Hypopituitarism

Ibrahim Salti MD, PhD, FRCPC,FACP

May 15, 2015

Learning 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

HYPOPITUITARISM
DEFINTION: 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 hypopituitarism

Possible sites
of lesions: hypothalamic
Or pituitary stalk

Hypothalamic hypopituitarism
Special Features:
Often includes ADH deficiency
Loss of DOPAMINE inhibition leads
to hyper-prolactinemia

Causes of hypothalamic hypopituitarism

1.
2.
3.

TRAUMA: esp. stalk injury

POST-SURGICAL DAMAGE
POST-RADIATION DAMAGE:

progressive
4.
5.
6.
7.

8.

may be occult and slowly

HYPOTHALAMIC NEOPLASMS :

primary or metastatic
GRANULOMATOUS DISORDERS e.g. Sarcoidosis
INFILTRATIVE DISORDERS e.g. Hemochromatosis,
Histiocytosis X
HEREDITARY: Genetic deficiency of one or more of
hypothalamic hormones. May be familial
May be associated with other somatic abnormalities
e.g. anosmia in Kallmanns syndrome
MISC CAUSES: e.g. vascular, birth trauma, aging

Pituitary hypopituitarism

Site
of lesions

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

Prolactin deficiency is expected

Causes of pituitary hypopituitarism

1.
2.

POST-SURGICAL DAMAGE
POST-RADIATION DAMAGE: may be occult

and slowly progressive

3.
4.
5.
6.
7.

ISCHEMIC NECROSIS esp. after post-partum

hemorrhage, (Sheehans syndrome)
Pituitary apoplexy: hemorrhage in a pituitary tumor
ischemia of the rest of the pituitary
LARGE PITUITARY TUMORS causing deficiencies
in the rest of the pituitary
GRANULOMATOUS DISORDERS e.g.

Eosinophylic granuloma
MISC CAUSES: e.g. hemochromatosis,
hypophysitis

Hypopituitarism in Patients
with Large Pituitary Tumors
Prevalence of Hormone deficits
Hormone
% Deficient

GH
94
FSH/ LH
88
TSH
60
PRL
20
ACTH

10

Hypopituitarism in Patients with

Large Pituitary Adenomas
Postulated mechanisms

Increased intra sellar pressure

Mechanical compression of portal
vessels/ pituitary stalk and/ or
Areas of focal ischemic necrosis

Arafah
ArafahBM,
BM,et
etalalJCEM
JCEM2000;
2000;85:1789-1793
85:1789-1793

Hypopituitarism in Patients with

Pituitary Adenomas-Continued

Reversible in 30-60 % of
patients
Reversibility depends on
presence of viable pituitary
tissue
Arafah
ArafahBM,
BM,et
etalalJCEM
JCEM2000;
2000;85:1789-1793
85:1789-1793

SEQUELAE OF HYPOPITUITARISM
TARGET ENDOCRINE ORGAN
DEFICIENCIES :
GROWTH HORMONE DEFICIENCY
PROLACTIN DEFICIENCY
ADH DEFICIENCY

Terminology 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

TARGET ORGAN DEFICIENCY IN

HYPOPITUITARISM
1. TSH DEFICIENCY leading to secondary or
tertiary hypothyroidism
2. FSH & LH DEFICIENCY leading to
secondary or tertiary hypogonadism
3. ACTH DEFICIENCY leading to secondary or
tertiary adrenocortical failure

FSH & 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

Male hypogonadism with

aging
Andropause: evidence from many cross
sectional studies e.g.

Age group
ng/dl
20-40y
40-60y
60-80y
80-100y

Percent with s. testosterone < 300

1%
7%
22%
36%

Vermulen et al JCEM 1991;73:221-224

Andropause: 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

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

TESTOSTERONE & FREE TESTOSTERONE WITH AGING

Manifestations 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

Partial Hypogonadism of Aging in Males

Mechanisms of Andropause:
Most studies suggest a combination of
1. Decreased FSH & LH secretion
2. Decreased testicular response to FSHLH
3. Increased SHBG resulting in decreased
free testosterone

Partial 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)

SEQUELAE OF HYPOPITUITARISM
TARGET ORGAN DEFICIENCY
GROWTH HORMONE DEFICIENCY
PROLACTIN DEFICIENCY
ADH DEFICIENCY

DWARFISM AS A RESULT OF PREPUBERTAL GH DEFICIENCY

NORMAL,
AGE 8 Y OLD

GH DEFICIENT
AGE 8 Y

MANIFESTATIONS 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

Growth hormone secretion at

different ages

Birth

Childhood

Puberty Adulthood

Old Age

Effect of aging on GH

Changes in serum IGF-I with

increasing age

AGE RELATED CHANGES IN GH

-

SOMATOPAUSE

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-1

SOMATOPAUSE-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

SEQUELAE OF HYPOPITUITARISM
TARGET ORGAN DEFICIENCY
GROWTH HORMONE DEFICIENCY
PROLACTIN DEFICIENCY
ADH DEFICIENCY

PROLACTIN DEFICIENCY
- Common in pituitary hypopituitarism- Unlike
hypothalamic hypopituitarism in which hyperprolactinemia is common
CONSEQUENCES:
- Failure of lactation after childbirth e.g. in
Sheehans syndrome
- No discernible abnormalities in males with
prolactin deficiency

The empty sella syndrome

a. Primary empty sella
A radiologic diagnosis
Normal pituitary is pushed down to the floor of
sella turcica
Little or no pituitary hormonal deficits

b. Secondary empty sella

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

Primary empty sella

Dynamic Tests of
Pituitary Function
TRH 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.

CRH TEST
Procedure:
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

CRH TESTINTERPRETATION:
1.

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

CRH TESTINTERPRETATION:
2.

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

GH & CORTISOL RESPONSES TO HYPOGLYCEMIA

INSULIN HYPOGLYCEMIA
Interpretation
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 test

Interpretation
Blunted GH Response:
Hypothalamic or Pituitary GH deficiency
Hypothyroidism or hyperthyroidism
Glucocorticoid excess
Obesity
Renal failure
Aging

LABORATORY ASSESMENT OF
GH SECRETION
1. TESTS FOR GH DEFICIENCY

GHRH Stimulation test

Insulin-induced hypoglycemia
Arginine stiumulation test
Measurement of GH during sleep
Clonidine stimulation test
L-DOPA stimulation test
Exercise test
Measurement of IGF-1

GHRH 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 TEST

RESPONSE IS DOSE RELATED

GHRH TEST
Interpretation
Blunted GH Response:
Pituitary GH deficiency
Delayed in hypothalamic causes of GH deficiency
Hypothyroidism
Cushings disease & glucocorticoid therapy
Estrogens in men
Obesity
Alcohol abuse
Hyperglycemia

GHRH TEST
Interpretation
Exaggerated GH Response:
Renal failure
Propranolol
Dopamine agonists

LABORATORY ASSESMENT OF
GH SECRETION
1. TEST FOR GH DEFICIENCY

GHRH Stimulation test

Insulin-induced hypoglycemia
Arginine stimulation test
Measurement of GH during sleep
Clonidine stimulation test
L-DOPA stimulation test
Exercise test
Measurement of IGF-1

Arginine 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
level

Arginine test
Interpretation
Blunted GH Response:
Pituitary and hypothalamic GH deficiency
Hypothyroidism or hyperthyroidism
Cushings disease & glucocorticoid therapy
Hyperglycemia
Obesity
Aging

Arginine test
Interpretation
Exaggerated GH Response:
Estrogens in men
Propranolol
Indomethacin

LABORATORY ASSESMENT OF
GH SECRETION
1. TEST FOR GH DEFICIENCY

GHRH Stimulation test

Insulin-induced hypoglycemia
Arginine stiumulation test
Measurement of GH during sleep
Clonidine stimulation test
L-DOPA stimulation test
Exercise test
Measurement of IGF-1

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 TEST
Interpretation
Blunted response of FSH & LH:
Pituitary hypogonadism
Hypothalamic hypogonadism ( improves after repeated testing )
Renal failure
Heavy exercise
Blind individuals
Prepuberty
Oral estrogens ( oral contraceptives)
Persons with elevated prolactin

GnRH TEST
Interpretation
Exaggerated response of FSH and LH:
Primary hypogonadism including
menopause
Renal 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 basalWomen 5-8 X increase over basal
TSH: 2-4 X increase at peak
Caution may cause flushing or hypertension

TRH TEST
Interpretation
Blunted Prolactin Response:
Pituitary hypopituitarism
Almost all patients with prolactinoma
Most patients with other causes of hyperprolactinemia
Hyperthyroidism
Dopamine agonistsAlcohol
Obesity
Renal failure
Severe illness, aging

TRH TEST
Interpretation
Exaggerated Prolactin Response:
Hypothalamic hypopituitarism
Hypothyroidism
Dopamine antagonists

TRH TEST FOR PROLACTIN

TRH TEST
Interpretation
Blunted TSH Response:
Pituitary hypopituitarism
Hyperthyroidism
Acute illness
Alcohol abuse
Chronic renal failure
Aging esp. males
Propranolol, somatostatin, glucocorticoids, dopamine agonists

TRH TEST
Interpretation
Exaggerated TSH Response:
Primary hypothyroidism
Estrogens
Dopamine antagonists
Theophylline
Lithium

TRH STIMULATION TEST

SEQUELAE OF HYPOPITUITARISM
TARGET 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 INSIPIDUS
1.

CENTRAL ( ADH deficiency )

a- Hypothalamic hypopituitarism
b- Idiopathic

2.

NEPHROGENIC ( Resistance to ADH )

a. Hereditary: defective ADH receptor
b. Acquired - Hypercalcemia
- Hypokalemia
- Renal tubular dysfunction e.g. Lithium toxicity

DIABETES INSIPIDUS
MANIFESTATIONS

Polyuria up to 4-6 liters per day

Polydipsia
Urinary hypo-osmolality despite plasma hyperosmolality
Abnormal response to water deprivation
Response to ADH or its analogues only in Central DI

Hyper-secretion of pituitary hormones

I.

Compensatory ( adaptive ) due to loss of

negative feedback

II.

Amplified physiologic response

III. 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 flushes

3. Hypersecretion of ACTH & MSH in primary
adrenocortical failure
- Leads to skin and mucous membrane hyper-pigmentation

Hyper-secretion of pituitary hormones

I.

Compensatory ( adaptive ) due to loss of

negative feedback

II.

Amplified physiologic response

III. Autonomous hypersecretion

Examples of hyper-secretion of pituitary

hormones as an amplified physiologic response
1.

Hyperprolactinemia 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

SIADHS
DEFINTION:
-ADH hypersecretion despite plasma
hypo-osmolalitiy
Urinary hyper-osmolality

Syndrome of Inappropriate ADH Secretion

SIADHS
MANIFESTATION
Hypo-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 disorders
3. Heart Failure
4. Hypothyroidism
5. Adrenocotical insufficiency
6. Drug induced

Syndrome of Inappropriate ADH Secretion

MECHANISM
ADH secretion by non-osmotic stimuli
over-rides the normal osmotic regulation
of ADH

Hyper-secretion of pituitary hormones

I.

Compensatory ( adaptive ) due to loss of

negative feedback

II.

Amplified physiologic response

III. Autonomous hypersecretion Usually

Due to Pituitary Tumors

Recommended Reading
Harrisons Principles of Internal Medicine
18th Edition
Chapters 339 and 340