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Panhypopituitarism
Background
Hypopituitarism is a clinical syndrome of deficiency in pituitary hormone
production. This may result from disorders involving the pituitary gland,
hypothalamus, or surrounding structures. Panhypopituitarism refers to
involvement of all pituitary hormones; however, only one or more pituitary
hormones are often involved, resulting in partial hypopituitarism. Pituitary
hormones of clinical significance include adrenocorticotropic hormone (ACTH,
ie, corticotropin), follicle-stimulating hormone (FSH), luteinizing hormone (LH),
growth hormone (GH), prolactin, thyroid-stimulating hormone (TSH, ie,
thyrotropin), and antidiuretic hormone (ADH).
Pathophysiology
When pituitary hormone production is impaired, target gland hormone
production is reduced because of a lack of trophic stimulus. Normally,
subphysiologic target hormone levels stimulate the pituitary gland to increase
trophic hormone production; however, in hypopituitarism, the pituitary gland
response is absent, suboptimal, or inappropriate with biologically inert
hormone production. This results in progressive secondary failure of the target
glands. Patients with hypopituitarism typically present with low target hormone
levels accompanied by low levels of the corresponding trophic hormone.
The trophic hormone level may appear to be within the reference range with a
corresponding subphysiologic target hormone level. Such a trophic hormone
level would be inappropriately low for the subphysiologic target hormone level.
Sometimes, the assayed trophic hormone level may be biologically inert.
Mortality/Morbidity
Four retrospective studies from the United Kingdom and Sweden show that
mortality is increased by 1.3- to 2.2-fold in hypopituitarism compared to ageand sex-matched cohorts. Morbidity is variable and may result from hormone
deficiency or underlying disease. Underlying disorders, such as tumors,
intracranial lesions, or systemic disease, may be asymptomatic or result in
morbidity that masks the hormone deficiency.
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Deficiency of ACTH with adrenal crisis or TSH with myxedema may be
life threatening.
GH deficiency causes more morbidity in children than in adults.
Sudden compromise of ACTH production may result in more profound
morbidity than slowly progressive deficiency.
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Gonadotropin deficiency with hypogonadism may cause morbidity
insidiously.
Morbidity is more profound in congenital hypopituitarism.
Race
No racial predilection exists.
Sex
Postpartum hypopituitarism causes an overall increase in the prevalence of
hypopituitarism in women.
Age
All ages are affected.
CLINICAL
History
Presentation varies from asymptomatic to acute collapse, depending on the
etiology, rapidity of onset, and predominant hormones involved.
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Initially, a patient with any hormone deficiency may be asymptomatic.
Individuals with the following deficiencies present with the indicated
condition:
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ACTH deficiency - Adrenal insufficiency
TSH deficiency - Hypothyroidism
Gonadotropin deficiency - Hypogonadism
GH deficiency - Individuals with GH deficiency present with
failure to thrive and short stature in children. Most adults are
asymptomatic, but some may experience fatigue and weakness.
o ADH deficiency - Polyuria and polydipsia
Other presenting features may be attributable to the underlying cause.
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Physical
A patient with a space-occupying lesion may present with
headaches or visual field deficits.
A patient with large lesions involving the hypothalamus may
present with polydipsia and syndrome of inappropriate secretion
of antidiuretic hormone (SIADH).
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Physical examination findings may be normal in subtle presentations.
Patients may present with features attributable to deficiency of target
hormones, including hypothyroidism, adrenal insufficiency,
hypogonadism, and failure to thrive.
Causes
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Tumors - Craniopharyngiomas, pituitary adenomas
Infiltrative processes - Sarcoidosis, histiocytosis X, hemochromatosis
Infections - Tuberculosis, syphilis, meningitis
Ischemia and infarction - Sheehan syndrome, apoplexy
Empty sella syndrome
Iatrogenic - Radiation, surgery, withholding previous chronic
glucocorticoid replacement
Trauma to the hypophysis
Congenital - Kallmann syndrome
Autoimmune - Lymphocytic hypophysitis
DIFFERENTIALS
Hyponatremia
Hypothyroidism
Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism
Pituitary Macroadenomas
Pituitary Microadenomas
Polyglandular Autoimmune Syndrome, Type I
Polyglandular Autoimmune Syndrome, Type II
Polyglandular Autoimmune Syndrome, Type III
WORKUP
Lab Studies
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Hormonal studies should be performed in pairs of target gland and their
respective stimulatory pituitary hormone for proper interpretation.
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ACTH and Cortrosyn stimulation test
TSH and thyroxine
FSH, LH, and either estradiol or testosterone (as appropriate for
sex)
Prolactin
GH provocative testing
Imaging Studies
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MRI or computed axial tomography of the pituitary
Other Tests
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Other tests to ascertain the likely underlying etiology are indicated by
the patient's presentation.
Procedures
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Cortrosyn stimulation testing
Histologic Findings
Findings depend on etiology (eg, tumors, infiltrations, infections, empty sella).
TREATMENT
Medical Care
Medical care consists of hormone replacement as appropriate and treatment
of the underlying cause.
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Glucocorticoids are required if the ACTH-adrenal axis is impaired. This
is particularly important in sudden collapse due to pituitary apoplexy or
acute obstetric hemorrhage with pituitary insufficiency. In such
circumstances, do not delay initiation of a possibly life-saving treatment
pending a definitive diagnosis.
Treat secondary hypothyroidism with thyroid hormone replacement.
Treat gonadotropin deficiency with sex-appropriate hormones. In men,
testosterone replacement is used and modified if the patient desires
fertility. In women, estrogen replacement is used with or without
progesterone as appropriate.
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GH is replaced in children as appropriate. GH is not routinely replaced
in adults unless the patient is symptomatic.
Surgical Care
Surgical care depends on the underlying cause and the severity of
hypopituitarism.
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In pituitary apoplexy, prompt surgical decompression may be life
saving if head imaging reveals tumor mass effect.
Extirpate macroadenomas that do not respond to medical therapy.
Consultations
Include an endocrinologist, a neurosurgeon, and a radiologist as appropriate.
Diet
No special diet is necessary unless dictated by an underlying disease
process. Salt use in adrenal insufficiency may be liberalized in special
circumstances (eg, excessive diaphoresis).
Activity
No restrictions are necessary unless dictated by an underlying disease
process.
MEDICATION
The goal of pharmacotherapy is to restore target hormones to physiologic
levels.
Drug Category: Glucocorticoids
Used in adrenal insufficiency. Cause profound and varied metabolic effects in
addition to modifying the body's immune response to diverse stimuli. The
naturally occurring glucocorticoids and many synthetic steroids have both
glucocorticoid and mineralocorticoid activity.
Drug Name
Hydrocortisone (Hydrocortone,
Hydrocort)
Description
Used as replacement therapy in
adrenocortical deficiency states and
may be used for their antiinflammatory effects.
Adult Dose
20-30 mg/d PO divided bid (often 15
mg in the morning and 10 mg in the
afternoon)
Pediatric Dose
Contraindications
<12 years: 1-2 mg/kg/dose IV bolus,
followed by 25-150 mg/d IV/IM divided
q6-8h
>12 years: 1-2 mg/kg IV bolus,
followed by 150-250 mg/d IV/IM
divided q6-8h
Documented hypersensitivity; viral,
fungal, or tubercular skin infections
Interactions
Corticosteroid clearance may
decrease with estrogens; may
increase digitalis toxicity secondary to
hypokalemia
Pregnancy
C - Safety for use during pregnancy
has not been established.
Precautions
Caution in hyperthyroidism,
osteoporosis, peptic ulcer, and
cirrhosis
Drug Category: Thyroid hormones
Used in hypothyroidism.
Drug Name
Levothyroxine (Synthroid, Levoxyl,
Levothroid)
Description
In active form, influences growth and
maturation of tissues. Involved in
normal growth, metabolism, and
development.
Adult Dose
100-200 mcg/d PO
Pediatric Dose
Contraindications
<6 months: 8-10 mcg/kg/d PO
6-12 months: 6-8 mcg/kg/d PO
1-5 years: 5-6 mcg/kg/d PO
6-12 years: 4-5 mcg/kg/d PO
>12 years: 2-3 mcg/kg/d PO
Documented hypersensitivity,
uncorrected adrenal insufficiency
Interactions
Cholestyramine may decrease
liothyronine absorption; estrogens
may decrease response to thyroid
hormone therapy in patients with
nonfunctioning thyroid glands; effect
of anticoagulants increased when
administered with liothyronine; activity
of some beta-blockers may decrease
when hypothyroid patient is converted
to a euthyroid state
Pregnancy
A - Safe in pregnancy
Precautions
Caution in angina pectoris or
cardiovascular disease, periodically
monitor thyroid status
Drug Category: Growth hormones
Used in the treatment of children who have growth failure associated with
chronic renal insufficiency up to the time of renal transplantation. Use in
conjunction with optimal management of chronic renal insufficiency.
Drug Name
Human growth hormone; somatropin
(Humatrope, Genotropin)
Description
Produced by recombinant DNA
technology. Stimulates growth of
linear bone, skeletal muscle, and
organs. Stimulates erythropoietin,
which increases red blood cell mass.
Adult Dose
Genotropin or Humatrope: 6-125
mcg/kg/d SC
Pediatric Dose
Genotropin: 160-240 mcg/kg SC qwk
divided in 6-7 doses
Humatrope: 180 mcg/kg IM/SC qwk
divided in 3-7 doses
Documented hypersensitivity;
pediatric patients with closed
epiphyses; evidence of tumor activity
or active neoplasia (intracranial
Contraindications lesions must be inactive and
antitumor therapy completed prior to
instituting therapy; discontinue if
evidence of tumor activity, recurrent
tumor growth, or neoplasia)
Interactions
Glucocorticoids reduce growthpromoting effects
Pregnancy
C - Safety for use during pregnancy
has not been established.
Precautions
Caution in diabetes, epiphyseal
closure, geriatric patients, transplant
patients, and use with other
hormones
Drug Category: Sex hormones
For replacement therapy in hypogonadism associated with a deficiency or
absence of endogenous testosterone or estrogen.
Drug Name
Testosterone (Andro-LA, Androderm,
Depo-Testosterone)
Description
Anabolic steroid that promotes and
maintains secondary sex
characteristics in androgen-deficient
males.
Adult Dose
50-400 mg IM q2-4wk
Pediatric Dose
Initiation of pubertal growth: 40-50
mg/m2/dose IM qmo until growth rates
fall to prepubertal levels
Terminal growth phase: 100
mg/m2/dose IM qmo until growth
ceases
Maintenance virilizing dose: 100
mg/m2 IM 2 times/mo
Documented hypersensitivity; severe
cardiac or renal disease; benign
prostatic hypertrophy with obstruction;
Contraindications
males with carcinoma of the breast or
prostate, undiagnosed genital
bleeding
Interactions
May increase effects of
anticoagulants
Pregnancy
X - Contraindicated in pregnancy
Precautions
Anabolic effects may enhance
hypoglycemia in pediatric age group;
monitor hand and wrist every 6 mo to
determine rate of bone maturation
Drug Name
Estrogens, conjugated (Premarin)
Description
Important in developing and
maintaining the female reproductive
system and secondary sex
characteristics; promotes growth and
development of the vagina, uterus,
fallopian tubes, and breasts. Affect
release of pituitary gonadotropins;
cause capillary dilatation, fluid
retention, and protein anabolism;
increase water content of cervical
mucus; and inhibit ovulation.
Predominantly produced by the
ovaries.
Adult Dose
Pediatric Dose
0.3-0.625 mg/d PO for 3 wk; off 1 wk,
repeat cycle
Not established
Documented hypersensitivity; known
or suspected pregnancy; breast
cancer, undiagnosed abnormal
genital bleeding, active
thrombophlebitis or thromboembolic
Contraindications disorders; history of thrombophlebitis,
thrombosis, or thromboembolic
disorders associated with previous
estrogen use (except when used in
treatment of breast or prostatic
malignancy)
Interactions
May reduce hypoprothrombinemic
effect of anticoagulants;
coadministration of barbiturates,
rifampin, and other agents that induce
hepatic microsomal enzymes may
reduce estrogen levels;
pharmacologic and toxicologic effects
of corticosteroids may occur as a
result of estrogen-induced inactivation
of hepatic P-450 enzyme; loss of
seizure control has been noted when
administered concurrently with
hydantoins
Pregnancy
X - Contraindicated in pregnancy
Precautions
Certain patients may develop
undesirable manifestations of
excessive estrogenic stimulation such
as abnormal or excessive uterine
bleeding or mastodynia; estrogens
may cause some degree of fluid
retention (exercise caution);
prolonged unopposed estrogen
therapy may increase risk of
endometrial hyperplasia
FOLLOW-UP
Further Inpatient Care
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In very ill hospitalized patients or in patients undergoing major
procedures, stress-dose steroids are required and are quickly tapered
to a maintenance schedule after the procedure.
Minor procedures or illnesses may not necessitate a change in steroid
dose or may require a simple doubling of the usual daily dose until the
illness resolves.
Other hormone replacements are continued at their usual maintenance
doses as appropriate.
Further Outpatient Care
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Follow-up care involves adjusting hormone replacement to physiologic
maintenance levels using the lowest dose. Monitor the patient to avoid
overreplacement.
All patients with hypopituitarism should carry some identification. This
is often in the form of an identification bracelet worn on the wrist or
neck. Some vendors include more than 20 lines of information in a tiny
pendant.
In/Out Patient Meds
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Glucocorticoids for adrenal insufficiency
Levothyroxine for hypothyroidism
Estrogen for hypogonadal women or testosterone for hypogonadal men
GH replacement for GH deficiency in the pediatric age group
Prevention
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Good obstetric care has reduced the incidence of postpartum
hypopituitarism.
Radiation therapy that minimizes exposure to the pituitary reduces
incidence and time of onset of hypopituitarism.
Experienced neurosurgeons employing high-resolution microscopic
hypophyseal surgery may reduce the likelihood of subsequent
hypopituitarism.
Complications
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An adrenal crisis is life threatening and should be treated promptly.
When hypothyroidism occurs concurrently with adrenal insufficiency,
glucocorticoids replacement should precede thyroid hormone
replacement. This reduces the likelihood of possible adrenal
insufficiency resulting from increased demands due to enhanced
metabolism.
Prognosis
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If adequately replaced, prognosis in hypopituitarism is good. Morbidity
is often related to the underlying disease process.
Patient Education
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Education emphasizes the need for lifelong hormone replacement,
increasing glucocorticoid replacement during stress, and seeking
prompt medical attention as appropriate.
Regular monitoring to avoid excessive hormone replacement is
important.
For excellent patient education resources, visit eMedicine's Endocrine
System Center and Growth Hormone Deficiency Center. Also, see
eMedicine's patient education articles Anatomy of the Endocrine
System, Hypopituitary, Growth Hormone Deficiency, and
Understanding Growth Hormone Deficiency Medications.
Medical/Legal Pitfalls
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A diagnosis of hypopituitarism may be missed if apparently normal
pituitary hormone levels are interpreted with respective subnormal
target organ hormone levels.
Adrenal insufficiency should be treated upon suspicion and definitive
diagnosis made posttherapy.
Adrenal replacement should precede thyroxine replacement to avoid a
possible addisonian crisis.
Hypopituitarism may manifest several years after radiation and in
chronic Sheehan syndrome.
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Replace all appropriate hormones.
Patients on GH and sex steroid replacement should be monitored for
neoplasms.
In acute pituitary failure, as in Sheehan syndrome, the ACTH
stimulation study finding may be normal because the adrenal glands
are not atrophied in the acute setting.
Special Concerns
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Provide long-term follow-up care for complications of
underreplacement or overreplacement.
Stressful situations warrant an adjustment in therapy.
Unlike adults, children require GH replacement.
REFERENCES
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Clayton RN. Mortality, cardiovascular events and risk factors in
hypopituitarism. Growth Horm IGF Res. Feb 1998;8 Suppl A:6976. [Medline].
Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary
dysfunction after radiation for brain tumors. N Engl J Med. Jan
14 1993;328(2):87-94. [Medline].
Dexter RN. Hypopituitarism. In: Becker KL, ed. Principles and Practice
of Endocrinology and Metabolism. 2nd ed. Baltimore, Md: Williams and
Wilkins;1995:169-80.
Garcia-Heras J, Kilani RA, Martin RA, Lamp S. A deletion of proximal
20p inherited from a normal mosaic carrier mother in a newborn with
panhypopituitarism and craniofacial dysmorphism. Clin
Dysmorphol. Jul 2005;14(3):137-40. [Medline].
Harzallah L, Migaw H, Harzallah F, Kraiem Ch. Diabetes insipidus and
panhypopituitarism revealing pituitary metastasis of small cell lung
carcinoma: a case report. Ann Endocrinol (Paris). Apr 2005;66(2 Pt
1):117-20. [Medline].
Koh WJ, Kwon OJ. Mycobacterium avium complex lung disease and
panhypopituitarism. Mayo Clin Proc. Jul 2005;80(7):961-2. [Medline].
Lasheen I, Doi SA, Al-Shoumer KA. Glucocorticoid replacement in
panhypopituitarism complicated by myelinolysis. Med Princ Pract. MarApr 2005;14(2):115-7. [Medline].
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Thorner MO, Vance ML, Horvath E. The anterior pituitary. In: Williams
Textbook of Endocrinology. 8th ed. Philadelphia, Pa: WB Saunders
and Co;1992:221-310.
Vance ML. Hypopituitarism. N Engl J Med. Jun 9 1994;330(23):165162. [Medline].
Wolfgang KHO. Hypopituitarism. In: Bardin CW, ed. Current Therapy in
Endocrinology and Metabolism. 6th ed. St. Louis, Mo: Mosby-Year
Book;1997:27-31.
Yamakita N, Yasuda K. Pulmonary Mycobacterium avium complex
infection in patients with panhypopituitarism not receiving hormone
replacement therapy. Mayo Clin Proc. Feb 2005;80(2):291. [Medline].
Panhypopituitarism
What is panhypopituitarism?
Hypopituitarism refers to a deficiency of one or more of the hormones secreted by the anterior
pituitary gland. Panhypopituitarism refers to an absence of all hormones released by the
pituitary gland.
Pituitary insufficiency in the adult is most commonly caused by a nonfunctioning tumor,
surgical removal or irradiation of the pituitary gland.
What are the symptoms?
The lack of pituitary hormones results in a reduction in the hormones released by the target
glands (i.e. thyroid, adrenals and gonads). When hypo- or pan- hypopituitarism results from
inherent disease or irradiation, symptoms develop gradually. After surgery, symptoms of
adrenal sufficiency can develop within days, and hypothyroidism after only a month.
In panhypopituitarism facial and body hair decrease and reproductive organs and muscle
tissue shrivel. There can be loss of libido, impotency, amennorhea, and infertility.
Hypoglycemia may occur due to a deficiency of growth hormone. There is also a loss of
normal skin pigmentation, which can become pale and waxy in appearance. Wrinkles may
develop around the eyes and mouth making the person appear older than normal. When
pituitary deficiency is severe there is extreme weight loss, emaciation, with eventual coma,
and if untreated, death.
How is it treated?
Because pituitary hormones are destroyed in the gastrointestinal tract, treatment of
hypopituitarism involves replacement of the deficient hormones of the target organs.
Additionally, within the last five years the FDA approved growth hormone for treatment in
those with panhypopituitarism. Growth hormone is self-administered by injection,
subcutaneously, on a daily basis.