Clinical manifestations of hypopituitarism

Damage to the anterior pituitary can occur suddenly or slowly, can be mild or severe, and can affect the secretion
of one, several, or all of its hormones The rapidity with which a disease affects anterior pituitary cells. Some
diseases, such as pituitary apoplexy, develop rapidly, causing sudden impairment of corticotropin (ACTH)
secretion and, consequently, sudden onset of symptoms of cortisol deficiency. Other insults, such as radiation
therapy to the pituitary or hypothalamus, usually act slowly, causing symptoms many months or, more likely,
years later. The severity of the hormonal deficiency. Complete ACTH and cortisol deficiency, as an example,
can cause symptoms under basal circumstances, while partial ACTH deficiency may cause symptoms only during
times of physical stress.The number of different anterior pituitary cells that are affected, leading to impairment
in the secretion of one, a few, or all the pituitary hormones (called panhypopituitarism).

Patients in whom the hypopituitarism is due to a sellar mass may also have symptoms related to the mass, such
as headache, visual loss, or diplopia. (

HORMONE DEFICIENCIES

ACTH deficiency (secondary adrenal insufficiency) results in cortisol deficiency. If severe causes vascular
collapse frfom loss of peripheral vascular tone. A less severe is postural hypotension and tachycardia. Mild,
chronic deficiency may result in lassitude, fatigue, anorexia, weight loss, decreased libido, hypoglycemia, and
eosinophilia. ACTH deficiency does not cause salt wasting, volume contraction, and hyperkalemia because it
does not result in clinically important deficiency of aldosterone.ACTH deficiency does not result in
hyperpigmentation. Both forms of adrenal insufficiency can cause hyponatremia. due to inappropriate secretion
of antidiuretic hormone (vasopressin) that is caused by cortisol (not aldosterone) deficiency

Moderately severe ACTH and cortisol deficiency may cause few or no symptoms and no physical findings.
Consequently, the adequacy of ACTH secretion should be evaluated biochemically in all patients who have
pituitary or hypothalamic disease

TSH Common symptoms include fatigue, cold intolerance, decreased appetite, constipation, facial puffiness,
dry skin, bradycardia, delayed relaxation phase of the deep tendon reflexes, and anemia. The degree of
symptoms and abnormal physical findings usually parallels the degree of thyroxine deficiency,

Gonadotropins Deficient secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) results in hypogonadotropic hypogonadism

In women, hypogonadism means ovarian hypofunction, which results in decreased estradiol secretion. The
clinical consequences of estradiol deficiency in women with secondary hypogonadism are similar to those seen in
women with primary hypogonadism (primary ovarian insufficiency [premature ovarian failure]). Findings in
premenopausal women include irregular periods , amenorrhea, anovulatory infertility, vaginal atrophy, hot
flashes. No physical findings of hypogonadism are detectable initially, but after several years, breast tissue
decreases and bone mineral density (BMD) declines.

In men, hypogonadism means testicular hypofunction, which results in infertility and decreased
testosterone secretion. The latter causes decreased energy and libido, and hot flashes if sufficiently severe, within
weeks to months, but does not cause decreased muscle mass (and perhaps strength) for several years.
Testosterone deficiency also causes decreased BMD

Growth hormone deficiency in children typically presents as short stature , in adults include changes in body
composition (increased fat mass with a decrease in lean body mass), decreased BMD, impaired quality of life, and
increased mortality rates. Prolactin The only known clinical manifestation of prolactin deficiency is the
inability to lactate after delivery. Isolated prolactin deficiency is rare

Hypothalamic diseases
Mass lesions Benign (craniopharyngiomas) and malignant tumors (metastatic from lung, breast, etc)
Radiation For CNS and nasopharyngeal malignancies
Infiltrative lesions Sarcoidosis, Langerhans cell histiocytosis
Infections Tuberculous meningitis
Other Traumatic brain injury, stroke
Pituitary diseases
Mass lesions Pituitary adenomas, other benign tumors, cysts
Pituitary surgery
Pituitary radiation
Infiltrative lesions Hypophysitis, hemochromatosis
Infection/abscess
Infarction Sheehan syndrome
Apoplexy
Genetic mutations
Empty sella

HYPOTHALAMIC DISORDERS

. Unlike diseases that involve the pituitary directly, any of these conditions can also diminish the secretion of
vasopressin, resulting in diabetes insipidus. Pituitary lesions alone do not cause diabetes insipidus, since some
vasopressin-producing neurons terminate in the median eminence. Tumors These include benign tumors that
arise in the hypothalamus, such as craniopharyngiomas, and malignant tumors that metastasize there, such as
lung and breast carcinomas. Radiation therapy The risk of pituitary dysfunction after cranial radiation is both
dose and time-dependent and may not become apparent until many years after treatment. / Infiltrative disorders
such as sarcoidosis and Langerhans cell histiocytosis can cause deficiencies of anterior pituitary hormones and
diabetes insipidus Infections Hypopituitarism can follow meningitis, / Traumatic brain injury Head
trauma of sufficient severity to fracture the skull base can cause hypothalamic hormone deficiencies, resulting in
deficient secretion of anterior pituitary hormones and vasopressin . Anterior pituitary deficiencies are common
acutely but much less common 3 and 12 months afterwards. /Both ischemic stroke [28,29] and subarachnoid
hemorrhage

PITUITARY DISORDERS Any disease that affects the pituitary gland can result in diminished secretion of
one or more pituitary hormones. Mass lesions that can cause hypopituitarism include pituitary adenomas, cysts,
metastatic cancer, and other lesions. The early stage of lymphocytic hypophysitis is characterized by
lymphocytic infiltration and enlargement of the pituitary. A mass lesion in the sella can cause temporary or
permanent damage by exerting pressure on pituitary cells. Conversely, reducing the size of the mass may relieve
the pressure and restore pituitary function. Among pituitary mass lesions, pituitary adenomas are most
commonly associated with hypopituitarism; in particular, clinically nonfunctioning pituitary adenomas
Pituitary surgery / Pituitary radiation / Hereditary hemochromatosis . Gonadotropin deficiency is the most
common endocrine abnormal

Hypophysitis Lymphocytic hypophysitis is the most common form of hypophysitis; the cause is usually
unknown. It is initially characterized by lymphocytic infiltration and enlargement of the pituitary; this stage is
followed by destruction of the pituitary cells. It often occurs in late pregnancy or the postpartum period.
Affected patients typically present with headaches of an intensity out of proportion to the size of the lesion and
hypopituitarism. Preferential hypofunction of ACTH and TSH-secreting cells has been described in many
papers, leading to adrenal insufficiency and hypothyroidism, . Hypophysitis may also occur as a complication of
anti-CTLA-4 immunotherapy, mostly with ipilimumab. Granulomatous hypophysitis sometimes accompanies a
known systemic granulomatous condition such as Wegener's granulomatosis and tuberculosis, and has been
reported following treatment of hepatitis C with interferon alpha and ribavirin . Plasmacytic (IgG4-associated)
hypophysitis Xanthomatous hypophysitis This condition, the most rare form of hypophysitis, is
characterized histologically by infiltration by foamy histiocytes [42,43].

Pituitary infarction (Sheehan syndrome) Infarction of the pituitary gland after postpartum hemorrhage has
long been recognized as a cause of hypopituitarism and is called Sheehan syndrome Clinical features include the
following:A history of postpartum hemorrhage so severe as to cause hypotension and require transfusion of
multiple units of blood.When the hypopituitarism is severe, development of lethargy, anorexia, weight loss,
and inability to lactate during the first days or weeks after delivery When the hypopituitarism is less severe,
failure of postpartum lactation and failure to resume menses in the weeks and months after delivery, and loss of
sexual hair, as well as milder degrees of fatigue, anorexia, and weight loss. When the hypopituitarism is mild,
possible delay in recognition for many years after the event Evaluation of postpartum hypopituitarism should be
performed whenever it is suspected after a delivery associated with unusually heavy blood loss. If the blood loss
is severe, and especially if it is associated with hypotension, the patient should be evaluated and treated for
adrenal insufficiency immediately. Other hormonal deficiencies can be evaluated four to six weeks later.

Rare causes of pituitary infarction include:Vascular insufficiency occurring during coronary artery bypass
surgery in older patients Snake bites in Southeast Asia (Russell's viper bites):
Pituitary apoplexy Sudden hemorrhage into the pituitary gland is called pituitary apoplexy. Hemorrhage
often occurs into a pituitary adenoma. In its most dramatic presentation, apoplexy causes the sudden onset of
excruciating headache, diplopia due to pressure on the oculomotor nerves, and hypopituitarism. All pituitary
hormonal deficiencies can occur, but the sudden onset of ACTH and therefore cortisol deficiency is the most
serious because it can cause life-threatening hypotension.. The acute symptoms and imaging evidence of a
pituitary mass confirms the diagnosis.Surgical decompression of the pituitary is often performed in cases with
severe or progressive impairment of vision or neurological symptoms The hypopituitarism, like the diplopia, may
improve after surgical decompression

Pituitary infection/abscess

Genetic diseases For many years, congenital deficiencies of one or more pituitary hormones have been
recognized. Several different mutations have been detected and the phenotypic results are variable, even in
patients who have the same mutation. The age of onset of the first hormonal deficiency, the order of the onset of
the various pituitary hormone deficiencies, and the severity of the deficiencies all vary. Almost invariably,
however, GH deficiency begins sometime in infancy or childhood and results in short stature. Most patients
receive GH therapy during childhood. However, in a family of three individuals with PROP-1 mutations who
did not receive GH therapy until adulthood, significant linear growth occurred in spite of their fairly advanced
bone age [86].

Empty sella An empty sella refers to an enlarged sella turcica that is not entirely filled with pituitary tissue.
It is a radiologic description and not a clinical condition. There are two types: Secondary empty sella is
characterized by association of the empty sella with an identifiable disease of the pituitary gland. One example
of an identifiable disease is a mass, such as a pituitary adenoma, that enlarges the sella but then is removed by
surgery, radiation, or infarction. In this type of empty sella, hypopituitarism can result from the adenoma itself,
its treatment, or infarction. A remnant of a partially removed pituitary adenoma could have residual function
Primary empty sella is characterized by a defect in the diaphragm sella that is thought to allow cerebrospinal
fluid (CSF) pressure to enlarge the sella , there is no consistent evidence of the existence of an "empty sella
syndrome."

Evaluation of a patient whose MRI shows an empty or partially empty sella, therefore, depends on what else is
seen in the sella and the clinical situation. The presence of a sellar mass, especially a lesion more than 1 cm in
size, requires evaluation for hormonal hypersecretion and hyposecretion, as does any other sellar mass. Clinical
evidence of hormonal excess or deficiencies requires biochemical evaluation of all pituitary hormones. In the
absence of a sellar mass and clinical evidence of hormonal excess or deficiency, measurement of thyroxine (T4)
and early morning cortisol could be performed, but the likelihood is that they will be normal.

The diagnosis of hypopituitarism, defined as deficient secretion of one or more pituitary hormones because of
pituitary or hypothalamic disease, is made by documenting subnormal secretion of these pituitary hormones in
defined circumstances. Each pituitary hormone must be tested separately

This suspicion can be based upon the knowledge that the patient has either a lesion known to cause
hypopituitarism or a symptom known to be caused by hypopituitarism. The knowledge that the patient has a
lesion that can cause hypopituitarism, eg, a sellar mass, is by itself sufficient reason to test for hypopituitarism

CORTICOTROPIN For normal health, the basal secretion of corticotropin (ACTH) must be sufficient to
maintain the serum cortisol concentration within the normal range. For survival, it must increase to raise serum
cortisol concentrations in times of physical stress.

Basal ACTH secretion To test basal ACTH secretion, serum cortisol should be measured at 8 to 9 AM,

A serum cortisol value of 3 mcg/dL (83 nmol/L; normal range 5 to 25 mcg/dL [138 to 690 nmol/L]),
confirmed by a second determination, is strong evidence of cortisol deficiency. Such a finding in the absence of
any known cause of hypopituitarism mandates measurement of serum ACTH. A serum ACTH value not higher
than normal is inappropriately low and establishes the diagnosis of secondary adrenal deficiency (ie, pituitary or
hypothalamic disease). A value higher than normal documents primary adrenal insufficiency (ie, adrenal
disease).

A serum cortisol value of 18 mcg/dL (497 nmol/L) indicates that basal ACTH secretion is sufficient
and also that it is probably sufficient for times of stress.
 A serum cortisol value >3 mcg/dL but <18 mcg/dL (497 nmol/L) that is persistent on repeat
determination is an indication to evaluate ACTH reserve.

ACTH reserve ACTH reserve should be measured in patients with intermediate serum cortisol values. We
suggest metyrapone testing when a test of ACTH reserve is required. Metirapone blocks 11-beta-hydroxylase
(CYP11B1), the enzyme that catalyzes the conversion of 11-deoxycortisol to cortisol, resulting in a reduction in
cortisol secretion. The ensuing fall in serum cortisol should, if the hypothalamic-pituitary-adrenal axis is normal,
cause an increase in ACTH secretion and therefore an increase in adrenal steroidogenesis up to and including 11-
deoxycortisol.

In normal subjects, administration of 750 mg of metyrapone orally every four hours for 24 hours results
in a decline in 8 AM serum cortisol to less than 7 mcg/dL (172 nmol/L) and an elevation in 8 AM serum 11-
deoxycortisol to 10 mcg/dL (289 nmol/L) at the end of the 24 hours . Patients taking phenytoin metabolize
metyrapone more rapidly than normal; as a result, each metyrapone dose should be 1500 mg. After the 8 AM
blood sample is taken at the end of the 24 hours, 100 mg of hydrocortisone should be administered intravenously
to reverse the cortisol deficiency caused by the metyrapone.

In patients who have decreased ACTH reserve due to hypothalamic or pituitary disease, the serum 11-
deoxycortisol concentration will be less than 10 mcg/dL (289 nmol/L) and the serum cortisol <7 mcg/dL (172
nmol/L) at the end of 24 hours.

Interpretation of the metyrapone test requires adequate inhibition of cortisol production. If the serum
11-deoxycortisol concentration at the end of 24 hours is <10 mcg/dL (289 nmol/L) but the serum cortisol
concentration is 7 mcg/dL (193 nmol/L), the reason for the insufficient rise in 11-deoxycortisol may be
insufficient inhibition by metyrapone. In this case, reasons for insufficient inhibition should be sought, such as
failure to take all of the metyrapone, rapid metabolism, and malabsorption. The test should be then be repeated
using a double dose of metyrapone. The advantages of the metyrapone test are that it can be administered to
adults of any age and the results correlate reasonably well with the serum cortisol response to surgical stress. The
principal disadvantage is that the patient must be observed in an inpatient setting so that blood pressure and
pulse can be measured lying and standing before each four-hourly dose for 24 hours. If postural hypotension
occurs, the test should be terminated by administration of 100 mg of hydrocortisone intravenously

Insulin-induced hypoglycemia test The rationale for this test is that hypoglycemia induced by insulin
administration is a sufficient stress to stimulate ACTH and therefore cortisol secretion. The test is performed by
administering 0.1 unit of insulin per kg of body weight and measuring serum glucose and cortisol before and 15,
30, 60, 90, and 120 minutes after the injection [4]. In normal subjects, serum cortisol increases to 18 mcg/dL
(498 nmol/L) if the serum glucose falls to <50 mg/dL (2.8 mmol/L). The advantage of this test is that the results
also correlate relatively well with the serum cortisol response to surgical stress. The disadvantages are that
hypoglycemia can be dangerous and constant monitoring is required

Cosyntropin stimulation test The rationale for the administration of cosyntropin (ACTH) is that the adrenal
glands atrophy when they have not been stimulated for a prolonged period; as a result, they do not secrete
cortisol normally in response to a bolus dose of ACTH. The test is usually performed by administering 0.25 mg
(25 units) of cosyntropin (synthetic ACTH 1-24) intramuscularly or intravenously and measuring serum cortisol
60 minutes later. A serum cortisol concentration of 18 mcg/dL (497 nmol/L) is considered a normal response.In
practice, this test is not often useful because a patient who has such severe ACTH deficiency that the adrenal
glands do not respond normally to cosyntropin will also probably have an 8 to 9 AM basal serum cortisol value
that is 3 mcg/dL (83 nmol/L) and therefore will not need a test of ACTH reserve. On the other hand, a patient
who has partial ACTH deficiency may respond normally to cosyntropin and requires a test of ACTH reserve

THYROTROPIN TSH deficiency Screening for hypothyroidism in patients with pituitary or hypothalamic
disease is therefore performed by measuring thyroxine, either total thyroxine (T4) and triiodothyronine (T3)
uptake or free T4

GONADOTROPINS

Men In a man with hypopituitarism, luteinizing hormone (LH) deficiency can best be detected by
measurement of the serum testosterone concentration. If it is repeatedly low at 8 to 10 AM and the LH
concentration is not elevated, the patient has secondary hypogonadism. When the serum testosterone
concentration is low, the serum LH concentration is usually within the normal range, but low compared with
elevated values in primary hypogonadism. If fertility is an issue, the sperm count should be determined.
Women In a woman of premenopausal age who has pituitary or hypothalamic disease but normal menses, no
tests of LH or follicle-stimulating hormone (FSH) secretion are needed because a normal menstrual cycle is a
more sensitive indicator of intact pituitary-gonadal function than any biochemical test. If the woman has
oligomenorrhea or amenorrhea, serum LH or FSH should be measured to be sure it is not high due to ovarian
disease. In addition, the following two tests should be obtained:

Measurement of serum estradiol. bAdministration of medroxyprogesterone, 10 mg daily for 10 days, to

determine if vaginal bleeding occurs after the 10-day course.

A low serum estradiol concentration and/or absence of vaginal bleeding indicate estradiol deficiency as a
consequence of gonadotropin deficiency, and warrant consideration of estrogen treatment. Normal results, in
association with oligomenorrhea or amenorrhea, could indicate sufficient gonadotropin secretion to maintain
normal basal estradiol secretion but insufficient to cause ovulation and normal progesterone secretion. This
situation should prompt consideration of intermittent progestin treatment.

The serum LH response to a single bolus dose of gonadotropin-releasing hormone (GnRH) is not helpful in
distinguishing secondary hypogonadism due to pituitary disease from that due to hypothalamic disease because
patients who have hypogonadism due to pituitary disease may have normal or subnormal serum LH responses to
GnRH, as may those who have hypothalamic disease.

GROWTH HORMONE Measurement of basal serum growth hormone concentration does not distinguish
reliably between normal and subnormal growth hormone secretion in adults. Three other criteria, however, are
useful:

Deficiencies of multiple other pituitary hormones The likelihood that the growth hormone response to all
provocative stimuli will be subnormal in patients who have organic pituitary disease, eg, a macroadenoma, and
deficiencies of corticotropin (ACTH), thyrotropin (TSH), and gonadotropins is about 95 percent

Serum insulin-like growth factor 1 (IGF-1) A serum IGF-1 concentration lower than the age-specific lower
limit of normal in a patient who has organic pituitary disease confirms the diagnosis of growth hormone
deficiency [

Provocative tests of growth hormone secretion Either insulin-induced hypoglycemia or the combination of
arginine and growth hormone-releasing hormone (GHRH) is a potent stimulus of growth hormone release.
Subnormal increases in the serum growth hormone concentration (<5.1 ng/mL for the former and <4.1 ng/mL for
the latter) in a patient who has organic pituitary disease confirms the diagnosis

PROLACTIN The main physiologic role of prolactin is for lactation. Women who have severe
hypopituitarism due to hypothalamic or pituitary disease may, in the postpartum period, have a serum prolactin
concentration that is inappropriately low and not be able to nurse. Routine testing for prolactin deficiency is not
currently performed

TREATMENT hypopituitarism increases long-term mortality, mainly due to cerebrovascular disease.

ACTH DEFICIENCY replacement with hydrocortisone as is the hormone the adrenal glands make normally,
but others prefer prednisone or dexamethasone for their longer durations of action. Most authorities recommend
hydrocortisone doses of 15 to 25 mg/day. Patients who are more severely deficient or weigh more tend to need
doses at the upper end of this range and vice versa .The patient should be instructed in the need for larger doses
in times of illness, surgery, procedures, and other stresses. An inadequate dose may result in persistence (or
recurrence) of the symptoms of cortisol deficiency, while an excessive dose can lead to symptoms of cortisol
excess and to bone loss. Unlike replacement of other pituitary-dependent hormones, no tests exist to assess
objectively the adequacy of the replacement of cortisol ,consequently, the adequacy of the replacement dose
must be judged by the much cruder clinical criteria, such as Cushingoid features when the dose is quite excessive
and symptoms of adrenal insufficiency when the dose is quite insufficient.

Unlike the situation in primary adrenal insufficiency, mineralocorticoid replacement is rarely necessary in
hypopituitarism.

TSH DEFICIENCY T4 (levothyroxine). T4 should not be administered until adrenal function, including
corticotropin (ACTH) reserve, has been evaluated . In a patient with coexisting hypothyroidism and
hypoadrenalism, treatment of the hypothyroidism alone may increase the clearance of the little cortisol that is
produced, thereby increasing the severity of the cortisol deficiency.Measurement of serum TSH cannot be used
as a guide to the adequacy of T4 replacement therapy. Starting with a weight-based T4 dose of 1.6 mcg/kg and
maintain the serum T4 or free T4 values in the middle of the normal range.

LH AND FSH DEFICIENCY

Men Testosterone replacement is indicated in men who have secondary hypogonadism and who are not
interested in fertility. Men with secondary hypogonadism who wish to become fertile can be treated with
gonadotropins if they have pituitary disease or with either gonadotropins or gonadotropin-releasing hormone
(GnRH) if they have hypothalamic disease.

Women Women with hypogonadism due to pituitary disease, who are not interested in fertility, should be
treated with estrogen-progestin replacement therapy. The goal of treatment is not the same as in
postmenopausal women, in whom the goal is to give estrogen and progestin only if necessary to relieve hot
flushes. Instead, the goal of treatment of women of premenopausal age is similar to that of replacement of
thyroxine (T4) and cortisol, ie, to replace the missing hormones as physiologically as possible.Toward this end,
we suggest treatment with estradiol (the estrogen the human ovaries secrete) transdermally, so estradiol is
absorbed into the systemic circulation (as when it is secreted by the ovaries). Women with an intact uterus must
also take a progestin to avoid the risk of endometrial hyperplasia or carcinoma. We also recommend that
estradiol be administered cyclically with progesterone or a progestin. Some clinicians suggest a traditional
regimen of estradiol on days 1 through 25 of each month and progesterone on days 16 through 25 of each month.
The goals are to achieve both a normal late-follicular serum estradiol concentration and menses the patient
considers normal. Another regimen is to give transdermal estradiol continuously throughout the month, with
progestin added days 1 to 10 of the calendar month. This regimen is similar to that used for treatment of
premature ovarian failure

). For women who develop cyclic mood changes (premenstrual syndrome) on either of these regimens, a
continuous daily regimen of both estrogen and a lower dose of progestin is usually better tolerated.

Women with secondary hypogonadism who wish to become fertile should be offered ovulation induction. Women
with GnRH deficiency are candidates for either gonadotropin therapy or pulsatile GnRH, while those with
gonadotropin deficiency due to pituitary disease are candidates only for gonadotropin therapy.

GROWTH HORMONE DEFICIENCY We do not recommend recombinant human growth hormone (GH) as
routine treatment for all patients with adult-onset GH deficiency. Many patients who develop GH deficiency in
adulthood have unfavorable serum lipid profiles, increased body fat, decreased muscle mass, decreased bone
mineral density, and a diminished sense of well-being. There is substantial evidence that GH treatment in these
patients increases muscle mass and reduces body fat. The evidence for improvement in bone mineral density is
good for men but not for women. The evidence concerning improvements in the sense of well-being, muscle
strength, and serum lipids is conflicting.

PROLACTIN DEFICIENCY currently no available treatment.