Hypopituitarism (Panhypopituitarism)

Updated: Nov 10, 2022
Author: Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Practice Essentials

Hypopituitarism is a clinical syndrome of deficiency in pituitary hormone production.[1, 2] This may result from disorders involving the pituitary gland, hypothalamus, or surrounding structures. Panhypopituitarism refers to the involvement of all pituitary hormones; however, if one or more, but not all, pituitary hormones are involved, this results in partial hypopituitarism.[2]  (Pituitary hormones are also known as central hormones.) (See Pathophysiology and Etiology.)

Pituitary gland physiology

The pituitary gland is divided into two parts: the anterior pituitary (adenohypophysis) and the posterior pituitary (neurohypophysis). The anterior pituitary receives signals from the hypothalamus that either stimulate or inhibit the secretion of pituitary hormones. These signals are in form of hormones, which are secreted directly into the systemic circulation, where they act on specific organs.

The actions of the pituitary gland can be modulated at many stages. The pituitary hormones, or target-organ hormones, can influence the hypothalamus and the pituitary to decrease or increase pituitary hormone secretion through long and short feedback loops. Hormones secreted by the anterior pituitary include the following:

  • Thyrotropin, or thyroid-stimulating hormone (TSH)
  • Gonadotropins, or follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
  • Somatotropin or growth hormone (GH)
  • Corticotropin, or adrenocorticotropic hormone (ACTH)
  • Mamotropin, or prolactin

Between the anterior and posterior part of the pituitary gland there is a segment called the pars intermedia. This region does not have any function.

The posterior pituitary does not produce its own hormones. The hypothalamus produces two hormones, vasopressin (VP) and oxytocin (OXT), that are secreted from the nerve axons into the capillary beds that supply the posterior pituitary, where they are stored in cells and ultimately released into the circulation.

Vasopressin, also called antidiuretic hormone (ADH), primarily acts on the V2 receptors of the distal tubules of the kidney to reabsorb water, which increases total body water and urine osmolality and decreases urine volume. Vasopressin, at high levels, also acts as a pressor on the V1 receptors of vascular smooth muscle. Oxytocin induces labor in pregnant women, causing contraction of uterine smooth muscle; the hormone also initiates the mechanics of breastfeeding. Other functions of oxytocin are still under investigation.

Adrenal crisis

An adrenal crisis (acute cortisol insufficiency), the most severe complication of hypopituitarism, is life threatening and should be treated promptly. When hypothyroidism occurs concurrently with cortisol insufficiency, glucocorticoid replacement should precede thyroid hormone replacement. This reduces the likelihood of possible cortisol insufficiency resulting from increased demands due to enhanced metabolism. (See Treatment and Medication.)

Hormone replacement

Patients with hypopituitarism are maintained on hormone replacement therapies for life unless the causative disorder is reversed by treatment or by natural history. These medically replaced patients are generally asymptomatic but require increased doses of glucocorticoids following any form of stress, emotional or physical. The most common stressor is infection. Not matching glucocorticoid dose to stress causes acute decompensation. These patients present with nausea and vomiting and may be hypotensive and ill-appearing. A patient's initial presentation of undiagnosed hypopituitarism may be with this life-threatening decompensated state under stress.

Signs and symptoms of hypopituitarism

These include the following, according to the specific hormone deficiency:

  • TSH deficiency - Hypothyroidism
  • Gonadotropin deficiency - Hypogonadism
  • GH deficiency - Failure to thrive and short stature in children; most adults are asymptomatic, but some may experience fatigue, weakness, alteration in body composition (increased fat mass relative to lean body mass), and decreased quality of life
  • Antidiuretic hormone (ADH) deficiency - Polyuria and polydipsia
  • Prolactin deficiency - Impaired lactation after delivery 

Workup in hypopituitarism

Hormonal studies should be performed in pairs of target glands and their respective stimulatory pituitary hormone for proper interpretation, as follows[3] :

  • ACTH (Cortrosyn) stimulation test (or morning cortisol and ACTH)
  • TSH and free thyroxine (free T4)
  • FSH, LH, and either estradiol (if amenorrheic) or morning testosterone (as appropriate for gender)
  • Prolactin
  • GH provocative testing with various stimulation tests
  • Insulinlike growth factor 1 (IGF-1) levels

In the presence of clinical or biochemical evidence of hypopituitarism, visualization of the sellar/suprasellar areas is needed to identify the nature of the causative disease process. This is best accomplished through computed tomography (CT) scanning or magnetic resonance imaging (MRI).

Management of hypopituitarism

Medical care consists of hormone replacement as appropriate and treatment of the underlying cause. Glucocorticoid (cortisol) is required if the ACTH-adrenal axis is impaired.[4]

Treat gonadotropin deficiency with gender-appropriate hormones. In men, testosterone replacement is used and is substituted with human chorionic gonadotropin (hCG) injections if the patient desires fertility. In women, estrogen replacement is used with or without progesterone as appropriate.

GH is replaced in children as appropriate. GH is not routinely replaced in adults unless the patient is symptomatic of GH deficiency after all other pituitary hormones have been replaced. Then, a 6-month trial of replacement GH therapy may be considered.

Surgical care in hypopituitarism depends on the underlying cause and clinical state. In pituitary apoplexy, prompt surgical decompression may be lifesaving if head imaging reveals clinically significant tumor mass effect. Microadenomas do not need surgical treatment unless GH or ACTH hypersecretion is present. Prolactinomas, small and large, generally respond to medical therapy with tumor shrinkage and alleviation of mass symptoms.

Debulk macroadenomas with mass symptoms that do not respond to medical therapy or are not expected to respond to medical therapy. Some asymptomatic nonsecreting macroadenomas may have an option of close clinical/radiologic observation. If radiotherapy is used, long-term new-onset hypopituitarism may occur and must be monitored.

Patient education

Education emphasizes the need for lifelong hormone replacement, increased glucocorticoid replacement during stress, having an alert bracelet that indicates the deficiencies, and prompt medical attention as appropriate. Regular monitoring to avoid excessive hormone replacement is important.

Furthermore, a patient with secondary adrenal insufficiency should have an emergency kit that includes a vial of high-dose hydrocortisone (Solu-Cortef) or dexamethasone, and a syringe .

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 or inappropriately normal 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.

Thus, pituitary function is assessed by the target gland function, not by measuring the pituitary hormone as an isolated event. As a result, the entire loop (pituitary and target organ) needs to be measured. This is in contrast to target gland function being assessed by the pituitary hormone. For example, adequate pituitary thyrotropin (TSH) secretion is best assessed by serum free T4. Primary thyroid gland hypofunction is best assessed by serum thyrotropin. The presence of a low serum free T4, with normal serum thyrotropin, indicates pituitary, not thyroid, disease, and central hypothyroidism would be missed by measuring only serum thyrotropin.

Etiology

Causes of hypopituitarism include pituitary adenomas or other intrasellar and parasellar tumors, inflammatory and infectious destruction, surgical removal, radiation-induced destruction of pituitary tissue, traumatic brain injury (TBI), subarachnoid hemorrhage, and postpartum pituitary infarction (Sheehan syndrome). Similar diseases originating in the hypothalamus or pituitary stalk may also result in pituitary insufficiency. Children may have a genetic cause of transcription factor deficiency, resulting in trophic hormone hyposecretion.

Pituitary tumors, or adenomas, are the most common cause of hypopituitarism in adults, although traumatic brain injury as a cause is being more frequently recognized.

Hypopituitarism resulting from pituitary adenomas is due to impaired blood flow to the normal tissue, compression of normal tissue, or interference with the delivery of hypothalamic hormones via the hypothalamus-hypophysial portal system.

In primary pituitary destruction, the anterior pituitary is destroyed, causing a deficiency in some or all pituitary hormones, including prolactin. Disease involving the hypothalamus or pituitary stalk may cause pituitary hormone deficiency with an elevated serum prolactin. This prolactin elevation may suggest the possibility of recovery of function if the offending mass is debulked. Pituitary tumors, or adenomas, can be secretory or nonsecretory. Approximately 30% of all macroadenomas larger than 10 mm produce at least 1 hormone. In such cases, the most common phenomenon is prolactin hypersecretion.

Hypothalamic disease involves destruction of the hypothalamus. This causes a deficiency or loss of hypothalamic regulatory hormone input to the pituitary, which leads to the loss of anterior pituitary hormone secretion, with an elevated serum prolactin level. Loss of antidiuretic hormone (ADH) from hypothalamic disease may have concomitant diabetes insipidus.

Hypersecretion of a pituitary hormone is suggestive of a secretory adenoma. Some pituitary adenomas may result in a deficiency in some pituitary hormones, but with concomitant hyperprolactinemia. Normally, dopamine, produced in the hypothalamus, inhibits prolactin secretion by the anterior pituitary. Compressing the pituitary stalk decreases the inhibitory effect of dopamine and increases prolactin levels.

Longstanding target gland hyposecretion may result in hyperplasia of the relevant pituitary cell secreting the trophic hormone, the level of which would be elevated. With an enlarged pituitary gland from the hyperplasia, a mass is simulated. Although uncommon, this may appear to be a pituitary adenoma, but the target gland is not hyperfunctioning.

Another common intracranial tumor is craniopharyngioma, a squamous cell tumor that arises from remnants of the Rathke pouch. One third of these tumors extend into the sella, while approximately two thirds remain suprasellar.

Sheehan syndrome occurs with a large volume of postpartum hemorrhage. During pregnancy, the pituitary gland enlarges due to hyperplasia and hypertrophy of the lactotroph cells, which produce prolactin. The hypophyseal vessels, which supply the pituitary, constrict in response to decreasing blood volume, and subsequent vasospasm occurs, causing necrosis of the pituitary gland. The degree of necrosis correlates with the severity of the hemorrhage. As many as 30% of women experiencing postpartum hemorrhage with hemodynamic instability may develop some degree of hypopituitarism. These patients can develop adrenal insufficiency, hypothyroidism, amenorrhea, diabetes insipidus, and an inability to breastfeed (an early symptom). Lymphocytic hypophysitis occurs most commonly in the postpartum state and may appear as Sheehan syndrome due to the resulting postpartum hypopituitarism.

Pituitary apoplexy denotes the sudden destruction of the pituitary tissue resulting from infarction or hemorrhage into the pituitary. The most likely cause of the apoplexy is brain trauma; however, it can occur in patients with diabetes mellitus, pregnancy, sickle cell anemia, blood dyscrasias or anticoagulation, or increased intracranial pressure. Apoplexy usually spares the posterior pituitary and solely affects the anterior pituitary. In patients with such underlying diseases, Sheehan syndrome can occur with lesser degrees of postpartum hemorrhage or hypotension.

Head trauma from a motor vehicle accident, a fall, or a projectile can cause hypopituitarism by direct damage to the pituitary or by injuring the pituitary stalk or the hypothalamus. Hypopituitarism may occur immediately, or it may develop months or years later. Recovery can occur from regeneration. Many studies show an incidence of 15-40%,[5] but a study by Kokshoorn et al found the incidence of clinically significant posttraumatic hypopituitarism to be low.[6]

In a study by Giuliano et al of hypopituitarism in adults associated with complicated mild traumatic brain injury, consequent GH deficiency existed in a subset of patients even several years postinjury. Visceral adiposity and metabolic changes were associated with the deficiency.[7]

Other causes of hypopituitarism include empty sella syndrome and infiltrative diseases. Empty sella syndrome occurs when the arachnoid herniates into the sella turcica through an incompetent sellar diaphragm and flattens the pituitary against bone, but resulting pituitary insufficiency is uncommon. Infiltrative diseases, such as Wegener granulomatosis and sarcoidosis, can cause destruction of the anterior pituitary. Lymphocytic hypophysitis is an autoimmune destructive disease that may be directed towards the pituitary or its stalk.

Physiologic or psychological states can influence the hypothalamus by impairing synthesis and secretion of regulating hormones. For example, poor nutrition may impair the hypothalamic secretion of gonadotropin-releasing hormone (GnRH), resulting in reversible pituitary gonadotropin deficiency. Medications may affect measured hormone levels, such as opioids decreasing serum LH, testosterone, and cortisol.

The degree of hormone deficiency varies greatly and depends on the extent of the process and its location. Some functional causes include emotional disorders, changes in body weight, habitual exercise, anorexia, bulimia, congestive heart failure (CHF), renal failure, and certain medications.

Hypopituitarism can occur in adult patients after cranial radiotherapy performed to treat nonpituitary tumors. Thus, patients who undergo cranial radiotherapy should be periodically assessed over a period of years for pituitary functions.[8]

Additional causes of hypopituitarism include the following:

  1. Histiocytosis X

  2. Hemochromatosis

  3. Tuberculosis

  4. Syphilis

  5. Meningitis

  6. Iatrogenic causes - Radiation,[8, 9] surgery, and withholding of chronic glucocorticoid replacement

  7. Kallmann syndrome

  8. Lymphocytic hypophysitis

  9. Transsphenoidal adenomectomy

  10. Congenital - Usually presents in childhood, but can present later with features such as delayed puberty; heritable pituitary disease usually involves homeodomain transcription factors[10]

  11. Immune checkpoint inhibitor–induced hypophysitis

With regard to item 9 above, in a study of 435 patients, Fatemi et al found evidence that the likelihood of hypopituitarism development after transsphenoidal adenoma removal is higher when the tumor is larger than 20 mm.[11] In contrast, some with hypopituitarism prior to adenomectomy may have improved pituitary function following surgery, if the cause of the hypopituitarism was increased suprasellar pressure resulting from the mass itself.

Epidemiology

Hypopituitarism is listed as a rare disorder by the National Institutes of Health (NIH), affecting less than 200,000 individuals in the United States. Internationally, hypopituitarism has an estimated incidence of 4.2 cases per 100,000 per year and an estimated prevalence of 45.5 cases per 100,000 (without gender difference).

Regal et al reported the first study detailing prevalence and incidence of hypopituitarism in a population in northwestern Spain. They studied an adult population of 146,000 and found a prevalence of 45.5 cases per 100,000 population.[12]

Generally speaking, the incidence of permanent pituitary deficiency following traumatic brain injury (TBI) is underestimated. The incidence/prevalence of hypopituitarism following TBI varies significantly between studies, with Gray et al finding, through the use of different reports, the prevalence of TBI-associated hypopituitarism to be 15-90%.[13]  A systematic review of 13 observational studies found an estimated prevalence of 27.5% for chronic phase anterior hypopituitarism following TBI.[14]

Hypopituitarism may also develop following intracranial bleeding, particularly in cases of aneurysmal subarachnoid hemorrhage (SAH). A systematic review found the pooled prevalence of hypopituitarism following aneurysmal SAH to be 31% at 3-6 months and 25% at over 6 months.[15]

Prognosis

Stable patients who are diagnosed with hypopituitarism have a favorable prognosis with replacement hormone therapy. These patients are monitored every year for central hormones, with replacement therapy adjusted as needed. However, patients with acute decompensation are in critical condition and may have a high mortality rate.

Mortality/morbidity

Four retrospective studies from the United Kingdom and Sweden showed that mortality is increased by 1.3- to 2.2-fold in patients with hypopituitarism, compared with age- and sex-matched cohorts.[16] Morbidity is variable and may result from hormone deficiency, from the underlying disease, or from inadequate long-term replacement therapy. The systemic effects of pituitary hormone deficiencies vary depending on the extent of pituitary involvement. Given that the pituitary acts on numerous endocrine sites, the consequences of pituitary dysfunction range from subclinical disease to panhypopituitarism. Underlying disorders, such as tumors, intracranial lesions, or systemic disease, may be asymptomatic or may cause morbidity that masks the hormone deficiency. Note the following:

  • Deficiency of ACTH with adrenal crisis or TSH with myxedema may be life threatening

  • GH deficiency causes more morbidity in children than in adults

  • There is a suggestion of increased cardiovascular disease resulting from GH deficiency

  • Sudden compromise of ACTH production may result in more profound morbidity than slowly progressive deficiency

  • Gonadotropin deficiency with hypogonadism may insidiously cause morbidity

  • Morbidity is more profound in congenital hypopituitarism

  • Inappropriate replacement therapy with thyroxin, glucocorticoids, or sex steroids may be associated with long-term morbidity

A study by O’Reilly et al indicated that in patients with hypopituitarism resulting from nonfunctioning pituitary adenomas, deficiencies of ACTH and gonadotropin increase mortality rates, as do excessive doses of hydrocortisone and suboptimal replacement of levothyroxine. The study included 519 patients, with a median follow-up of 7.0 years.[17]

Cardiovascular disease is significantly higher among hypopituitary patients.[18] Female patients with hypopituitarism who are receiving controlled thyroid and steroid hormone substitution, but without GH replacement, have a more than 2-fold increase in cardiovascular mortality compared with the general population.[18] Hypopituitary patients have a lower high-density lipoprotein cholesterol level and a higher low-density/high-density lipoprotein ratio.[18]

However, a literature review by Giagulli et al indicated that neither short- nor long-term GH supplementation significantly reduces cardiovascular risk in adults with a GH deficit resulting from either isolated GH deficiency or compensated panhypopituitarism. Nonetheless, both groups of patients in the study did show an increase in fat-free mass, a decrease in fat mass, and a reduction in low-density lipoprotein cholesterol.[19]

A retrospective study by Abe et al indicated that metabolic syndrome is common in adults with hypopituitarism. The investigators found that out of 99 adult patients with hypopituitarism, the prevalence of metabolic syndrome, which overall was 39.4%, was significantly greater in patients over age 50 years, with higher body mass index (BMI) and untreated GH deficiency also being risk factors for the syndrome. Metabolic syndrome in patients with hypopituitarism was particularly characterized by a reduced high-density–lipoprotein cholesterol level.[20]

There is a higher incidence of cerebrovascular morbidity and mortality following pituitary radiotherapy.

Other complications of hypopituitarism include visual deficits and, due to a limited ability of the endocrine system to respond appropriately, susceptibility to infection and other stressors. Decreased quality of life has been documented by standardized questionnaires.

Hypopituitarism and COVID-19

A study by Frara et al suggested that a bidirectional interplay exists between hypopituitarism and coronavirus disease 2019 (COVID-19). On the one hand, hypopituitarism renders patients more susceptible poor outcomes in COVID-19, due to underlying metabolic alterations leading to complications such as diabetes mellitus, obesity, and vertebral fractures.[21] On the other hand, COVID-19 may induce local vascular events that can directly or indirectly damage the pituitary gland, resulting in loss of glandular function.

 

Immune Checkpoint Inhibitors and Hypopituitarism

Hypophysitis is a common endocrinologic side effect attributed to immune checkpoint inhibitors, which have been used in cancer therapy. Hypophysitis has particularly been found to occur with the use of CTLA-4 antibodies and with combination therapy.[22] The most common axes affected are the gonadal, thyroid, and adrenal axes, with the affect on the gonadal axis leading to hypogonadism, that on the thyroid axis causing hypothyroidism, and the affect on the adrenal axis resulting in central adrenal insufficiency.

It is important to perform a hormonal workup on patients who are taking immune checkpoint inhibitors and who present with signs and symptoms of adrenal insufficiency, hypothyroidism, and/or hypogonadism.

 

Presentation

History

Presentation varies from asymptomatic to acute collapse, depending on the etiology, rapidity of onset, and predominant hormones involved. Initially, a patient with any hormone deficiency may be asymptomatic. Individuals with the following deficiencies present with the indicated condition:

  • ACTH deficiency - Adrenal (cortisol) insufficiency

  • TSH deficiency - Hypothyroidism

  • Gonadotropin deficiency - Hypogonadism

  • GH deficiency - Failure to thrive and short stature in children; most adults are asymptomatic, but some may experience fatigue, weakness, alteration in body composition (increased fat mass relative to lean body mass), and decreased quality of life. 

  • ADH deficiency - Polyuria and polydipsia

  • Prolactin deficiency - Impaired lactation after delivery 

Other presenting features may be attributable to the underlying cause. A patient with a space-occupying lesion may present with headaches, double-vision, or visual-field deficits. A patient with large lesions involving the hypothalamus may present with polydipsia/polyuria or, rarely, syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Physical Examination

Physical examination findings may be normal in subtle presentations. Patients may present with features attributable to deficiency of target hormones, including hypothyroidism (with a small, soft thyroid gland), adrenal insufficiency, hypogonadism (with small, soft testes in men), and failure to thrive. In women, loss of adrenal and ovarian function results in loss of all androgens; loss of axillary and pubic hair may result.

In the stable patient, with the diverse complaints associated with hypopituitarism, a complete physical examination, including thyroid palpation, genital inspection, and ophthalmic examination, can support the diagnosis of hypopituitarism. During the neurologic and ophthalmic examinations, check specifically for visual acuity, extraocular movements, and bitemporal hemianopsia. Also look for evidence of hormonal hypersecretion due to a large functioning adenoma, such as signs of Cushing disease, acromegaly, or galactorrhea.

 

DDx

Diagnostic Considerations

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. Blood could be drawn to measure serum cortisol and ACTH prior to initiating glucocorticoid therapy. Adrenal replacement should precede thyroxine (T4) replacement to avoid a possible acute cortisol insufficiency state.

Hypopituitarism may manifest several years after radiation exposure and in chronic Sheehan syndrome. In acute pituitary failure, as in Sheehan syndrome, the ACTH stimulation test may be normal because the adrenal glands are not atrophied in the acute setting, requiring at least 3 months.

Differential Diagnoses

 

Workup

Approach Considerations

Hormonal studies should be performed in pairs of target glands and their respective stimulatory pituitary hormone for proper interpretation, as follows[3] :

  • ACTH (Cortrosyn) stimulation test (or morning cortisol and ACTH)

  • TSH and thyroxine (free T4)

  • FSH, LH, and either estradiol (if amenorrheic) or morning testosterone (as appropriate for gender)

  • Prolactin

  • GH provocative testing with various stimulation tests

  • IGF-1 levels

Corticotropin deficiency may be evident with the finding of a decreased serum cortisol level. However, a low cortisol level may not help to distinguish primary adrenal insufficiency from secondary adrenal insufficiency due to hypopituitarism. The conditions can be differentiated on clinical grounds. A patient with secondary causes due to pituitary dysfunction has a relatively pale complexion (not hyperpigmented), a normal aldosterone response, normal serum potassium, and low/normal morning ACTH level, measured in the morning due to its highest circadian levels. Hyponatremia may occur.

The opposite is true for primary adrenal insufficiency. Hyperpigmentation in primary adrenal insufficiency is due to increased ACTH production with concomitant overproduction of melanocyte-stimulating hormone, which is coupled with ACTH in a mutual precursor. ACTH elevation, measured any time, suggests an adrenal etiology. Hyperkalemia may be present, owing to concomitant aldosterone deficiency, which does not occur with ACTH insufficiency. Hyponatremia may result from cortisol insufficiency, and thus does not separate pituitary from adrenal disease.

Histologic findings in hypopituitarism depend on etiology (eg, tumors, infiltrations, infections, empty sella). Other tests to ascertain the likely underlying etiology are indicated by the patient's presentation.

ACTH (Cortrosyn) Stimulation Test

The ACTH stimulation test, which evaluates the hypothalamic-pituitary-adrenal axis, is a superior tool in the diagnosis of adrenal insufficiency, but it does not generally separate pituitary from adrenal causation. This dynamic test measures serum cortisol levels before and after a 1- or 250-mcg dose of ACTH. The cortisol level should be greater than 500 pmol/L (may be  less in some assays) 30 minutes after ACTH administration in patients with normal adrenal function.

A low cortisol level that fails to rise after ACTH administration represents an abnormal cortisol response, a response seen in primary adrenal insufficiency. However, because of adrenal atrophy with chronic ACTH insufficiency, the cortisol response is often abnormal in patients with hypopituitarism. A poor response requires the serum ACTH, or other clinical clues, to separate pituitary from primary adrenal disease.

Other provocative tests for ACTH/cortisol function are the insulin-induced hypoglycemia test and the glucagon stimulation test. These may be needed within the acute stage of ACTH deficiency, such as following pituitary surgery.

TSH and Thyroxine

Assessment of thyroid function is important in the evaluation of ACTH deficiency. In a hypothyroid state, cortisol clearance decreases, causing an increase in the serum cortisol level. If thyroid replacement is initiated, the cortisol level may be inappropriate to the new state, initiating an adrenocortical crisis.

In suspected TSH deficiency, measure serum TSH and thyroxine. A normal level of total free T4 rules out hypothyroidism. A low thyroxine and low/normal serum TSH and a small, soft thyroid gland confirm the diagnosis of TSH deficiency.

FSH, LH, and Estradiol or Testosterone

LH and FSH deficiencies may indicate secondary hypogonadism. Elevated FSH and LH levels differentiate primary hypogonadism from secondary hypogonadism. A low testosterone level in a man, or an amenorrheic woman with low estradiol and low/normal serum FSH/LH, indicates secondary hypogonadism.

In men, measuring testosterone levels is useful, if properly performed. A decreased testosterone level should be associated with an increase in FSH and LH levels if pituitary function is normal. Low or normal FSH or LH levels in the face of low testosterone indicate hypopituitarism. Serum testosterone is best measured early in the morning owing to a diurnal rhythm that falls through the day. There may be other causes of a low testosterone level, such as poor nutrition, stress, hyperprolactinemia, or chronic opioid use. A low level of sex hormone binding protein may give a low total testosterone level (but with the free testosterone level being normal). A finding of low total testosterone needs to be confirmed with a repeat test, which should include a measurement of non-protein-bound (free) testosterone.

Semen analysis also may be performed. A normal semen sample usually excludes hypogonadism from a primary or secondary source. Semen analysis is performed only if fertility is being considered.

GH provocative testing and prolactin testing

Given that GH secretion is pulsatile and low in most adults through most of the day, a single low serum level cannot be interpreted, whereas a single elevated or normal serum GH level can exclude the diagnosis of GH deficiency. Best is a provocative test for GH secretion. The serum IGF-1 may be useful for GH deficiency in children but not in adults, as up to a third of adults with proven GH deficiency by provocative testing may have a normal serum IGF-1. There are various GH stimulation tests, with glucagon and hypoglycemia being the most definitive. GH-releasing hormone (GHRH) for such testing is difficult to obtain.

Prolactin deficiency can also be verified by directly measuring serum levels. As with most other pituitary hormones, secretion of prolactin is episodic; more than 1 value is necessary for diagnosis. However, testing is rarely necessary since most patients are asymptomatic, and the results are not clinically relevant unless a woman wishes to lactate.

Water Deprivation Test and Vasopressin Stimulation Test

A water deprivation test can help to differentiate psychogenic polydipsia from diabetes insipidus and nephrogenic diabetes insipidus. Supervise patients constantly to inhibit water intake, as patients with psychogenic polydipsia often use any means possible to consume water (eg, drinking from a toilet bowl). While withholding water, take urine samples hourly to measure urine osmolalities, with serum osmolarity measured at the beginning and end.

If the cause is psychogenic, urine osmolality increases while serum osmolality remains normal. If urinary concentrations do not increase in a water deprivation test, despite the rise in serum osmolarity, the diagnosis of diabetes insipidus is established (central or nephrogenic).

At the time of stability of the urine osmolarity, a vasopressin stimulation test may assist in discriminating between central and nephrogenic diabetes insipidus. Administer either 5 units of aqueous vasopressin or 1-2 mcg of desmopressin (DDAVP) subcutaneously. After 1 hour, acquire an additional set of serum and urine specimens. An increase in urine osmolality and a decrease in serum osmolality support a central cause of diabetes insipidus and a lack of arginine vasopressin (AVP). If osmolalities remain unchanged, the patient has nephrogenic diabetes insipidus (resistance to AVP).

This test is with some limitations in interpretation, so added serum measurements of AVP or copeptin (the C terminus of the vasopressin precursor) may improve test interpretation.

Magnetic Resonance Imaging

A study by Li et al concluded that magnetic resonance imaging (MRI) findings can be correlated with pituitary function and can provide evidence of multiple pituitary hormone deficiencies. The study included 96 pituitary hormone ̶ deficient children and 90 controls. The authors used MRI findings from the hypothalamic-pituitary region to divide the hormone-deficient patients into 5 stages. Based on serum concentrations of ACTH, cortisol, GH, insulinlike growth factor-1 (IGF-1), free T4, TSH, FSH, LH, testosterone, estradiol, and prolactin in the patients and controls, a positive correlation was found between the MRI-based stages and the number of pituitary hormone deficiencies in patients.[23, 24]  However, MRI does not eliminate the need for appropriate biochemical testing.

In the presence of clinical or biochemical evidence of hypopituitarism, visualization of the sellar/suprasellar areas is needed to identify the nature of the causative disease process. This is best performed through computed tomography (CT) scanning or MRI. The presence of a mass with hormonal hypersecretion indicates that it is likely a secretory pituitary adenoma. In the absence of hypersecretion, any mass/infiltrate may be of unknown etiology, but certain characteristics on CT scanning/MRI may suggest the pathologic cause in some cases. The presence of a lesion requires correlation with the clinical/biochemical data, and the absence of any visible lesion suggests a nonorganic cause in most cases.

 

Treatment

Approach Considerations

Missed or delayed diagnosis of hypopituitarism could potentially lead to permanent disability or death. Medical care consists of hormone replacement as appropriate and treatment of the underlying cause. Glucocorticoid (cortisol) is 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 lifesaving treatment pending a definitive diagnosis. Treat secondary hypothyroidism with thyroid hormone replacement.[4]

Treat gonadotropin deficiency with gender-appropriate hormones. In men, testosterone replacement is used and substituted with human chorionic gonadotropin (hCG) injections if the patient desires fertility. In women, estrogen replacement is used with or without progesterone as appropriate.

GH is replaced in children as appropriate. GH is not routinely replaced in adults unless the patient is symptomatic of GH deficiency, after all other pituitary hormones have been replaced. Then, a 6-month trial of replacement GH therapy may be considered.

Surgical care depends on the underlying cause and clinical state. In pituitary apoplexy, prompt surgical decompression may be lifesaving if head imaging reveals clinically significant tumor mass effect. Microadenomas do not need surgical treatment unless GH or ACTH hypersecretion is present. Prolactinomas, small and large, generally respond to medical therapy with tumor shrinkage and alleviation of mass symptoms. Debulk macroadenomas with mass symptoms that do not respond to medical therapy or are not expected to respond to medical therapy. Some asymptomatic nonsecreting macroadenomas may have an option of close clinical/radiologic observation. If radiotherapy is used, long-term new-onset hypopituitarism may occur and must be monitored.

The most common causes of nonsecreting pituitary adenomas are variants of gonadotropin-secreting tumors. In perhaps a third of these lesions, treatment with the potent dopamine agonist cabergoline may result in some decrease in mass or prevention of recurrence.[25]

A retrospective study by Graffeo et al indicated that in radiation-naïve patients receiving single-fraction stereotactic radiosurgery for pituitary adenoma, a mean gland dose of less than 11.0 Gy may reduce the likelihood of posttreatment hypopituitarism. The investigators found that in patients who received this lower dose, the rates of hypopituitarism at 2 and 5 years were 2% and 5%, respectively, compared with 31% and 51%, respectively, for those who received a mean dose of 11.0 Gy or higher.[26]

A study by Lee et al found that in patients with nonfunctioning pituitary adenomas, gross-total resection and/or adjuvant radiotherapy appear to prevent tumor recurrence or regrowth. The study involved 289 patients, 193 of whom had gross-total resection, 53 of whom had near-total resection, and 43 of whom had subtotal resection.[27]

A literature review by Li et al indicated that in the surgical treatment of pituitary adenomas, endoscopic transsphenoidal surgery is more successful than microscopic transsphenoidal surgery in gross tumor removal and, unlike the microscopic technique, does not significantly affect cerebrospinal fluid leak risk. Moreover, the endoscopic surgery significantly decreases septal perforation risk and is not linked to an increased risk for meningitis, epistaxis, hematoma, hypopituitarism, hypothyroidism, hypocortisolism, total mortality, or recurrence.[28]

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.

No special diet is necessary in patients with hypopituitarism unless dictated by an underlying disease process. Also, no activity restrictions are necessary unless dictated by an underlying disease process. Include an endocrinologist, a neurosurgeon, and a radiologist in consultations, as appropriate.

The World Health Organization's 2017 classification of pituitary tumors lists adenoma subtypes that may be more aggressive and likely to recur, requiring additional therapy.[29]

Prevention

Good obstetric care has reduced the incidence of postpartum hypopituitarism. Radiation therapy that minimizes exposure of the pituitary reduces the time of onset of hypopituitarism. Experienced neurosurgeons employing high-resolution microscopic hypophyseal surgery may reduce the likelihood of subsequent hypopituitarism.

Long-Term Monitoring

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.

Follow-up care also involves adjusting hormone replacement to physiologic maintenance levels using the lowest dose. Monitor the patient to avoid overreplacement. The incidence of new neoplasms is increased in young people treated with GH who had previous tumor treatment.[30]  This does not appear to be the case in adult patients. Excessive glucocorticoid or thyroid doses, or inadequate sex steroid doses, have been associated with decreased bone mineral density.

Screening

Screening for hypopituitarism should be offered to patients with a history of TBI, SAH, pituitary microadenoma, pituitary radiation therapy, transsphenoidal surgery, or prolactinoma treatment and to GH-deficient children who have achieved their full height.[31, 32, 33]

 

Medication

Medication Summary

The goal of pharmacotherapy is to restore target hormones to physiologic levels. Medications used in hypopituitarism vary depending on the specific hormone deficiency that exists. As previously stated, patients with hypopituitarism are usually maintained on hormone replacement therapies for life. These patients are generally asymptomatic but require increased doses of glucocorticoids following any form of stress, emotional or physical. The most common stressor is infection. Not matching glucocorticoid dose to stress causes acute decompensation.

Corticosteroids

Class Summary

These agents are used in adrenal insufficiency. They 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 glucocorticoid and mineralocorticoid activity.[30] In the past, these agents were used in a higher-than-physiological dose. Presently, a dose equivalent to 15-20 mg/day of hydrocortisone is recommended in adults.

Hydrocortisone (Hydrocortone, A-Hydrocort, Solu-Cortef, Cortef)

Hydrocortisone is used as replacement therapy in adrenocortical deficiency states and may be used for its anti-inflammatory effects. For hypotensive patients and acute management, use intravenous (IV) preparation.

Prednisone

This is an alternative to hydrocortisone in patients with adrenal insufficiency.

Thyroid hormones

Class Summary

These agents are used in hypothyroidism.

Levothyroxine (Synthroid, Levoxyl, Levothroid, Tirosint, Unithroid)

In active form, levothyroxine influences the growth and maturation of tissues. It is involved in normal growth, metabolism, and development. Endocrinologists can monitor and adjust the doses to optimal effect. A serum free thyroxine value in the upper third of normal range is the goal.

Antidiuretic hormone replacements

Class Summary

These agents are used for the replacement of vasopressin.

Vasopressin (Pitressin)

This is an intramuscular or subcutaneous injection of an ADH analog that has vasopressor and ADH activity. It increases water resorption at the distal renal tubular epithelium (ADH effect) and promotes smooth-muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). It is rarely used today for long-term therapy.

Desmopressin acetate (DDAVP, Stimate)

This agent is a longer-acting ADH derivative that can be used intranasally (also orally and sublingually); it increases the cellular permeability of the collecting ducts, resulting in the resorption of water by the kidneys.

Growth hormones

Class Summary

These agents are 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.

Human growth hormone; somatropin (Humatrope, Genotropin, Saizen)

This is produced by recombinant deoxyribonucleic acid (DNA) technology. It stimulates the growth of linear bone, skeletal muscle, and organs and stimulates erythropoietin, increasing red blood cell mass. Actions are either direct or from the hepatic production of IGF-1.

Estrogens/Progestins

Class Summary

These hormones are used for replacement therapy in hypogonadism associated with a deficiency or absence of endogenous testosterone or estrogen.

Estrogens, conjugated (Premarin)

Estrogen is important in the development and maintenance of the female reproductive system and secondary sex characteristics, promoting the growth and development of the vagina, uterus, fallopian tubes, and breasts. It affects the release of pituitary gonadotropins; causes capillary dilatation, fluid retention, and protein anabolism; increases the water content of cervical mucus; and inhibits ovulation. Metabolic effects include maintenance of bone density. Estrogen is predominantly produced by the ovaries.

Estradiol (Alora, Climara, Elestrin, Vivelle-Dot, Estrace, Estraderm, EstroGel)

Estradiol increases synthesis of DNA, RNA, and many proteins in target tissues. It may be given transdermally by patch or gel, or orally in micronized form.

Medroxyprogesterone (Provera, Depo-Provera)

Administer cyclically 12 d/mo to prevent endometrial hyperplasia that unopposed estrogen may cause. In young women, regular withdrawal bleeding is preferable because even young women with premature ovarian failure have a 5-10% chance of spontaneous pregnancy (unlike postmenopausal women). If an expected withdrawal bleeding is absent, perform a pregnancy test (and a timely diagnosis of pregnancy will not be missed). Other causes of amenorrhea may also remit spontaneously and result in an unexpected pregnancy.

Progesterone (Prometrium)

This agent is used to prevent endometrial hyperplasia.

Desogestrel and ethinyl estradiol (Desogen, Ortho-Cept, Velivet, Azurette, Cyclessa)

The combination of desogestrel and ethinyl estradiol reduces the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary by decreasing the amount of gonadotropin-releasing hormones (GnRHs). This is one example of an oral contraceptive pill (OCP). All the modern formulations are equally efficacious, although some of the newer (so-called third-generation) pills have a larger progestin effect and may offer greater efficacy.

Norgestimate and ethinyl estradiol (Ortho Cyclen, Sprintec, TriNessa, Ortho Tri-Cyclen)

The combination of norgestimate and ethinyl estradiol reduces the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary by decreasing the amount of gonadotropin-releasing hormones (GnRHs).

Androgens

Class Summary

Androgens are used for replacement therapy in hypogonadism associated with a deficiency or absence of endogenous testosterone.

Testosterone (Depo-Testosterone, Androderm, AndroGel, Testim, Andriol)

Testosterone is an anabolic steroid that promotes and maintains secondary sex characteristics in androgen-deficient males. Physiological amounts may be given by intramuscular injection every 1-2 weeks, daily by transdermal patch or gel, or several times daily by oral testosterone undecanoate, the latter of which is not available in all countries.

 

Questions & Answers

Overview

What is hypopituitarism (panhypopituitarism)?

What is the physiology of the pituitary gland relative to hypopituitarism (panhypopituitarism)?

How is hypopituitarism (panhypopituitarism) treated in an adrenal crisis?

What is the role of glucocorticoids in the treatment of hypopituitarism (panhypopituitarism)?

What is included in patient education about hypopituitarism (panhypopituitarism)?

What is the pathophysiology of hypopituitarism (panhypopituitarism)?

What causes hypopituitarism (panhypopituitarism)?

What causes hypopituitarism (panhypopituitarism) in pregnant women?

What is the role of traumatic brain injury (TBI) in the etiology of hypopituitarism (panhypopituitarism)?

What are less common causes of hypopituitarism (panhypopituitarism)?

What is the prevalence of hypopituitarism (panhypopituitarism)?

What is the prognosis of hypopituitarism (panhypopituitarism)?

Which factors increase the risk of mortality and morbidity from hypopituitarism (panhypopituitarism)?

What are the cardiovascular complications of with hypopituitarism (panhypopituitarism)?

What are the noncardiovascular complications of hypopituitarism (panhypopituitarism)?

Presentation

Which clinical history findings are characteristic of hypopituitarism (panhypopituitarism)?

Which physical findings are characteristic of hypopituitarism (panhypopituitarism)?

DDX

How is an acute cortisol insufficiency state prevented in hypopituitarism (panhypopituitarism)?

When is the ACTH stimulation test normal in patients with hypopituitarism (panhypopituitarism)?

What are the differential diagnoses for Hypopituitarism (Panhypopituitarism)?

Workup

What is the role of lab testing in the workup of hypopituitarism (panhypopituitarism)?

Which histologic findings are characteristic of hypopituitarism (panhypopituitarism)?

What is the role of adrenocorticotropic hormone (ACTH) stimulation test in the diagnosis of hypopituitarism (panhypopituitarism)?

What is the role thyroid function testing in the diagnosis of hypopituitarism (panhypopituitarism)?

What is the role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) assessment in the diagnosis of hypopituitarism (panhypopituitarism)?

Which lab tests should be performed in the evaluation of hypopituitarism (panhypopituitarism) in men?

What is the role of growth hormone (GH) provocative testing and prolactin testing in the diagnosis of hypopituitarism (panhypopituitarism)?

What is the role of a vasopressin stimulation test in the diagnosis of hypopituitarism (panhypopituitarism)?

What is the role of a water deprivation test in the diagnosis of hypopituitarism (panhypopituitarism)?

What is the role of imaging studies in the diagnosis of hypopituitarism (panhypopituitarism)?

Treatment

How is hypopituitarism (panhypopituitarism) treated?

How are pituitary adenomas treated in patients with hypopituitarism (panhypopituitarism)?

How is hypopituitarism (panhypopituitarism) prevented?

What is included in long-term monitoring of hypopituitarism (panhypopituitarism)?

Medications

What is the role of drug treatment for hypopituitarism (panhypopituitarism)?

Which medications in the drug class Androgens are used in the treatment of Hypopituitarism (Panhypopituitarism)?

Which medications in the drug class Estrogens/Progestins are used in the treatment of Hypopituitarism (Panhypopituitarism)?

Which medications in the drug class Growth hormones are used in the treatment of Hypopituitarism (Panhypopituitarism)?

Which medications in the drug class Antidiuretic hormone replacements are used in the treatment of Hypopituitarism (Panhypopituitarism)?

Which medications in the drug class Thyroid hormones are used in the treatment of Hypopituitarism (Panhypopituitarism)?

Which medications in the drug class Corticosteroids are used in the treatment of Hypopituitarism (Panhypopituitarism)?