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  more...
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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 .



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.



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.



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]



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.


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.