Are You Sure the Patient Has Hypopituitarism?
Hypopituitarism is defined as partial or complete deficiency in one or more of the hormones produced by the anterior pituitary gland (ACTH, TSH, FSH, LH, GH, prolactin) or posterior pituitary (ADH, oxytocin). Panhypopituitarism refers to decreased production of all of the pituitary hormones of the anterior pituitary (adenohypophysis) with or without deficiency of posterior pituitary (neurohypophysis) function.
The clinical manifestations seen in patients with deficiencies of pituitary hormones that control target glands (ACTH, TSH, and gonadotropins) are generally those of primary deficiencies of target gland hormones, with a few important exceptions.
The presentation and clinical manifestations of hypopituitarism may vary and are determined by the following factors:
Which of the pituitary hormones are affected?
The severity of the deficiency of each affected hormone
The acuity and duration of hormone deficiencies
The age of onset
Patients who have hypopituitarism due to a pituitary tumor or parasellar mass lesion may have symptoms of headache and visual field defects.
In diseases which can affect the whole anterior pituitary the order in which loss of anterior hormone production occurs is often predictable. In most cases, secretion of GH, FSH, and LH decreases before declines in TSH and ACTH levels are observed. Therefore the earliest clinical presentation in children may be growth delay, and in adults hypogonadism.
Exceptions to this rule are not uncommon and isolated pituitary hormone deficiencies, though rare, do occur. Prolactin deficiency is rare and suggests near total destruction of the anterior pituitary gland, such as can be seen with pituitary apoplexy. It should be noted that the most common causes of anterior pituitary failure such as pituitary adenomas and pituitary irradiation do not commonly lead to ADH deficiency(central diabetes insipidus).
ADH deficiency is more commonly caused by lesions affecting the hypothalamus or pituitary stalk and may be caused by trauma (including surgical trauma), parasellar or suprasellar tumors (such as craniopharyngioma or metastases) or infiltrative diseases (e.g., sarcoidosis, Langerhans cell histiocytosis).
Since pituitary hormone deficiencies may be partial and can develop slowly, patients may display few of the expected symptoms or signs. Therefore laboratory testing of patients with suspected hypopituitarism and for those at risk for hypopituitarism is essential.
What are the Clinical Manifestations of Growth Hormone Deficiency (GHD)?
Children with GHD present with short stature and have subnormal growth velocity. Other manifestations include delayed tooth eruption, cherubic appearance and in severe cases, poor muscle development.
Adult growth hormone deficiency (AGHD) is characterized by the following:
Alterations in body composition with increased fat mass and decrease in lean body mass including muscle
Diminished sense of well-being and quality of life
Decreased exercise capacity
Elevations in serum LDL cholesterol
Low bone mineral density
Increased risk of cardiovascular disease
What Are the Clinical Manifestations of Gonadotropin Deficiency (Hypogonadotropic Hypogonadism)?
In males, decreased LH and FSH secretion leads to low testosterone production and infertility. Patients may present with decreased libido, erectile dysfunction, hot flashes and loss of secondary sex characteristics such as muscle mass and body hair. Further examination often will reveal reduced testicular volume, mild anemia, and diminished bone mineral density.
Secondary hypogonadism in females results in loss of ovarian function with anovulation and decreased estrogen production. Clinical features include amenorrhea or oligomenorrhea, osteoporosis, hot flashes, breast atrophy, and vaginal dryness. In women who have both gonadotropin and ACTH deficiency serum androgen levels will be low resulting in loss of sexual hair such as pubic and axillary hair.
Gonadotropin deficiency in children of either gender will result in delayed or absent puberty. The variation in pubertal timing should be taken into consideration when assessing puberty in children. Delayed puberty is defined by lack of signs of sexual maturation (testicular enlargement or breast development) by 14 years in boys and 13 years in girls. In some cases with partial gonadotropin deficiency, patients may develop signs of puberty but will not progress to a fully mature state (more than 5 years after the initial pubertal onset). Growth velocity is often subnormal due to the lack of pubertal growth spurt.
What are the Clinical Manifestations of TSH Deficiency (Secondary Hypothyroidism)?
Patients with TSH deficiency have symptoms and signs of hypothyroidism. These include fatigue, weight gain, cold intolerance, difficulty with memory and concentration, dry skin, hair loss, myalgias, constipation, and hoarseness. Physical exam may reveal bradycardia, dry skin, edema, pallor, and delay in relaxation phase of deep tendon reflexes. Laboratory investigations often show normocytic anemia, hyperlipidemia, and hyponatremia.
Children with hypothyroidism may have growth retardation with increased adiposity. Developmental delay, although not as severe as in primary hypothyroidism, can occur if the condition is not identified early enough. Children with TSH deficiency may not have obvious symptoms and it is important to screen for this condition in patients with suspected hypopituitarism.
What Are the Clinical Manifestations of ACTH Deficiency (Secondary Adrenal Insufficiency)?
Decreased ACTH secretion results in diminished production of cortisol and adrenal androgens, while aldosterone production, which is largely regulated by renin production from the kidneys, remains largely unaffected. Therefore, in contrast to patients with primary adrenal insufficiency, those with secondary adrenal insufficiency do not present with hyperkalemia, salt wasting, and volume contraction nor do they become hyperpigmented.
Mild chronic deficiency in cortisol production may manifest as fatigue, weight loss, anorexia, nausea and abdominal pain. Postural changes, first tachycardia, then hypotension, may be elicited on exam, and laboratory testing may reveal hyponatremia, mild hypoglycemia and eosinophilia. In severe cortisol deficiency, especially in acute deficiency or in patients who are stressed from critical illness, cortisol deficiency may lead to “adrenal crisis” with tachycardia, hypotension and in extreme circumstances death from distributive shock.
What Are the Clinical Manifestations of Prolactin Deficiency?
The only manifestation of diminished lactotroph function is inability to lactate. It is important to note that most patients with hypopituitarism will have normal or slightly elevated prolactin levels except for those with near total absence or destruction of the gland or specific genetic defects.
What Are the Clinical Manifestations of ADH Deficiency (Central Diabetes Insipidus)?
Central diabetes insipidus (DI) will present with polyuria and polydipsia. Patients may present with dehydration and hypernatremia. Production of dilute urine will continue despite water restriction and will improve after administration of ADH (vasopressin) or DDAVP (desmopressin), a longer-acting vasopressing agonist. Mild forms of central DI may be masked by concurrent ACTH deficiency and DI may worsen once treatment of adrenal insufficiency with glucocorticoids is initiated.
Causes/Who Is at Risk?
Hypopituitarism is caused by diseases that affect the pituitary gland itself to decrease hormone production directly, or by disorders affecting the hypothalamus or pituitary stalk that interfere with generation or transmission of hypothalamic releasing factors. The most common cause of hypopituitarism (70-80% of all cases) is pituitary or peripituitary mass lesions or is a consequence of surgery or radiation used to treat such tumors. The common causes of hypopituitarism are summarized in
. The incidence is 1-4 new cases per 100,000 population per year. Hypopituitarism may be acquired or congenital and affects males and females at an equal rate. There are no known variations in incidence-based on ethnic or geographic factors.
Pituitary and Peripituitary tumors
Pituitary adenoma (generally macroadenomas >1 cm in diameter)
CNS tumors (meningioma, glioma, ependymoma, germinoma, chordoma)
Pituitary or CNS irradiation
Infiltrative and Inflammatory Diseases
Langerhans cell histiocytosis
Snake bites in southeast Asia (Russel’s viper bites)
Genetic pituitary or hypothalamic transcription factor defects
Primary empty sella
Congenital hypothalamic dysfunction syndromes (Prader-Willi, Kallmann, septo-optic dysplasia)
Pituitary and Peripituitary Tumors
Mass lesions in the sella can decrease pituitary hormone production by directly compressing the pituitary gland or by interfering with transmission of hypothalamic releasing factors via compression of the pituitary stalk. Patients with such lesions may recover partial or complete pituitary function after decompression of the gland or stalk is achieved by surgical removal of the mass. While pituitary microadenomas (defined as pituitary adenomas measuring <1 cm in diameter) may be associated with excess hormone production they very rarely are a cause of decreased hormone secretion. If hypopituitarism is diagnosed in patients with a small pituitary microadenoma, a cause for hypopituitarism other than the microadenoma should be searched for, or the diagnosis of hypopituitarism should be questioned.
Pituitary or CNS Irradiation
Hypopituitarism frequently develops after radiation treatment of pituitary tumors, other intracranial tumors and head and neck malignancies with an onset anywhere from a few months after radiation until 10 years or more after. Therefore, annual testing of pituitary hormones is advised for patients who have received pituitary radiation.
Traumatic brain injury (TBI) may lead to hypothalamic hormone deficiencies as well as central DI. Hormone deficiencies may improve within a few months after trauma, while other hormone deficiencies may develop within the first year after trauma. Growth hormone deficiency is the most common deficiency and has been linked to mild repetitive head trauma as well as a single head trauma leading to severe TBI.
Acute hemorrhage or infarction of a preexisting pituitary adenoma is referred to as pituitary apoplexy. This may lead to acute hormone deficiencies, the most serious of which is cortisol deficiency. Due to the rapidly expanding sellar mass, patients may experience headache, nausea, vomiting, altered mental status, ophthalmoplegia, and acute visual disturbance. Hormone deficiencies are often permanent, but some resolve spontaneously or as a result of decompressive surgery. Management may be conservative with high dose glucocorticoids and close observation or by urgent surgical decompression, which is especially warranted in cases of neurologic or visual compromise.
Postpartum hemorrhage severe enough to cause hypotension may lead to infarction of the pituitary gland, leading to acute onset of hypopituitarism otherwise known as Sheehan’s syndrome. If deficiencies are mild diagnosis may be delayed and an empty sella may develop.
When the sella turcica is enlarged and not entirely filled with pituitary tissue, it is referred to as an empty sella. This can be primary, in which it is due to a congenital defect in the diaphragma sella and increased CSF within the sella turcica may enlarge the sella. The majority of such patients have entirely normal pituitary function due to a thin rim of functioning pituitary tissue. Secondary empty sella is caused by surgery, trauma, or infarction and is often associated with hypopituitarism. Congenital pituitary transcription factor defects may lead to formation of only a very small pituitary gland and the appearance of an empty sella on imaging studies.
Infiltrative and Inflammatory Diseases
Inflammatory lesions affecting the pituitary or hypothalamus may present with hypopituitarism or with symptoms directly caused by the sellar mass such as headache, ophthalmoplegia, and visual field defects.
Lymphocytic hypophysitis is a relatively rare autoimmune disease in which lymphocytic infiltration of the pituitary gland may lead to subacute onset of pituitary enlargement with partial or complete hypopituitarism. It is seen more commonly in women and is most often diagnosed in late pregnancy or post-partum. In contrast to other causes of hypopituitarism, the most common hormone deficiencies observed with autoimmune hypophysitis are of ACTH and TSH. High-dose glucocorticoid treatment generally will shrink the mass lesion, but recovery of hormone deficiencies is variable and deficiencies are often permanent.
Immune checkpoint inhibitor-associated hypophysitis has been observed in patients treated for several types of cancer including melanoma, renal cell carcinoma and lung cancer. This adverse effect is most common with ipilimumab treatment and has also been reported less commonly with nivolumab/pembrolizumab. Onset of hypophysitis after initiation of cancer therapy is 5-36 weeks. While most oncology guidelines suggest discontinuing the offending cancer therapy and treating with high dose glucocorticoids, some experts have suggested continuing the immune checkpoint inhibition in cases where it has proven effective as an anti-cancer treatment provided the severity of hypophysitis is mild and treatment with hormone replacement is given.
Langerhans cell histiocytosis most commonly leads to ADH deficiency, but may also cause anterior hypopituitarism.
In hereditary hemochromatosis, iron deposition in the pituitary can result in hypogonadotropic hypogonadism and may be reversed by periodic phlebotomy. Other pituitary hormone deficiencies are rare.
Congenital Causes of Hypopituitarism
Congenital hypopituitarism is due to pituitary dysplasia or tissue-specific transcription factor mutations. Pituitary dysplasia can manifest as aplastic, hypoplastic, or ectopic pituitary. Perinatal asphyxia, intracranial hemorrhage, and CNS infection can also cause an early-onset of hypopituitarism.
A number of genetic mutations in genes encoding transcription factors necessary for differentiation of anterior pituitary cells have been described. Defects of genes responsible for early differentiation of pituitary cells (e.g., HESX1, LHX3, LHX4) result in more severe forms of multiple pituitary hormone deficiency (MPHD). Other genetic defects may lead to isolated hormone deficiencies (e.g., GH1, KAL, DAX-1).
PROP-1 gene mutations are the most common known cause of genetic MPHD and may occur as familial MPHD or sporadically. Deficiencies of GH, PRL, FSH, LH, and TSH occur. ACTH deficiency is less common but has been described. The age and order of onset of hormone deficiencies may vary; however, GH deficiency always occurs early in childhood. The pituitary gland is generally small or normal in size but occasionally may appear enlarged.
Defects in the PIT-1 gene lead to decreased GH, TSH, and prolactin secretion, while ACTH and gonadotropins are not affected. Both autosomal dominant and recessive transmissions have been described.
HESX1 mutations result in septo-optic dysplasia (pituitary hypoplasia, optic nerve hypoplasia, and midline defects such as agenesis of the corpus callosum). Patients have panhypopituitarism with deficiencies in all of the anterior pituitary hormones.
Isolated pituitary hormone deficiencies are also associated with a number of known genetic mutations. Among these, defects in TPIT and POMC may cause isolated ACTH deficiency, while KAL1 and FGFR mutations may be found in hypogonadotropic hypogonadism.
What Else Could the Patient Have?
The main consideration in the differential diagnosis of hypopituitary states is distinguishing “secondary” hormone deficiency states, defined as those caused by lack of pituitary hormone secretion, from “primary” hormone deficiencies due to diseases of the target gland.
Another very important consideration is that in persons who have “non-pituitary” illness there may be a functional decrease in secretion of one or more pituitary hormones. For instance critically ill patients will often have decreased circulating IGF-I levels, gonadotropins as well as low serum TSH and thyroxine values. Women with anorexia nervosa and/or intense exercise regimens may have low gonadotropin production referred to as “hypothalamic” or “functional” amenorrhea.
There are many causes of alterations in pituitary hormone production that do not meet the definition of hypopituitarism. Common examples include the relative hypogonadotropic hypogonadism that can be seen with obesity and low IGF-I levels observed in chronic liver disease. In all of these circumstances the alterations in hormone secretion are not due to organic disease of the pituitary or hypothalamus and may be reversed once the underlying causative illness resolves.
Key Laboratory and Imaging Tests
Who should be tested?
Indications for testing for hypopituitarism are a history of pituitary disease (i.e., finding of a sellar mass on imaging) or symptoms suggestive of hypopituitarism, especially in individuals at high risk (i.e., history of cranial irradiation or head trauma). Also, the presence of one or more pituitary hormone deficiencies is a reason to test for the possibility of concurrent subclinical deficiencies in other pituitary hormones.
Screening of the general population is not recommended. Testing of persons with nonspecific symptoms and those at low risk of panhypopituitarism with a full panel of pituitary hormone measurements is also not warranted. In the majority of cases of hypopituitarism hormone deficiencies develop in a predictable order; therefore, in persons with a low index of suspicion for hypopituitarism, evidence of normal gonadotropic function suggests normal pituitary function.
Therefore in women the presence of regular menses (i.e., ovulatory cycles) and fertility makes hypopituitarism unlikely. In postmenopausal women documentation of the expected elevation in FSH suggests adequate pituitary function, and unless there is a high index of suspicion for other pituitary hormone deficiencies, measurements of all of the pituitary hormones may not be necessary in these circumstances.
Which Laboratory Tests Should Be Ordered?
The diagnosis of hypopituitarism requires the demonstration of subnormal target hormone production together with low or inappropriately “normal” levels of the trophic pituitary hormone. Thus a male with low serum testosterone levels without an increase in gonadotropin levels has hypogonadotropic hypogonadism. The finding of a low serum T4 concentration together with a TSH value that is not elevated suggests TSH deficiency (secondary hypothyroidism). This observation underscores the importance of measuring both the pituitary hormone and the target hormone. For instance the diagnosis of secondary hypothyroidism may be entirely overlooked if TSH is measured alone without a concurrent measurement of serum thyroxine.
Since hormone levels may have diurnal variation (of particular significance for cortisol and testosterone) it is recommended to draw blood between 8 and 9 a.m. in a nonstressed individual to determine basal hormone production. For assessment of thyroid hormone production (TSH status) and gonadal function, basal or non-stimulated hormone levels are adequate to make a diagnosis. However, to diagnose ACTH deficiency and GH deficiency, particularly in cases of partial deficiency, determination of basal hormone levels may not suffice and dynamic endocrine testing with stimulatory/provocative tests is often necessary to make a conclusive diagnosis.
Initial laboratory tests to assess for hypopituitarism
Assessment of pituitary function involves assessing each pituitary hormone “axis” individually
Adrenal (HPA) axis: a.m. cortisol
Thyroid axis: TSH and free T4
Gonadal axis: Men – a.m. testosterone, LH, FSH; women – estradiol, LH, FSH, progesterone (day 21 of cycle)
GH axis: IGF-I
Lactotroph axis: PRL
ADH: Plasma and urine osmolality
Dynamic Endocrine Testing in the Diagnosis of Hypopituitarism
Which patients need dynamic testing? Which test should be performed?
Since ACTH and GH are secreted in discrete pulses, low basal levels alone cannot be assumed to indicate deficiency, and stimulatory tests to assess the reserve or capacity of the GH axis and HPA axis are often necessary to diagnose deficiencies of these hormones. Stimulatory tests have also been described to assess gonadotroph function (GnRH test, clomid challenge) and TSH secretion (TRH test), however due to the high general accuracy of basal hormone levels in diagnosing deficiency of these hormones, stimulatory tests are rarely needed to diagnose secondary forms of hypogonadism or hypothyroidism.
Dynamic tests used for diagnosis of ACTH (corticotropin) deficiency
Initial testing to assess adequacy of ACTH production is an early morning serum cortisol level determined at 8 or 9 a.m. Patients taking glucocorticoid replacement other than dexamethasone should be instructed to withhold their dose for 24 hours prior to measurement of serum cortisol to avoid interference from cross-reactivity of the medication with the cortisol assay. A plasma cortisol concentration above 18 mcg/dL (500 nmol/L) is evidence of adequate ACTH production while an early morning cortisol level less than 3 mcg/dl (100 nmol/L) should be considered evidence of adrenal insufficiency.
Measurement of ACTH levels alone are not helpful and ACTH levels should generally be measured only after the cortisol level is determined to be low. The finding of an elevated serum ACTH level in a patient with low morning cortisol levels indicates primary adrenal insufficiency whereas ACTH levels that are low or inappropriately within the normal range concurrent with low cortisol levels suggests secondary adrenal insufficiency due to inadequate pituitary ACTH production.
In situations where early morning levels of cortisol are indeterminate (between 3 and 18 mcg/dl) dynamic testing of the HPA axis are necessary to rule out partial ACTH deficiency. Such tests include the insulin tolerance test (ITT), ACTH stimulation tests, metyrapone test, and glucagon test. There are pros and cons to each of these tests and the decision regarding which test to implement will depend on patient characteristics, availability, and institutional preferences.
ACTH Stimulation Test
Stimulation of adrenal cortisol production by administration of synthetic ACTH (Cosyntropin, Cortrosyn, Synacthen) is the most frequently utilized dynamic test to diagnose adrenal insufficiency, either primary or secondary. The rationale of its use in the diagnosis of ACTH deficiency is that the adrenal glands will atrophy after severe ACTH deficiency, resulting in diminished basal cortisol production and a decreased acute response to stimulation even by high doses of ACTH. Correlation of this test with the ITT and other “classical” tests is extremely high.
The commonly used “high dose” test involves measurement of baseline cortisol and ACTH levels followed by administration of Cortrosyn 0.25 mgIV and measurement of serum cortisol at 30 and 60 minutes after the injection. An adequate response to high-dose ACTH stimulation is considered to be a peak cortisol value above 18 mcg/dL.
This test is ideal for assessing patients suspected of having primary adrenal insufficiency or severe secondary adrenal insufficiency (complete deficiency of ACTH), but may provide false negative results for patients with only partially diminished ACTH production who may therefore respond to a high dose of exogenous ACTH. A low dose 1 mcg Cosyntropin test may lower this false-negative rate and may be the more reliable of the two tests for patient suspected of having ACTH deficiency.
Insulin Tolerance Test (ITT)
Also known as the insulin-induced hypoglycemia test, the ITT has long been considered the gold standard test to assess the integrity of the HPA axis. The purpose of the test is to stimulate ACTH secretion in response to the physiologic stress of hypoglycemia. ITT is contraindicated for elderly patients or those with history of cardiovascular or cerebrovascular disease or seizure disorder. It should be performed by experienced staff in a monitored environment and requires monitoring of blood sugar and for neuroglycopenic symptoms, which may need to be reversed with IV glucose. The protocol for this test involves measuring baseline cortisol and glucose levels followed by an IV bolus of insulin (0.1 unit/kg body weight, higher for patients with insulin resistance) then measuring serum cortisol and glucose values at 15, 30, 60, 90, and 120 minutes. An adequate response to hypoglycemia is defined as a peak cortisol level over 18 mcg/dl once a glucose concentration below 50% of the baseline level or 40 mg/dl (whichever is higher) is achieved. Because hypoglycemia is a stimulant of not only ACTH but also of growth hormone secretion, GH levels are often measured at the same time points to assess patients for coexisting growth hormone deficiency.
Metyrapone decreases cortisol synthesis by blocking 11-beta-hydroxylase, the adrenal enzyme involved in the conversion of 11-deoxycortisol (11-DOC) to cortisol. The purpose of administering metyrapone is to temporarily decrease plasma cortisol levels, which in persons with an intact HPA axis would be expected to result in an increase in ACTH secretion and therefore a peak in 11-DOC levels. Though several protocols for this test exist, the most practical is the single-dose overnight metyrapone test in which the patient is given metyrapone by mouth (30 mg/kg) at midnight with a snack and blood is drawn the following morning between 8 and 9 a.m. for cortisol, ACTH and 11-DOC determination. For reliable interpretation of this test the morning cortisol must decrease to levels below 5 mcg/dl in which case a concurrent serum 11-DOC concentration >7 mcg/dL can be taken as evidence of adequate ACTH “reserve”. Though metyrapone administration generally results in much higher ACTH levels in subjects with an intact HPA axis when compared to those with secondary adrenal insufficiency, there is significant overlap in ACTH levels between the two groups making it impossible to set a reliable cut-off to diagnose ACTH deficiency by assessing only the ACTH response to metyrapone.
Glucagon Stimulation Test
Intramuscular administration of glucagon in adults at a dose of 1 mg (1.5 mg for persons over 90 kg body weight) stimulates both ACTH and GH secretion. When compared to insulin induced hypoglycemia, glucagon is a weaker stimulus of ACTH release. Glucagon testing may be a safer and more practical, although less reliable alternative to the ITT. Patients may experience nausea, vomiting, and abdominal cramping during the test.
Dynamic Testing for the Diagnosis of Growth Hormone Deficiency (GHD)
Who should be tested for GHD?
Since tests for the diagnosis of GHD are imperfect, only those persons at increased risk for GHD should undergo testing. Such individuals are those with known pituitary or parapituitary mass lesions, CNS irradiation, coexisting deficiency of other pituitary hormones, history of head trauma, and children with poor growth. Nonspecific symptoms such as fatigue or weight gain in patients without the above risk factors should not be considered sufficient reason to test for GHD and may lead to false-positive results. The decision to perform testing for GHD may also be influenced by whether the patient is ultimately a candidate for GH replacement.
Since GH is secreted in brief pulses, mostly during sleep, and because persons with normal GH secretion may have very low levels between these pulses on random measurements, determination of unstimulated serum GH levels is usually not helpful in diagnosing GH deficiency. Many of the effects of GH are mediated by IGF-I and due to its long half-life in the circulation, IGF-I levels are of some utility in the diagnosis of GHD. However, it must be kept in mind that IGF-I levels may be low for reasons other than GHD, such as malnutrition or liver disease.
Conversely IGF-I levels in the lower half of the normal range may be seen in more than a third of older adults with proven GHD. Therefore, provocative tests of GH secretion are often needed to diagnose or rule out GHD. One common situation in which a GH provocative testing may be unnecessary is in a patient with a known organic pituitary disease (e.g., macroadenoma) who is already known to have deficiency of multiple other pituitary hormones together with a low serum IGF-I concentration, in which the probability of GHD is almost 100%.
Growth hormone stimulation can be achieved with a variety of tests. The gold standard test is the insulin tolerance test (ITT). GHRH-arginine and glucagon stimulation are also reliable tests. Arginine alone, clonidine, L-DOPA, even in combination, are less reliable and much more likely to provide false-positive results. However, most pediatric endocrinology centers in the United States still use these combinations due to the shorter duration of the test and the availability of the drugs. The exact cutoff values for peak GH levels to diagnose AGHD varies by test and are lower in obese patients, for each of the recommended tests above a peak stimulated GH level of <3 ng/mL is consistent with AGHD. In children, the cutoff level of <10 ng/ml has been accepted for making the diagnosis in the United States. Stimulation with an agonist mimetic of the gut peptide ghrelin has been proposed as a safe, simple test, and preliminary results suggest an accuracy similar to the other riskier tests; but it has still not been widely validated.
Management and Treatment of the Disease
The one pituitary hormone deficiency that may need to be treated emergently is that of ACTH. In severely ill hypopituitary patients, even with coexisting hypothyroidism, glucocorticoids should be administered before or at the same time as thyroid hormone replacement. Replacement of sex steroid and GH deficiency is not emergent and may be instituted after treatment for ACTH and TSH deficiencies commences.
Pituitary apoplexy is an emergency and should always be treated with stress dose glucocorticoids. Urgent neurosurgical consultation is advised and patients exhibiting evidence of progressive neurologic compromise should be considered for urgent surgical decompression.
Occasionally hypopituitarism may be reversed by treatment of the underlying cause (e.g., decompression of the pituitary after surgical treatment for a mass lesion, glucocorticoid therapy for lymphocytic hypophysitis). However, in most cases of hypopituitarism hormone deficiencies are permanent and treatment is aimed at optimizing hormone replacement with hormones of the target glands, similar to treatment of primary deficiencies of the target glands themselves.
Thus the treatment of ACTH deficiency is replacement of glucocorticoids, TSH deficiency is treated by replacement with levothyroxine and sex-steroid replacement is the cornerstone of the management of hypogonadotropism. Direct replacement of pituitary hormones may be used when treating infertility with gonadotropins and when replacing growth hormone.
Ideally, treatment regimens should replicate physiologic hormone levels, though no replacement regimen can exactly achieve the biorhythms of normal pituitary hormone production. Although laboratory monitoring is essential in hypopituitary patients who are treated with hormone replacement therapy, dose titration relies heavily on assessing for clinical symptoms and signs of under-replacement or over-replacement. The aim of treatment is to provide hormone replacement doses sufficient to prevent symptoms of hormone deficiency while monitoring closely for subtle evidence of over-replacement.
Treatment of ACTH Deficiency (Secondary Adrenal Insufficiency)
Production of cortisol and adrenal androgens is primarily regulated by ACTH while aldosterone is generated mainly under the influence of the renin-angiotensin system. Therefore the treatment of ACTH deficiency is primarily that of glucocorticoid replacement. Women with hypopituitarism may benefit from replacement of the adrenal androgen DHEA, although this is still a matter of controversy. In contrast to primary adrenal insufficiency, there is rarely need for mineralocorticoid replacement in hypopituitary patients.
The ideal glucocorticoid replacement regimen is unknown. The most commonly used regimens utilize either hydrocortisone, prednisone, methylprednisolone or dexamethasone at doses identical to those recommended for the treatment of primary adrenal insufficiency. (See chapter on “Adrenal Insufficiency.”) There are advantages and disadvantages to the use of each of these.
Hydrocortisone is the most commonly prescribed glucocorticoid replacement. It is identical to cortisol and when given in two or three divided doses can mimic physiologic levels relatively closely. It is recommended to initiate therapy based on body surface area with 8-12 mg/m2and to titrate the dose over time based on clinical symptoms and signs. Therefore a reasonable regimen would be 10 mg upon rising and 5 mg at noon and again in the early evening. Preliminary studies of a modified-release hydrocortisone preparation have demonstrated more physiologic serum cortisol levels, making this an attractive treatment option in the future.
Dexamethasone is the most potent of the glucocorticoids and has the longest half-life. Average daily requirement is 0.25-0.5 mg. Advantages include once daily dosing as well as lack of interference with cortisol assays. Its main disadvantage is the large variation in rate of metabolism and clearance, and thus effective potency among individuals.
Prednisone can be dosed once daily or in two divided doses and physiologic replacement doses are 2.5-7.5 mg/d. Use of cortisone acetate is not advocated as it requires conversion to hydrocortisone which results in great variability in cortisol levels achieved while on treatment.
Both dexamethasone and prednisone have growth suppression effect in children and should be used only when growth is complete.
Special Considerations in Treatment of Secondary Adrenal Insufficiency
Unfortunately, in contrast to replacement of other hormones, there is no reliable laboratory test that can be used to assess the adequacy of glucocorticoid replacement. Measurements of serum cortisol, salivary cortisol and 24 hour urine cortisol, which are very helpful in assessing cortisol excess, are not useful in titrating doses of hydrocortisone replacement. Insufficient dosing will lead to recurrence of symptoms of adrenal insufficiency and often patients are overtreated which can result in subtle findings of cortisol excess, such as bone loss and hypertension and in more severe cases development of iatrogenic Cushing’s syndrome.
Patients and families should be educated about the need for increased glucocorticoid replacement (“stress dose steroids”) during medical illness and advised to obtain a medic-alert bracelet (See chapter on “Adrenal Insufficiency”).
Glucocorticoid replacement in patients with hypopituitarism may occasionally increase urinary output and “unmask” underlying mild central diabetes insipidus. In patients with multiple pituitary hormone deficiencies, glucocorticoids should be replaced before other hormone therapies are initiated, particularly before thyroid hormone is replaced. Initiating thyroid hormone replacement in an untreated adrenally insufficient individual carries the risk of inducing adrenal crisis.
DHEA at doses of 25-50 mg daily may improve well-being and sexual function in women with hypopituitarism. Not all patients respond to replacement and most available preparations are considered over-the-counter supplements and therefore are not tested or regulated by the FDA.
Treatment of TSH Deficiency (Secondary Hypothyroidism)
Levothyroxine is the preferred treatment of hypothyroidism, of both the primary or secondary varieties. Generally the starting dose is approximately 1.6 mcg/kg/d; however, in persons with only mildly decreased serum thyroxine levels a lower dose may be given initially and adjusted in 4- to 6-week intervals based on serum free T4 levels. In elderly patients or those with ischemic heart disease levothyroxine may be initiated at lower doses (25-50 mcg/d) and titrated slowly. (See chapter on “Hypothyroidism.”) In infants, the starting dose is usually 8-10 mcg/kg/d and is 4-6 mcg/kg/d in older children.
As opposed to the situation with primary hypothyroidism in which serum TSH is the most reliable indicator of adequacy of levothyroxine dose, in hypothyroidism due to pituitary TSH deficiency the serum TSH is an unreliable marker and treatment should be adjusted to obtain serum free T4 levels near the middle of the normal range with careful attention to symptoms and signs of hypothyroidism or iatrogenic hyperthyroidism. Since solid free T4 levels are not completely independent of changes in thyroid binding globulin (TBG), it may be helpful to measure free T4 by equilibrium dialysis when TBG levels differ from the mean, as in women taking oral estrogen.
Treatment of Gonadotropin Deficiency (Hypogonadotropic Hypogonadism)
Treatment of hypogonadism due to pituitary gland failure depends on whether fertility is desired, in which case treatment with gonadotropins or GnRH is indicated. Otherwise treatment consists of replacement of the deficient sex steroids similar to treatment of hypogonadism from any cause. (See chapters on “Treatment of Male Hypogonadism” and on “Treatment of Female Hypogonadism”).
Treatment of Hypogonadotropic Hypogonadism in Men
Testosterone replacement in men is beneficial in reversing symptoms of hypogonadism and has additional benefits on bone and muscle mass as well as erythropoiesis. Past preparations for oral testosterone replacement included methylated testosterone esters which were associated with an increased risk of liver tumors.
Commonly used forms of testosterone replacement include injectable testosterone esters (i.e., 100 mg I.M. weekly or 200 mg every 2 weeks), transdermal testosterone patches and gels, implantable subcutaneous pellets (400-600 mg Q4-6 months), and buccal preparations. (See chapter on “Treatment of Male Hypogonadism.”) Recent guidelines have emphasized the importance of following patients with annual assessments of testosterone levels, PSA, hematocrit, and prostate exam.
Induction of spermatogenesis can be achieved by injections of hCG (2000 IU SC three times weekly), which has the biological activity of LH, followed if necessary by addition of FSH (300 IU SC three times weekly). (See chapter on “Treatment of Male Infertility.”)
In boys, Testosterone treatment is usually started at a low dose (50 mg monthly) with a gradual increment to reach the adult dose in 2 years.
Treatment of Hypogonadotropic Hypogonadism in Women
All hypopituitary women under the age of 50 should receive estrogen replacement, preferably with transdermal estradiol. Women with an intact uterus should also receive progesterone replacement to protect the endometrium from the deleterious effects of unopposed estrogen. (See chapter on “Treatment of Female Hypogonadism.”) Women who wish to become pregnant should be offered ovulation induction. For those with GnRH deficiency pulsatile GnRH therapy may be an option, while women with either GnRH deficiency or gonadotropin deficiency can be treated with gonadotropin replacement. (See chapter on “Treatment of Female Infertility.”)
In girls, the replacement is usually started with estrogen alone. The dose is gradually increased and progesterone is usually added after 2 years of estrogen replacement.
Treatment of Growth Hormone Deficiency (GHD)
Adult Growth Hormone Deficiency (AGHD)
GH replacement may reverse many of the symptoms and signs of AGHD. Potential benefits include improvements in body composition, sense of well-being, bone density, lipid profile, exercise capacity, and quality of life. Patient selection remains controversial and not all patients benefit similarly from GH replacement. Adverse effects result mainly from sodium and fluid retention and can be avoided by initiating treatment with low doses and careful dose titration.
Side effects may include soft tissue swelling and edema, arthralgias, myalgias, headache, and carpal tunnel syndrome. In adults it is recommended to start replacement with a relatively low dose of HGH (somatropin) 0.2- 0.3 mg SC daily (lower in elderly patients) and titrate the dose upward in 0.1-0.2 mg increments at 4-8 week intervals based on side effects and serum IGF-I levels, targeting levels in the upper half of the age and sex matched reference range.
GH replacement is contraindicated in patients with active malignancies; however, in surveillance studies it has not been demonstrated to increase incidence of new tumors or to cause increased risk of progression or recurrence of pituitary adenomas.
Growth Hormone Deficiency in Children
The aim of treatment is to achieve a familial-targeted height. The starting dose is between 25-50 ug/kg/day, 6-7 days per week. The dose is adjusted based on patient’s weight and growth velocity. Monitoring of serum IGF-1 to prevent an excessive dose has also been commonly used. The possible side effects include headaches, increased intracranial pressure, scoliosis and slipped capital femoral epiphysis (SCFE). Pediatric endocrinologists often use bone age study to determine if the treatment should be discontinued (typically bone age of 16-17 years in boys and 15 years in girls).
Integration of Pituitary Hormone Replacement Therapy
Several potential interactions exist for patients treated with multiple hormone replacement therapies. Initiation or change in replacement regimen for one pituitary hormone deficiency may lead to a change in dose requirements of other hormone replacements. The commencement of thyroxine replacement in an underreplaced adrenally insufficient patient may cause increased clearance of cortisol leading to symptoms of adrenal insufficiency.
Estrogen therapy often leads to a need for increased dosing of thyroxine and GH as a result of its effect to increase thyroxine binding globulin (TBG) and to decrease GH-mediated IGF-I production. Patients started on GH replacement may experience a slight decrease is serum free T4 levels and reduced conversion of cortisone to cortisol, this last consideration being most clinically relevant in those patients taking cortisone acetate (
|Deficient Hormone||Replacement Regimen||Monitoring|
|ACTH||Hydrocortisone 15-25 mg/d in 2-3 divided doses (e.g., 10 mg PO a.m. and 5 mg PO p.m.)
Prednisone or methylprednisolone 2.5-5 mg PO once daily
Dexamethasone 0.25-1 mg PO once daily
|Measurement of serum cortisol is not useful
Monitor for clinical symptoms and signs of under/over-replacement
|TSH||Levothyroxine 1.6-2 mcg/kg PO once daily
Starting dose may be lower (e.g., 25 mcg total daily) in elderly patients, those with CVD or for patients with only partial or mild TSH deficiency
|Serum free T4|
Testosterone gel applied to skin 50-100 mg daily
Estradiol transdermal patch (0.5-0.75 mg once or two times weekly)
|Serum testosterone and free testosterone
Monitor for regular periods and symptoms and signs of estrogen deficiency
|GH||Somatropin (HGH), initiate at 0.1-0.3 mg SC and titrate every 4-8 weeks based on IGF-I or side effects||serum IGF-I|
|ADH (vasopressin)||DDAVP (desmopressin)
Intranasal: 10-20 mcg (1-2 sprays) once or twice daily
Oral: 0.1-0.4 mg PO once or twice daily
Subcutaneous: 0.5-1 mcg SC once or twice daily
urine volume and urine osmolality
Significant decreases in quality of life, morbidity, and mortality have been associated with hypopituitarism. Patients often develop a phenotype similar to that of the metabolic syndrome with increased adiposity, decreased lean body mass and an increase in CVD risk factors. Optimization of hormone replacements as well as aggressive monitoring and treatment for CVD risk factors may improve outcomes. There may also be an increased risk of osteoporosis and fractures in this population warranting surveillance of bone density.
Patients should have at least annual evaluation by an endocrinologist experienced in managing hypopituitarism with both clinical and laboratory assessment of the adequacy of current hormone replacements and for complications associated with hypopituitarism or of over-replacement of hormones. Patients with known sellar mass lesions should have periodic imaging of the sella, preferably with contrast enhanced MRI.
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- Are You Sure the Patient Has Hypopituitarism?
- What are the Clinical Manifestations of Growth Hormone Deficiency (GHD)?
- What Are the Clinical Manifestations of Gonadotropin Deficiency (Hypogonadotropic Hypogonadism)?
- What are the Clinical Manifestations of TSH Deficiency (Secondary Hypothyroidism)?
- What Are the Clinical Manifestations of ACTH Deficiency (Secondary Adrenal Insufficiency)?
- What Are the Clinical Manifestations of Prolactin Deficiency?
- What Are the Clinical Manifestations of ADH Deficiency (Central Diabetes Insipidus)?
- Causes/Who Is at Risk?
- Pituitary and Peripituitary Tumors
- Pituitary or CNS Irradiation
- Head Trauma
- Pituitary Apoplexy
- Sheehan's Syndrome
- Empty Sella
- Infiltrative and Inflammatory Diseases
- Congenital Causes of Hypopituitarism
- What Else Could the Patient Have?
- Key Laboratory and Imaging Tests
- Management and Treatment of the Disease
- Treatment of ACTH Deficiency (Secondary Adrenal Insufficiency)
- Special Considerations in Treatment of Secondary Adrenal Insufficiency
- Treatment of TSH Deficiency (Secondary Hypothyroidism)
- Treatment of Gonadotropin Deficiency (Hypogonadotropic Hypogonadism)
- Treatment of Hypogonadotropic Hypogonadism in Men
- Treatment of Hypogonadotropic Hypogonadism in Women
- Treatment of Growth Hormone Deficiency (GHD)
- Adult Growth Hormone Deficiency (AGHD)
- Growth Hormone Deficiency in Children
- Integration of Pituitary Hormone Replacement Therapy