (GHD) in

adults:

• Investigate only if GH replacement

therapy is being contemplated

• Diagnosis is difficult since normal GH

secretion is pulsatile and serum GH

levels are nearly undetectable for most

of the day

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• Also, adults (particularly men)

physiologically tend to produce less

GH when they are over age 50 or have

abdominal obesity

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• Therefore, it is often inferred by

symptoms in the presence of pituitary

destruction or other pituitary hormone

deficiencies

• GHD is present in 96% of patients with

≥3 pituitary hormone deficiencies and

a low serum IGF-1

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• Low IGF-1, but is not sensitive (about

50%) and not specific either in Adult

GHD

• Very low IGF-1 levels (<84 mcg/L) are

indicative of GHD in the absence of

conditions that lower it (eg,

malnutrition, prolonged fasting, oral

estrogen, hypothyroidism, uncontrolled

DM, liver failure)

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• GH <5 ng/ml w exercise (however, by

age 40, most normal adults have lost

their GH response to exercise)

• Provocative GH-stimulation testing to

help diagnose adult GHD has a

sensitivity of only 66%

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• Therefore, a therapeutic trial of GH

therapy should be considered for

symptomatic patients who have either

a serum IGF-1 <84 mcg/L or three

other pituitary hormone deficiencies

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• In the absence of those two conditions,

provocative GH-stimulation testing

may be indicated for the following

patients:

1) Young adult patients who have

completed GH therapy for

childhood GHD and have achieved

maximal linear growth

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

2) Patients who have a hypothalamic

or pituitary tumor or who have

received surgery or radiation

therapy to these areas

3) Patients who have had prior head

trauma, stroke, or encephalitis

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• Such testing usually entails measuring

serum GH following provocative

stimuli:

o =>

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

o Insulin Tolerance Test ‘ITT’

o Glucagon stimulation test

o Oral macimorelin (a GH

secretogogue) GH stimulation test

o L-arginine (may be combined with

GHRH)

o Oral clonidine (in children)

Hypopituitarism: Lab Findings

� To evaluate GHD in adults (continued):

• The glucagon stimulation test is a

practical alternative to traditional

provocative GH stimulation testing to

diagnose pathologic GH deficiency or

functional GH deficiency due to aging

or obesity

Hypopituitarism: Lab Findings

� To evaluate the DI:

Diabetes Insipidus (DI)

Diabetes Insipidus

It usually results from a decrease of 75%

or more in the

� secretion or

� action

of AVP (ADH)

Diabetes Insipidus

� A decrease in the secretion of AVP

1) Primary deficiency of AVP

secretion

2) Secondary deficiency of AVP

secretion

Diabetes Insipidus

� A decrease in the secretion of AVP

1) Primary deficiency of AVP

secretion ~ it is referred to

variously as central DI, cranial DI,

neurohypophyseal DI, neurogenic

DI, or pituitary DI

Diabetes Insipidus

1) Central DI (primary deficiency of AVP

secretion) ~ Causes:

• Congenital Malformations

• Genetic defect (example:

DIDMOAD or Wolfram syndrome)

• Acquired (head injury, (para)sellar

surgery, neoplasms, etc…)

• Idiopathic

• Gestational DI =>

Diabetes Insipidus

1) Central DI (primary deficiency of AVP

secretion) ~ Causes:

• Gestational DI: excessive placental

production and/or impaired

clearance of vasopressinase ~ it

occurs during pregnancy ‘last

trimester’ or postpartum; associated

with oligohydramnios, preeclampsia,

or hepatic dysfunction ~ also can be

called Vasopressinase-induced DI

Diabetes Insipidus

� A decrease in the secretion of AVP

2) Secondary deficiency of AVP

secretion: it results from excessive

intake of fluids => AVP secretion

inhibition ~ it is referred to as

primary polydipsia and can be

divided into 3 subcategories =>

Primary Polydipsia (PP)

� can be divided into 3 subcategories:

i. Dipsogenic DI

o characterized by inappropriate thirst

caused by a reduction in the set of

the osmoregulatory mechanism

o sometimes occurs in association

with multifocal diseases of the brain

such as neurosarcoid, tuberculous

meningitis, and multiple sclerosis

but is often idiopathic

Primary Polydipsia (PP)

� can be divided into 3 subcategories:

ii. Psychogenic polydipsia

o not associated with thirst

o the polydipsia is a feature of

obsessive compulsive disorder or

psychosis/schizophrenia

Primary Polydipsia (PP)

� can be divided into 3 subcategories:

iii. Iatrogenic results from

recommendations to increase fluid

intake for its presumed health

benefits

Diabetes Insipidus

It usually results from a decrease of 75%

or more in the

� secretion or

� action

of AVP (ADH)

Diabetes Insipidus

� A decrease in the action of AVP

1) Primary deficiency in the

antidiuretic action of AVP

2) Secondary deficiency in the

antidiuretic action of AVP

Diabetes Insipidus

� A decrease in the action of AVP

1) Primary deficiency in the

antidiuretic action of AVP~ it

results in nephrogenic DI~ causes:

� genetic defect

� metabolic abnormality

(hypercalcemia, hypokalemia,

hypercalciuria)

� poisoning (heavy metals)

Diabetes Insipidus

� A decrease in the action of AVP

1) Primary deficiency in the

antidiuretic action of AVP~ it

results in nephrogenic DI~ causes:

� kidney disease (polycysctic kidney

disease, sickle cell anemia,

infiltrative disease, pyelonephritis,

recovery from acute tubular

necrosis, urinary obstruction)

Diabetes Insipidus

� A decrease in the action of AVP

1) Primary deficiency in the

antidiuretic action of AVP~ it

results in nephrogenic DI~ causes:

� drug therapy (such as lithium,

cisplatin, amphotericin B,

rifampin, demeclocycline,

aminoglycosides)

� idiopathic

Diabetes Insipidus

� A decrease in the action of AVP

2) Secondary deficiency in the

antidiuretic action of AVP ~ it

results from polyuria itself ~it is

caused by washout of the

medullary concentration gradient

and/or suppression of aquaporin

function

Hypopituitarism: Lab Findings

� To evaluate the DI:

Hypopituitarism: Lab Findings

� To evaluate the DI:

• A urine volume <2 L/24 h w normal

urine creatinine (20-30 mg/kg/day) and

in the absence of hypernatremia rules

out DI

• Dilute urine (sg < 1.006; Urine

Osmolarity <300 mOsm/L)

• Hyperuricemia (↓ Urate tubular

clearance)

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• Plasma AVP is usually low (<1

pg/mL) in central DI (and primary

polydipsia)

• Whereas in Nephrogenic DI,

plasma AVP level is normal or

elevated (>1 pg/mL) while the

Urine Osmolarity is low (less than

300 mOsm/L)

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• However, plasma AVP assay is not

widely available because it is

difficult to interpret clinically given

the short half-life of circulating

AVP and its binding to platelets

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• A C-terminal fragment of pre-pro-

AVP called copeptin has no known

biologic function but has a much

longer half-life in the circulation,

which makes it a relatively stable

surrogate marker of AVP secretion

• The measurement of copeptin was

found to compare favorably with the

measurement of AVP

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• A single baseline measurement of

serum copeptin level greater than

21.4 pmol/L was found to

differentiate nephrogenic DI from

the other polyuric states (namely,

central DI and primary polydipsia)

with nearly 100% sensitivity and

specificity

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• The hypertonic saline infusion test

with copeptin measurement

(hypertonic saline-stimulated

copeptin measurement) can be used

to differentiate between central DI

and primary polydipsia

• The test involves a single iv infusion

of 3% saline over 3 hours =>

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• … => copeptin shall increase above

a specified cutoff in primary

polydipsia whereas it shall not

increase above the cutoff in central

DI (in nephrogenic DI it shall

remain high, pre- & post- infusion)

• The diagnostic accuracy of the test

is high (96.5% in one study)

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• Another test called ‘indirect water-

deprivation test’ can also

differentiate between Central DI,

Nephrogenic DI, and Primary

Polydipsia but with a moderate

diagnostic accuracy of 70-76.6%

• The test involves a 17-hour fast, …

=>

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• … => the collection of multiple

plasma and urine samples, and the

administration of desmopressin at

the end of the fast

� In severe (complete) DI (both

central and nephrogenic), U-

Osmo will remain low (i.e. <300

mOsm/L) at the end of the fast

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

� Whereas in Primary Polydipsia,

urine will typically become

maximally concentrated (i.e.,

>600 mOsm/L) at the end of the

fast

• Desmopressin is then given

(desmopressin challenge) to

distinguish between Central DI and

Nephrogenic DI =>

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

=> Central DI: ↑U-Osmo by >50%

with reduction in thirst and polyuria

=> Nephrogenic DI: Little or no

change in U-Osmo and no response

in thirst or polyuria

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• In primary polydipsia, the

desmopressin challenge causes no

significant reduction in polydipsia,

but it does reduce polyuria which

produces hyponatremia (this can be

severe and become fatal, and thus

the test requires close observation)

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• There are DI cases (central or

nephrogenic) where the defect is

partial (or mild, i.e. not complete or

not severe) and the water fast/

deprivation can yield a concentrated

urine but not to the maximum (i.e.

more than 300 but less than 600

mOsm/L)

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• Also, in some cases of primary

polydipsia (PP) the urine doesn’t

become maximally concentrated

with the water fast/deprivation

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• And those were the reasons behind

the moderate diagnostic accuracy of

the indirect water-deprivation test

even with the measurement of

copeptin levels, serum sodium

levels, or urine-to-plasma osmolality

ratios during the water deprivation

(as they did not improve the

accuracy)

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• Compared with the indirect water-

deprivation test, the hypertonic

saline infusion test with copeptin

measurement has shorter test times

and greater patient adherence but is

associated with more adverse effects

(such as vertigo and nausea) and

higher serum sodium levels

(requires closer monitoring and …

=>

Hypopituitarism: Lab Findings

� To evaluate the DI (continued):

• (and … => potentially becoming

problematic; for example, it could

induce congestive heart failure in

high-risk patients)

Hypopituitarism � To evaluate the DI (continued):

• Brain MRI can be helpful in

differentiating pituitary (central DI)

from primary polydipsia

Hypopituitarism � To evaluate the DI (continued):

• In healthy persons, the posterior

pituitary emits a hyperintense signal

visible in T1-weighted midsagittal

images

• This “bright spot” is almost always

present in patients with primary

polydipsia but is always absent or

abnormally small in patients with

central DI (even if it’s partial)

Hypopituitarism � To evaluate the DI (continued):

• The MRI is also useful in searching

for pathology responsible for central

DI or the dipsogenic form of

primary polydipsia

Hypopituitarism � To evaluate the DI (continued):

• The principal caveat is that MRI is

not reliable for differential diagnosis

of DI in patients with empty sella

because they typically lack a bright

spot even when their AVP secretion

and action are normal

Hypopituitarism � To evaluate the DI (continued):

• MRI also cannot be used to

differentiate central from

nephrogenic DI because many

patients with nephrogenic DI also

lack a posterior pituitary bright spot,

probably because they have an

abnormally high rate of AVP

secretion and turnover

Hypopituitarism

Treatment

Hypopituitarism: Treatment

� To treat the hypoadrenalism:

• Hydrocortisone tablets 15-35 mg/d in

2-3 divided doses

• Some patients feel better w prednisone

(3-7.5 mg/d in two divided doses)

• Higher doses during sickness and

surgery

Hypopituitarism: Treatment

� To treat the hypothyroidism:

• Levothyroxine (LT4) to keep FT4 in

the high-normal range

• Typical maintenance dose is about 1.6

mcg/kg/d

• TSH assessment is useless for

monitoring Rx

• LT4 should be given only after

assessing for cortisol deficiency or

already receiving GC

Hypopituitarism: Treatment

� To treat the hypogonadism in males:

• Testosterone Rx

• If fertility desired:

� HCG (equivalent to LH), and if

sperm counts remains low after 6-12

months => add FSH injections

� If pituitary intact => leuprolide

(GnRH analog) by intermittent

subcutaneous (sc) injection instead

Hypopituitarism: Treatment

� To treat the hypogonadism in males:

• If fertility desired (continued):

� Intracytoplasmic Sperm Injection

(ICSI )

� Clomiphene (a selective estrogen

receptor modulator ‘SERM’) can

sometimes work when pituitary is

intact

Hypopituitarism: Treatment

� To treat the hypogonadism in females:

• Estrogen/Progesterone Rx

• If fertility desired:

� Clomiphene citrate

� HCG & FSH injections

Hypopituitarism: Treatment

� To treat the GHD: