Hypopituitarism …

Douglas J Lanska MD MS MSPH

General Neurology

Updated 05.09.2024
Released 10.30.1994
Expires For CME 05.09.2027

Hypopituitarism

Author: Douglas J Lanska MD MS MSPH

See Contributor Disclosures

Hypopituitarism

In This Article

Quick Link

Introduction

Overview

The pituitary gland sits in the sella turcica and is divided into two parts, the anterior and posterior. Hypopituitarism results from the partial or complete loss of one or more of six hormones made and released by the anterior pituitary gland. Non-tumoral causes constitute a major group of childhood hypopituitarism. Once fully established and prolonged (greater than 6 months), hypopituitarism is generally permanent, although spontaneous recovery can rarely occur. There are many causes of hypopituitarism, including tumors in or around the pituitary gland, whole brain radiation therapy or focused radiation therapy that includes the sella turcica in the treatment field, chemotherapy, operative damage, major head trauma, subarachnoid hemorrhage, infections, and perinatal and prenatal causes.

Key points

	• Hypopituitarism results from the partial or complete loss of one or more of six hormones made and released by the anterior pituitary gland.
	• Non-tumoral causes constitute a major group of childhood hypopituitarism.
	• Once fully established and prolonged (greater than 6 months), hypopituitarism is generally permanent, although spontaneous recovery can rarely occur.
	• Not all intrasellar enhancing lesions causing hypopituitarism are pituitary adenomas.
	• A pituitary abscess is an intrasellar infection; it responds to antibiotic therapy and surgery, and although the abscess resolves eventually, protracted hypopituitarism often remains protracted, requiring prolonged hormone replacement therapy.
	• After traumatic brain injury, anterior pituitary hormonal function should be assessed to attain maximal improvement in cognitive and physical function as well as quality of life.

Historical note and terminology

Hypopituitarism results from the partial or complete loss of one or more of the six hormones made and released by the anterior pituitary gland: growth hormone, adrenocorticotropic hormone, prolactin, thyroid stimulating hormone, luteinizing hormone, and follicle-stimulating hormone. The posterior pituitary is the storage gland for the hypothalamic hormones, antidiuretic hormone, and oxytocin. Although complete deficiency of anterior pituitary hormones is often called "panhypopituitarism," this term should be reserved for complete loss of anterior and posterior pituitary hormones, including the neuropeptides vasopressin and oxytocin.

The crucial physiologic roles of the pituitary gland were not suspected until the late 19th century and were not clearly defined until the first third of the 20th century. In the second century, Galen of Pergamum taught that the hypophysis acted as a funnel or drain for secreted mucus (pituita) made by the brain to pass into the nasopharynx. In the 16th century, Vesalius claimed that phlegm from the cerebral ventricles passed down the infundibulum into the gland and finally out the nose. Acromegaly was described by various authors from the 16th through 19th centuries, but when pituitary pathology was recognized in such cases, it was initially unclear if the pituitary enlargement was the cause or consequence of the disease (32). The first clear evidence suggesting a more important role for the pituitary gland was published in 1886. French neurologist Pierre Marie (1853-1940) described (and named) the disease of acromegaly, which was associated in his case with the replacement of the pituitary body gland by a tumor (68).

Pierre Marie, French neurologist (1853-1940)

Photograph taken around 1900 by French photographer Louis Eugène Pirou (1841-1909). Marie described the relationship between a pituitary adenoma and acromegaly in 1886. (Courtesy of Wikimedia Commons. Public domain.)

American neurosurgeon Harvey Cushing (1869-1939) had suspected that a clinical disorder was associated with pituitary destruction (30), but in 1914 German physician Morris Simmonds (1855-1925) provided the first clear description of pituitary insufficiency, which he termed "pituitary cachexia" (95).

Harvey Williams Cushing, American neurosurgeon (1869-1939)

Photograph taken in 1938. Cropped from a picture of Cushing and English neurophysiologist Sir Charles Scott Sherrington (1857-1952). (Courtesy of the Wellcome Institution. Creative Commons Attribution 4.0 International license....

Simmonds detailed the necroscopic findings of a 46-year-old woman whose illness began after childbirth and was complicated by severe puerperal fever. The clinical findings included marked weight loss, premature aging, marked muscular weakness, and anemia. Subsequent reports stressed a common relationship between childbirth and the clinical syndrome, which led Reye to speculate in 1926 and 1928 that pituitary destruction was caused by thrombosis in the setting of pituitary hyperplasia during pregnancy (85; 86). This view was fully confirmed by the 1937 report of British pathologist Harold Leeming Sheehan (1900-1988) in his classic article on ischemic postpartum necrosis of the pituitary (93). Ischemic pituitary necrosis is now often variously named eponymically as Reye-Sheehan syndrome or Sheehan syndrome.

Clinical manifestations

Presentation and course

	• The initial clinical presentation of hypopituitarism spans a spectrum from the rare life-threatening episodes of acute adrenal insufficiency to the slow, insidious development of nonspecific symptoms.
	• Hypopituitarism tends to have a slow and gradual presentation over a period of weeks to months due to the slow depletion of pituitary hormones.
	• Hypopituitarism can remain clinically silent until a stressful event catalyzes the presentation of marked symptoms.
	• When hypopituitarism arises from pituitary destruction by masses, mechanical symptoms such as headache and visual loss often predominate.
	• Frequently, hormonal deficiencies are not complete and are clinically silent unless a patient is under a physiological stress.

The initial clinical presentation of hypopituitarism spans a spectrum from rare life-threatening episodes of acute adrenal insufficiency to the slow, insidious development of nonspecific symptoms such as lassitude and fatigue, which are often ignored by patients, their families, and their physicians. Hypopituitarism tends to have a slow and gradual presentation over a time period of weeks to months due to the slow depletion of pituitary hormones. Hypopituitarism can remain clinically silent until a stressful event catalyzes the presentation of marked symptoms (108). Detection of hypopituitarism is especially difficult in elderly patients who frequently present with nonspecific symptoms. Specific signs and symptoms depend on the organ system(s) affected, the degree and rapidity with which hormonal deficiencies develop, and whether the patient is a child or adult. When hypopituitarism arises from pituitary destruction by masses, mechanical symptoms such as headache and visual loss often predominate. Frequently, hormonal deficiencies are not complete and are clinically silent unless a patient is under a physiological stress.

The signs and symptoms of hypopituitarism depend on the particular hormones that have been diminished. For instance, low cortisol levels can present as hypotension, hypoglycemia, hyponatremia, or hyperkalemia. Hyponatremia with hypopituitarism-induced adrenal insufficiency may result in recurrent episodes of altered sensorium (09). Low levels of thyroid hormones can lead to altered mental status, hypothermia, lethargy, or edema. If the sex hormones, testosterone or estrogen, are affected there may be decreased libido, hair loss, or amenorrhea. Growth hormone deficiency can present as decreased muscle mass or lethargy (108).

Although most symptoms of hypopituitarism are similar to those that occur with failure of the target gland, there are some important differences. For example, hypocortisolism from hypopituitarism lacks the hyperpigmentation that occurs in primary adrenal failure (Addison disease). Symptoms of hypothyroidism from hypopituitarism do not include myxedema coma because the thyroid gland continues to make and release small amounts of thyroid hormone even without activation by thyroid stimulating hormone. Hypoprolactinemia is unusual with hypopituitarism and is detected only as the inability to lactate appropriately in the puerperium; more commonly, mild elevations in serum prolactin occur (less than 150 ng/mL), frequently producing galactorrhea in women (and rarely in men).

Growth hormone deficiency had traditionally been thought to be asymptomatic in adults. However, a cluster of characteristics are now recognized as features of the adult growth hormone deficiency syndrome; these include increased body fat, decreased lean body mass, decreased oxygen consumption, abnormal lipid profiles, osteopenia, fatigue, and decreased sense of well-being. Many of these features improve with replacement therapy (Inzucchi 1997).

Diabetes insipidus is characterized by polyuria and polydipsia. With partial deficiencies, thirst and urination are not abnormal until the individual is osmotically stressed and subsequently utilizes a diminished reserve of vasopressin. Oxytocin deficiency is generally coincident with diabetes insipidus and is infrequently observed independently. Deficiency is only recognizable in women who are unable to lactate because of the absence of milk ejection (“let-down”).

Finally, loss of more than one hormone can lead to "masking" of symptoms. For example, ACTH deficiency (hypocortisolism) will mask diabetes insipidus because cortisol is required for the distal tubule of the kidney to maintain water impermeability.

The presentation of hypopituitarism can be different in children than in adults. For example, in children, growth hormone deficiency causes growth delay and hypoglycemia, and gonadotropin deficiency prevents pubertal development.

Prognosis and complications

Hypopituitarism may progressively increase in severity, particularly when the etiology is neoplastic, infiltrative, or radiation induced. Once fully established and prolonged (greater than 6 months), it is generally permanent, although spontaneous recovery can rarely occur.

Quality of life may not return to normal. Some patients treated for hypopituitarism have associated depression, anxiety, memory loss, and emotional distress that were not present prior to presentation (28; 96). Several studies have documented a reduced quality of life in patients treated for hypopituitarism due to persisting psychological and physical impairments. These complaints are partly caused by intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion.

Hypopituitarism has also important socioeconomic effects, with increased annual health costs compared to the normal population (105).

Patients with hypopituitarism have increased mortality (103). Affected women have higher mortality than affected men, but it is unknown if the increased mortality is attributable to the treatments such as sex hormone supplementation. The disease has also been associated with increased mortality from other disorders. For instance, deaths from vascular disorders are more common in the hypopituitarism population compared to the general population. Age at presentation of hypogonadism is a predictive factor for survival (82).

Clinical vignette

Case 1. Metastatic papillary thyroid cancer presenting with hypopituitarism (56). A 74-year-old man presented with weakness, fatigue, and anorexia. After the detection of low thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels, further endocrine testing revealed decreased AM cortisol, adrenocorticotropic hormone (ACTH), luteinizing hormone, and follicle-stimulating hormone, as well as mildly elevated prolactin levels. Hydrocortisone and levothyroxine were initiated. Examination findings included bitemporal hemianopsia and a palpable, right-sided thyroid nodule. Pituitary MRI revealed a pituitary mass with suprasellar extension, right cavernous sinus invasion, and optic chiasm compression. Thyroid ultrasonography revealed multiple nodules in both lobes and a dominant hypoechoic 7.2 nodule in the right lobe. Cytology via fine-needle aspiration of the thyroid nodule suggested papillary thyroid cancer. Neck CT showed a deviated trachea, obliterated right internal jugular vein, and substernal extension of the thyroid. Thorax CT revealed pulmonary nodules consistent with metastases. Positron emission tomography-computed tomography (PET-CT) revealed increased fluoro-deoxyglucose (FDG) uptake in the thyroid gland with substernal extension, pituitary gland, left ninth rib, pulmonary nodules, retrosternal and retroclavicular lymph nodes, and right femur. Total thyroidectomy with central and right lateral neck dissection confirmed the diagnosis of diffuse follicular variant of papillary thyroid carcinoma. Because of visual field defects, transsphenoidal surgery was performed. Histological and immunohistochemical evaluations confirmed pituitary metastasis from the papillary thyroid cancer. Radioactive iodine treatment and gamma knife radiotherapy of the pituitary gland were performed. A significant decrease in the thyroglobulin levels was observed after sorafenib treatment.

Pituitary mass with suprasellar extension (T1 MRI)

Sagittal T1-weighted pituitary MRI shows pituitary mass with suprasellar extension (thick white arrows) in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. (Left) precontra...
Pituitary mass with invasion of the right cavernous sinus and optic chiasm compression (T1 MRI)

Coronal T1-weighted pituitary MRI showing pituitary mass with invasion of the right cavernous sinus (curved white arrow) and optic chiasm compression (short white arrows) in a 74-year-old man with diffuse follicular variant pap...
Deviated trachea, obliterated internal jugular vein, and substernal extension of the thyroid (CT)

Coronal neck CT images with contrast show deviated trachea, obliterated internal jugular vein, and substernal extension of the thyroid in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to ...
Deviated trachea and obliterated internal jugular vein (CT)

Axial neck computed tomography images with contrast show deviated trachea and obliterated internal jugular vein in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. Abbrevia...
Deviated trachea and obliterated internal jugular vein (CT)

Sagittal neck computed tomography images with contrast show deviated trachea and obliterated internal jugular vein in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. Abbre...
Increased fluoro-deoxyglucose uptake in the thyroid gland with substernal extension (PET)

Positron emission tomographic images show increased fluoro-deoxyglucose uptake in the thyroid gland with substernal extension in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pitui...
Increased fluoro-deoxyglucose uptake in the left ninth rib (PET)

Positron emission tomographic images show increased fluoro-deoxyglucose uptake in the left ninth rib in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. (Source: Kırkgoz T,...
Increased fluoro-deoxyglucose uptake in one of the pulmonary metastatic nodules (PET)

Positron emission tomographic images show increased fluoro-deoxyglucose uptake in one of the pulmonary metastatic nodules in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary...
Total thyroidectomy with central and right lateral neck lymph node dissection

From a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary. The thyroid capsule was not observed over the right thyroid lobe. The tumor was extrathyroidal. The right internal jug...
Serum thyroglobulin variation following the initiation of radioiodine and sorafenib treatments after total thyroidectomy

Serum thyroglobulin variation following the initiation of radioiodine and sorafenib treatments after total thyroidectomy in a 74-year-old man with diffuse follicular variant papillary thyroid cancer metastatic to the pituitary....

Case 2. Hypopituitarism due to a large osteoclastoma arising from the sphenoid bone invading the pituitary fossa in a patient with parathyroid carcinoma (12). A 47-year-old woman previously diagnosed with primary hyperparathyroidism underwent a parathyroidectomy 6 years earlier, with histological examination indicating a parathyroid adenoma. After surgery, she continued to exhibit high serum parathyroid hormone (PTH) and calcium levels, with development of bone pain and spontaneous fractures. She also reported weight loss of about 10 kg over the past year, associated with weakness and hair loss, as well as impaired peripheral vision. Ophthalmological examination revealed bitemporal hemianopsia, with maintenance of visual acuity and no changes in the optic fundus.

Laboratory tests included serum PTH 3200 pg/mL (reference range 19–65), total calcium 14.5 mg/dL (reference range 8.4–10.2), serum phosphate 2.4 mg/dL (reference range 2.5–4.5), albumin 2.4 g/dL (reference range 3.5–5.2), alkaline phosphatase 1224 U/L (reference range 35–104), lactate dehydrogenase (LDH) 598 U/L (reference range 135–214), blood urea nitrogen (BUN) 21 mg/dL (reference range 17–49), serum creatinine 0.8 mg/dL (reference range 0.8–1.5), hemoglobin 8.4 g/dL (reference range 12–5.8), hematocrit 25.7% (reference range 33–47.8), and 25-hydroxyvitamin D (25OHD) 6.9 ng/mL (deficiency < 20).

Neck ultrasound showed a 2.2 cm nodule adjacent to the inferior part of the right thyroid lobe and a 1.9 cm nodule adjacent to the superior part of the right lobe, showing a marked uptake with technetium-99m sestamibi scintigraphy. There was also a large kidney stone in the right renal pelvis. The distal 1/3 radius bone mineral density was 0.357 g/cm² with a t-score of −6.0 SD.

Skull x-ray showed a salt and pepper appearance, lamina dura resorption on the central lower teeth, and enlargement and erosion of the of the sella turcica. MRI showed a 3.1 cm contrast-enhanced mass invading the pituitary fossa and causing compression of the optic chiasm. Laboratory tests to assess pituitary function included adrenocorticotropic hormone (ACTH) less than 5 pg/mL, free thyroxine (FT4) 0.67 ng/dL, thyroid-stimulating hormone (TSH) 0.52 mU/L, luteinizing hormone (LH) 14.98 mUI/mL, stimulating hormone follicle 2.0 mUI/ mL, prolactin (PRL) 7.45 ng/mL, basal cortisol 6.6 μg/dL, and insulin tolerance test with a peak cortisol level of 7.9 μg/dL.

Sella turcica enlargement (skull x-ray)

X-ray from a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: Bandeira L, de Oliveira LB, de Lima MV, Rêgo D, Griz L, Bandeira F. Hypopituitarism...
Lesion invading the pituitary fossa (T2 MRI)

T2-weighted cranial MRI shows the presence of a 3.1 cm lesion invading the pituitary fossa in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: ...
Lesion invading the pituitary fossa (T1 MRI)

T1-weighted cranial MRI shows the presence of a 3.1 cm lesion invading the pituitary fossa in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. (Source: ...
Infiltrative lesion compromising the bony segments of the skull and face (T1 MRI)

T1-weighted cranial MRI shows an infiltrative lesion compromising the bony segments of the skull and face in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituita...

Histology of a transsphenoidal biopsy was consistent with an osteoclastoma (also known as a giant cell tumor of bone or a myeloid sarcoma). Nodules located adjacent to the thyroid were excised, and histopathological examination demonstrated neoplasia with diffuse proliferation and rare cell nests, mitotic figures, necrosis, and capsular and vascular invasion with emboli.

In the perioperative period, the patient received intravenous hydrocortisone therapy, which was weaned during hospitalization. She also received levothyroxine 50 mcg/day. Intravenous hydration and pamidronate were administered to reduce serum calcium. She was kept under intensive monitoring and did not present hypocalcemia due to bone hunger syndrome.

After 1 year, she showed marked clinical improvement, especially in well-being, with normalization of the pituitary corticotroph function, a reduction (but not normalization) of PTH levels, and normalization of serum calcium levels, characterizing a normocalcemic hyperparathyroidism. Pituitary MRI showed shrinkage of the sphenoid bone osteoclastoma.

Significant regression of pituitary fossa lesion 1 year after parathyroidectomy (T1 MRI)

T1-weighted cranial MRI shows significant regression of pituitary fossa lesion 1 year after parathyroidectomy in a 47-year-old woman with a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopit...

Biological basis

	• The anterior pituitary and hypothalamus form a functional unit, with each anterior pituitary hormone under direct control by hypothalamic centers.
	• Regulation of pituitary hormone secretion occurs by the release of specific hypothalamic hormones into the portal capillary plexus of the infundibulum that targets the anterior pituitary.
	• Disturbances at any level of this anatomical unit—at hypothalamic, stalk, or pituitary level—can potentially lead to hypopituitarism.
	• For lesions that directly affect the pituitary gland, the observed probability of hormone loss is roughly GH > LH/FSH >> ACTH > TSH >> PRL.
	• The most common lesions associated with hypopituitarism are masses within the pituitary gland, the most prevalent of which are large pituitary adenomas (macroadenomas) that may secrete hormones or may be nonfunctional.
	• Macroadenomas may cause hypopituitarism by various mechanisms, including compression of the normal pituitary gland, occlusion of the portal capillary flow of hypothalamic hormones, and compression of the hypothalamus.
	• Pituitary apoplexy is a potentially lethal event that results from hemorrhage into the pituitary gland, typically hemorrhage into a pituitary macroadenoma
	• Pituitary apoplexy becomes symptomatic via neurologic deficits or through severe adrenal crisis resulting from the acute lack of adrenocorticotropic hormone.
	• Postpartum pituitary necrosis (also known as Reye-Sheehan syndrome or Sheehan syndrome) typically occurs with difficult parturition associated with hypotension and blood loss, which produces a generally painless destruction of the pituitary gland.
	• In ischemic pituitary necrosis, the anterior pituitary is at high risk for vascular compromise because the nurturing blood flow arises mainly from the portal capillary plexus.
	• Empty sella syndrome (ie, little or no pituitary tissue visible within the sella turcica on imaging) is sometimes reported as a "cause" of hypopituitarism (eg, with increased intracranial pressure), but it may be instead a consequence of pituitary damage, or it may be incidental without disrupted pituitary function.
	• Approximately 15% to 20% of patients with traumatic brain injury develop chronic hypopituitarism, which is a major cause of treatable morbidity among survivors.

Etiology and pathogenesis

The anterior pituitary and hypothalamus form a functional unit with each anterior pituitary hormone under direct control by hypothalamic centers.

Sagittal section through the sella turcica

Sagittal section through the sella turcica, showing the anterior and posterior lobes of the pituitary gland, the infundibulum, and the optic chiasm. (From: Gray H. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 191...

This regulation occurs by the release of specific hypothalamic hormones into the portal capillary plexus of the infundibulum that targets the anterior pituitary. Disturbances at any level of this anatomical unit—at hypothalamic, stalk, or pituitary level—can potentially lead to hypopituitarism (104).

For lesions that directly affect the pituitary gland, the observed probability of hormone loss is roughly GH > LH/FSH >> ACTH > TSH >> PRL. The most common lesions are masses within the pituitary gland. The most prevalent of these are large pituitary adenomas (macroadenomas) that may secrete hormones or may be nonfunctional. A macroadenoma is defined by a size greater than 10 mm, whereas microadenomas are smaller than this. Macroadenomas may cause hypopituitarism by various mechanisms, including compression of the normal pituitary gland, occlusion of the portal capillary flow of hypothalamic hormones, and compression of the hypothalamus. The potential for hypopituitarism increases as macroadenomas invade the suprasellar space, compressing the optic chiasm, and ultimately the hypothalamus. Virtually all of these individuals develop growth hormone deficiency, and approximately 30% also lose other pituitary hormones, although the loss may not be permanent if the tumor is removed (03) or is reduced by medical therapy (74). In a study of 269 patients with nonfunctioning pituitary adenomas, half (49%) of the patients were asymptomatic; the prevalence of hypopituitarism was 59% in symptomatic patients and 27% in the asymptomatic group (40). Eighty-seven percent of the pituitary adenomas in this study were macroadenomas (40).

Secretory tumors generally produce clinical syndromes such as acromegaly that may conceal or draw attention away from hypopituitarism arising either from destruction of the pituitary or interference with the hypothalamic-pituitary unit. Diabetes insipidus is unusual with anterior hypopituitarism that arises from intrasellar macroadenomas. However, lesions that arise from the suprasellar region (such as craniopharyngiomas, meningiomas, lymphomas, and germ cell tumors) or that are immediately adjacent to the posterior lobe (such as Rathke cleft cysts) typically affect the neurohypophysis and are often associated with clinical diabetes insipidus.

Pituitary apoplexy is a potentially lethal event that results from hemorrhage into the pituitary gland, typically hemorrhage into a pituitary macroadenoma. Pituitary apoplexy becomes symptomatic via neurologic deficits or through severe adrenal crisis resulting from the acute lack of adrenocorticotropic hormone. This clinical state is characterized by headache, visual disturbances including field defects (bitemporal hemianopsia) and diplopia from ocular cranial nerve abnormalities (arising from compression of cranial nerves III, IV, and VI within the cavernous sinus), nausea, vomiting, neck rigidity, altered or depressed mental status, and if the hypothalamus is appreciably compressed, vegetative symptoms and signs including vascular instability. Pituitary apoplexy almost always produces acute hypocortisolism due to ACTH deficiency.

Another cause of acute hypopituitarism is postpartum pituitary necrosis (also known as Reye-Sheehan syndrome or Sheehan syndrome) (93). This typically occurs with difficult parturition associated with hypotension and blood loss, which produces a generally painless destruction of the pituitary gland. In ischemic pituitary necrosis, the anterior pituitary is at high risk for vascular compromise because the nurturing blood flow arises mainly from the portal capillary plexus. In conditions in which the vascular supply is compromised, eg, microvascular disease of diabetes mellitus or reduced blood flow to the hyperplastic gland during pregnancy, necrosis ensues. Rarely, diabetes insipidus ensues (less than 1% to 2% of the time), but it is often masked by coincident hypocortisolism. Rarely, diabetes insipidus can be the only damage observed (94; 80). Subsequent to pituitary destruction, there is an absence of lactation (due to loss of prolactin) and amenorrhea. Hypothyroidism and hypocortisolism may be missed due to their insidious onset, and the condition may go undetected for many years. A similar syndrome can develop, often spontaneously, in other conditions in which the portal blood supply is limited due to vascular disease or obstruction, particularly in diabetes mellitus. Multiple risk factors (eg, pregnancy and sickle cell disease) raise the possibility of necrosis (102). Rarely, hemorrhage and necrosis can occur in normal pituitaries, due to hantaviral disease (24; 98). The thirst center may be affected by ischemic damage, and the osmotic threshold for the onset of thirst in patients with Sheehan syndrome is increased (06).

Pituitary injury may also be caused by medical treatment. Direct destruction of the pituitary frequently occurs as a complication of surgical treatment of pituitary lesions and often produces hormonal deficiencies of growth hormone and the gonadotropins. Anterior hypopituitarism is a common result of radiation therapy, especially when delivered for treatment of pituitary tumors. However, pituitary injury also commonly occurs after whole brain radiation and occasionally from radiation delivered to treat head and neck tumors, which also includes the pituitary-hypothalamic unit within the treatment field. Radiation-induced damage typically has a prolonged time of onset. The pattern of pituitary hormone deficiency is extremely variable and may occur many years after radiation. In a study of 66 patients who received standard pituitary radiation at 5 years after the treatment, 100% had growth hormone deficiency, 91% had gonadotropin deficiency, 77% had ACTH deficiency, and 42% had thyroid stimulating hormone deficiency (63). Because of the prolonged time of onset of insufficiency, patients receiving radiotherapy must be followed throughout life for the development of hypopituitarism. Medications can also cause hypopituitarism, including immune checkpoint inhibitors (eg, pembrolizumab, atezolizumab) (42; 47).

Empty sella syndrome (ie, little or no pituitary tissue visible within the sella turcica on imaging) is sometimes reported as a "cause" of hypopituitarism (eg, with increased intracranial pressure), but it may be instead a consequence of pituitary damage, or it may be incidental without disrupted pituitary function. Increased intracranial pressure can lead to herniation of the subarachnoid space, which can in turn lead to compression of the pituitary gland. The term “empty sella” was coined to refer to the neuroradiological or pathological-anatomical finding of an apparently empty sella turcica (19). This situation develops because the sella turcica is filled with cerebrospinal fluid and the hypophyseal tissue at its base is flattened. Consequently, an empty sella is often regarded as a herniation of the subarachnoid space into the sella turcica (69). A distinction is made between partial empty sella syndrome, with less than 50% of the volume of the sella turcica filled with CSF, and "complete" empty sella syndrome, with more than 50% of the volume of the sella turcica filled with CSF (07).

Traumatic brain injury is now recognized as an important cause of hypopituitarism (58; 92; 37) and can occur with even multiple mild episodes of traumatic brain injury (70). Direct trauma, such that may occur from accidents (35), projectiles such as bullets (65), and carotid aneurysms (81), can also cause hypopituitarism either immediately after the injury or following a delay of several years. Pituitary dysfunction, present months or years after traumatic brain injury, is now well recognized in adults. A review of pediatric data has also confirmed that hypopituitarism may occur after both mild and severe traumatic brain injury, with growth hormone and gonadotrophin deficiencies the most common abnormalities (01).

Chronic hypopituitarism is a major cause of treatable morbidity among survivors of traumatic brain injury (57; 25). The pathophysiology of hypopituitarism after traumatic brain injury is not fully understood, and most theories involve transection of or damage to the pituitary stock (eg, associated with basilar skull fracture), but some have suggested venous infarction of the venous system surrounding the pituitary gland, pituitary injury from trauma-associated hypotension or elevated intracranial pressure, hypoxic brain injury, and more. Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms for pituitary dysfunction following moderate or severe traumatic brain injury (29). Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe traumatic brain injury (101; 25). Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening. One study found that 78% of patients developed inappropriately low plasma cortisol following traumatic brain injury (48). In addition, low plasma cortisol and cranial diabetes insipidus were predictive of mortality and long-term pituitary deficits in traumatic brain injury patients. Patients with traumatic brain injury who develop hypopituitarism frequently present metabolic alterations, in particular altered glucose levels, insulin resistance, and hypertriglyceridemia (84).

Many systemic diseases can infiltrate the pituitary and produce hypopituitarism. Many tumors metastasize to the pituitary, including breast, lung, prostate, renal cell, and thyroid cancers (56); the initial lesion generally occurs within the posterior pituitary due to its excellent blood supply, so the clinical presentation is often with partial or, more rarely, complete diabetes insipidus. In addition, all granulomatous diseases, including tuberculosis, Wegener granulomatosis, and fungal diseases, but especially sarcoidosis, can infiltrate the hypothalamus and the pituitary; this usually produces a basilar meningitis and panhypopituitarism (both anterior and posterior hormone deficiencies). Rarely, an intrasellar mass lesion, such as a tuberculoma, syphilitic gumma, or aspergillus abscess, directly destroys pituitary tissue. Langerhans cell histiocytosis ("histiocytosis X") has a predilection for the basal hypothalamus. Lymphocytic infiltration can produce a pituitary mass and hypopituitarism—a condition termed “lymphocytic hypophysitis” (05); this generally occurs in young women in the postpartum period but has been reported in a postmenopausal woman (73) as well as in men (83).

Pituitary destruction is also part of the spectrum of the autoimmune polyglandular failure syndrome, which can produce simultaneous central and end organ dysfunction. Hypophysitis is one of the immune-related adverse events associated with immunotherapy, including immune checkpoint inhibitors (eg, CTLA-4, PD-1, and PD-L1 inhibitors), which typically involve the corticotrophic, thyrotrophic, and gonadotrophic axes or produce pananterior hypopituitarism (46; 27; 52). A paraneoplastic autoimmune hypophysitis, anti-PIT-1 hypophysitis, results from ectopic expression of pituitary antigens present in tumors causing production of autoantibodies and autoreactive cytotoxic T cells that specifically harm pituitary cells (13; 14; 50; 53; 54).

The iron overload that results from hemochromatosis targets the anterior pituitary gland (as well as other endocrine glands), especially the gonadotrophs (basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration).

There are many less common causes of hypopituitarism. These include congenital causes (eg, septo-optic dysplasia), direct trauma, and infiltrative diseases.

Congenital or neonatal hypopituitarism may be due to aberrations in embryological development, de novo and inherited genetic mutations, and perinatal and neonatal events (75; 76; 16; 38; 44; 55; 21; 110). Neonatal-onset hypopituitarism is usually detected in childhood due to growth arrest, but diagnosis may occasionally be delayed until adulthood. The anterior pituitary gland is derived from ectoderm, whereas the posterior pituitary is derived from neural ectoderm. Neonatal hypopituitarism can be further divided into congenital and perinatal/neonatal causes. Congenital causes include maternal hyperglycemia, congenital infections (such as syphilis and toxoplasmosis), hypothalamic-pituitary developmental defects, severe midline defects (such as those associated with cleft lip/palate), and genetic mutations. There are over 19 genetic mutations identified that can result in anterior pituitary hypoplasia, an ectopic posterior pituitary gland, or isolated loss of hormone producing cells (60).

Perinatal causes of hypopituitarism include birth trauma/asphyxiation (which can result in damage to the pituitary stalk), neonatal sepsis, and hemochromatosis (which often leads to a transient hypopituitarism) (60).

Epidemiology

	• The most common causes of hypopituitarism depend on age.
	• The most common causes of hypopituitarism in children are congenital disorders and sequelae from whole brain irradiation.
	• The most common causes of hypopituitarism in young adults, are nonadenomatous tumors, particularly craniopharyngiomas and dysgerminomas.
	• In adults, the predominant causes of hypopituitarism are pituitary macroadenomas or damage from medical treatment such as surgery, radiation, and chemotherapy.

The overall prevalence of hypopituitarism in an adult Caucasian population in northwestern Spain was 45.5 cases per 100,000 population (91).

In a systematic review, the pooled prevalence of hypopituitarism was 28% in the chronic phase after traumatic brain injury but 47% in the chronic phase after aneurysmal subarachnoid hemorrhage (92). Another study found an even higher prevalence of pituitary dysfunction after aneurysmal subarachnoid hemorrhage, but this does not affect 6- to 12-month clinical outcomes: pituitary dysfunction (particularly dysfunction of the pituitary-gonadal axis) was present in 92% of cases in the acute phase, in 83% in the subacute phase, and in 83% in the chronic phase (88). Some studies have shown an association between the severity of traumatic brain injury and development of post-traumatic hypopituitarism, with hypopituitarism more frequent among patients with severe traumatic brain injury. The rates of neuroendocrine dysfunction after acute aneurysmal subarachnoid hemorrhage have been extremely variable, ranging from 4% to 92% in different studies less but still considerable variability in patients with chronic aneurysmal subarachnoid hemorrhage (47% to 83%) (10).

In the 2016 systematic review and evidence-based guidelines, the Congress of Neurological surgeons found a high prevalence of hypopituitarism (37% to 85%) among patients evaluated for pretreatment endocrinological evaluation of nonfunctioning pituitary adenomas (39). The most common hormonal axis deficiency was growth hormone deficiency (61% to 100%), followed by hypogonadism (36% to 95%), adrenal insufficiency (17% to 62%), and hypothyroidism (8% to 81%) (39). No point estimates were provided (39). Hyperprolactinemia was seen in 25% to 65% of patients, with a mean level of 39 ng/mL and with a minority of patients exceeding a serum prolactin level of 200 ng/mL.

A later retrospective study from two medical centers found that hypopituitarism was present in 80% of 246 patients with nonfunctioning pituitary macroadenomas (02).

Differential diagnosis

Confusing conditions

The differential diagnosis always includes most importantly primary endocrine gland failure, which usually involves only one hormone class but is multiple in the polyendocrine failure syndrome. Measurement of pituitary hormones as well as end hormones will usually distinguish these cases. Occasionally, polyendocrine failure syndrome will also involve the pituitary, and as such, is a cause of hypopituitarism. This distinction is of practical importance only to recognize the presence of concomitant adrenal failure that will require the addition of mineralocorticoids to glucocorticoids as maintenance therapy.

Associated or underlying disorders

The differential diagnosis of hypopituitarism depends on age (91). The most common causes of hypopituitarism in children were congenital disorders and sequelae from whole brain irradiation. In young adults, non-adenomatous tumors, particularly craniopharyngiomas and dysgerminomas, were the most common causes. In adults, the predominant causes of hypopituitarism were pituitary macroadenomas or damage from medical treatment such as surgery, radiation, and chemotherapy.

Anorexia nervosa, a psychiatric illness most common among young women, will produce some of the endocrine findings of hypopituitarism (secondary amenorrhea and borderline biochemical central hypothyroidism) because of severe starvation. The marked weight loss that is present in this condition is unlike hypopituitarism and, therefore, is a critical diagnostic feature. Interestingly, the original descriptions of pituitary cachexia by Simmonds stressed marked weight loss, so patients with anorexia nervosa were inappropriately categorized as having this disease until Sheehan's work clarified this issue (95; 93). In addition, patients with anorexia usually have activation of the hypothalamic-pituitary-adrenal axis, as opposed to the central hypoadrenalism encountered in those with true hypopituitarism.

In a study of 33 cases of pituitary abscess, symptoms were generally typical of an intrasellar mass, generally without any symptomatic evidence for infection (64). Diabetes insipidus, hypopituitarism, and headaches were the most salient features. MR imaging with and without gadolinium revealed an intrasellar mass with an enhancing rim. Thirty cases were treated with antibiotics and surgery (transsphenoidal evacuation), whereas three patients were treated with antibiotics only. Despite some recurrences, abscesses resolved in nearly all cases; however, protracted hypopituitarism remained protracted necessitated hormone replacement therapy.

Features of Oliver-McFarlane syndrome include chorioretinopathy, pituitary dysfunction with hypopituitarism, and trichomegaly-chorioretinopathy (90; 45). This condition may mimic choroideremia-hypopituitarism association (72). However, the latter condition is associated with a family history of progressive blindness and similar maternal fundoscopic appearances. In addition, mutations occur in the choroideremia gene. The choroideremia gene encodes for a protein, the Rab escort protein-1, or REP1, which is involved in membrane trafficking).

In cases of congenital hypopituitarism, pituitary stalk interruption is a well-known entity, but only rarely has a known genetic cause been assigned to these cases. PROKR2 variants in some cases suggest a potential role of the prokineticin pathway in pituitary development (87).

Hypopituitarism is a well-known manifestation among the multitude of neurologic abnormalities that occur with nonsyndromic mitochondrial disorders. A high index of suspicion is needed for diagnosis.

Diagnostic workup

	• Definitive diagnosis of hypopituitarism primarily depends on certain laboratory studies, particularly the measurement of basal anterior pituitary and target organ hormone levels.
	• The usual tests include thyroid stimulating hormone, thyroxine, follicle stimulating hormone, luteinizing hormone, estradiol in women or testosterone in men, prolactin, insulin-like growth factor 1, and morning (AM) cortisol.
	• If growth hormone deficiency is suspected, at least one growth hormone provocative test should be done.
	• Biochemical assessment of hormone deficiencies requires the simultaneous determination of both pituitary and end organ hormones, which will allow the determination of whether the lesion is central (hypopituitarism) or at the end organ level (primary deficiency syndrome).
	• Multiple hormone deficiencies strongly suggest a cranial/pituitary etiology.
	• Partial hormonal deficiencies are often characterized by hormone levels that are within the “normal” range, and consequently, they must be assessed by dynamic testing.
	• Once hypopituitarism has been biochemically defined in patients with symptoms or signs of central lesions, imaging studies of the hypothalamic and pituitary region should be obtained.
	• Pituitary microadenomas measure less than 10 mm in diameter and are usually intrasellar, whereas macroadenomas are 10 mm or more in diameter.
	• Macroadenomas often produce enlargement of the sella turcica and may cause erosion of portions of it.
	• In the 2016 systematic review and evidence-based guidelines, the Congress of Neurological Surgeons recommended high-resolution MRI (level II) as the standard for preoperative assessment of nonfunctioning pituitary adenomas, which may be supplemented with CT (level III) and fluoroscopy (level III).
	• Not all sellar enhancing lesions causing hypopituitarism are pituitary adenomas as evidenced, for example, by anecdotal reports of giant aneurysms of the internal carotid artery causing hypopituitarism.
	• In the 2016 systematic review and evidence-based guidelines, the Congress of Neurological Surgeons recommended preoperative ophthalmologic evaluation, including both functional and anatomic assessment, in the evaluation of patients with pituitary macroadenomas.

Definitive diagnosis of hypopituitarism primarily depends on certain laboratory studies, particularly the measurement of basal anterior pituitary and target organ hormone levels. Usual tests include thyroid stimulating hormone, thyroxine, follicle-stimulating hormone, LH, estradiol in women or testosterone in men, prolactin, insulin-like growth factor 1, and morning (AM) cortisol (82).

A significant limitation of diagnosis is recognizing when hypopituitarism is likely based on medical history, examination findings, or associated circumstances (eg, traumatic brain injury, subarachnoid hemorrhage, major blood loss) (100).

If growth hormone deficiency is suspected, at least one growth hormone provocative test should be done. An insulin tolerance test is the gold standard. Following administration of insulin, growth hormone deficiency is defined as a peak growth hormone response less than 3 ug/L. After an overnight fast, intravenous insulin 0.05 to 0.15 units/kg is injected, and blood glucose and growth hormone levels are measured at 0, 30, 60, 90, and 120 minutes. A normal growth hormone response is a peak of at least 5 mg/l.

Thyroid stimulating hormone deficiency is established by low basal serum free/total thyroxine levels with a normal to low thyroid stimulating hormone level. Routine use of a thyrotrophin releasing hormone (TRH) stimulation test is not indicated in adults. Gonadotrophin deficiency is associated with low serum testosterone in the presence of normal or low gonadotrophin levels in men and low serum estradiol concentrations in premenopausal women. A gonadotrophin releasing hormone (GnRH) provocation test has not been found to provide any additional information in adults (22).

Normally, antidiuretic hormone (ADH) release from the posterior pituitary is influenced by changes in plasma osmolality. However, in cranial diabetes insipidus, the lack of this response results in large urine output classically with low osmolality. The standard 8-hour water deprivation test is used diagnostically in these cases. It entails closely supervised dehydration of a previously well-hydrated patient with measurement of basal and hourly plasma and urine osmolalities, as well as urine volumes. After 8 hours, intramuscular desmopressin 2 mg is injected, and then blood and urine osmolalities are remeasured. Initially dilute urine (less than 300 mOsmol/kg) at the end of fluid deprivation becomes concentrated after desmopressin in patients with cranial diabetes insipidus but remains dilute in patients with nephrogenic diabetes insipidus.

Screening for hypocortisolism is more problematic. An excellent assessment can be made based on a morning serum cortisol level. If this level is above 10 µgm/dL, the hypothalamic-pituitary-adrenal axis is likely normal. Stimulation by synthetic ACTH (cosyntropin test) is also useful, but it may be misleading in states of acute ACTH deficiency in which the adrenal cortex has not yet atrophied (82).

Biochemical assessment of hormone deficiencies requires the simultaneous determination of both pituitary and end organ hormones, which will allow the determination of whether the lesion is central (hypopituitarism) or at the end organ level (primary deficiency syndrome).

Multiple hormone deficiencies strongly suggest a cranial/pituitary etiology. Occasionally, mechanical effects predominate, such as bitemporal hemianopsia, resulting from upward mass effect on the optic chiasm. Because the macula (and, therefore, central vision), is usually spared with mass lesions of the pituitary, profound losses in peripheral vision often occur without the patient's knowledge.

Complete hormonal deficiency syndromes are usually easy to diagnose after the initial suspicion is raised by determining that the end organ hormone level is low, with correspondingly low or inappropriately normal central hormone levels. Partial hormonal deficiencies, however, are often characterized by hormone levels that are within the “normal” range, and consequently they must be assessed by dynamic testing.

Once hypopituitarism has been biochemically defined or in patients with symptoms or signs of central lesions, imaging studies of the hypothalamic and pituitary region should be obtained. Pituitary microadenomas measure less than 10 mm in diameter and are usually intrasellar, whereas macroadenomas are 10 mm in diameter or more. Macroadenomas often produce enlargement of the sella turcica and may cause erosion of portions of it. There may also be extension into the suprasellar cistern, sphenoid sinus, or cavernous sinus (79).

In the 2016 systematic review and evidence-based guidelines, the Congress of Neurological Surgeons recommended high-resolution MRI (level II) as the standard for preoperative assessment of nonfunctioning pituitary adenomas, which may be supplemented with CT (level III) and fluoroscopy (level III) (23). On T1-weighted MR images, adenomas are hypo- to iso-intense and have poor uptake of gadolinium. On T2-weighted MR images, adenomas are isointense to white matter (79). Currently, MR imaging provides the most complete anatomical information and should be employed whenever possible (although hypopituitarism is not excluded by normal MRI of the sellar and parasellar region). MRI findings associated with traumatic damage include pituitary-stalk deviation, signal inhomogeneity (attributable to hemorrhage or infarction), or an empty sella (18).

Ectopic posterior pituitary (MRI)

(A)Sagittal T1 precontrast, (B) sagittal T1 postcontrast, (C) coronal T1 precontrast, and (D) coronal T1 postcontrast images demonstrate a nondescended posterior hypophysis situated just posterior to the optic chiasm in an 18 year...

Not all sellar enhancing lesions causing hypopituitarism are pituitary adenomas as evidenced, for example, by anecdotal reports of giant aneurysms of the internal carotid artery causing hypopituitarism (62). Although symptoms are similar to those of pituitary adenomas, the presence of rim-like calcification around the intrasellar mass on CT and flow-related effects on T2-weighted MRI support the diagnosis of an aneurysm. Confirmation of an intrasellar cerebral aneurysm is obtained with a cerebral angiogram (61). The prevalence of intrasellar giant aneurysms is estimated at 0.2% (49).

A comparative study found that MR imaging findings were similar in patients with lymphocytic hypophysitis and those with pituitary adenomas; however, the presence of the parasellar T2 dark sign in lymphocytic hypophysitis was a specific finding that distinguished it from pituitary adenoma (77).

In the 2016 systematic review and evidence-based guideline, the Congress of Neurological Surgeons recommended preoperative ophthalmologic evaluation including both functional and anatomic assessment in the evaluation of patients with pituitary macroadenomas (78). The evaluation may provide prognostic factors for recovery and, when paired with postoperative evaluation, can document postoperative changes (78; 79). In addition to formal ophthalmologic examination, tests of value include automated static perimetry and optical coherence tomography. A normal retinal nerve fiber layer thickness demonstrated on optical coherence tomography supports an increased propensity for visual recovery, whereas those with a thin retinal nerve fiber layer show limited improvement over a longer time frame (months) (31). Older patients and patients with longer duration (more than 4 months) of vision loss should be counseled regarding the reduced chance of improvement in vision postoperatively (78).

Individuals presenting with optic nerve hypoplasia are at high risk for neuroradiologic and endocrine abnormalities (71). The neuroradiologic features are predictive of the presence and the type of hypopituitarism, though the etiology remains unidentified in the majority of cases.

Congenital hypopituitarism. Diagnosis of congenital hypopituitarism is based on a combination of clinical, laboratory, imaging, and genetic findings (21). Laboratory testing should address all hormonal axes. Imaging should include brain MRI with thin slices centered on the hypothalamic-pituitary region. Genetic testing should include next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, or genomic analysis.

Management

	• The goals of hormone replacement therapy in hypopituitarism are to achieve normal levels of the circulating hormones with minimal side effects.
	• For isolated hormone deficiencies, treatment consists of replacing individual hormones and periodically checking for the effectiveness of treatment as well as development of additional hormone deficiencies.
	• For panhypopituitarism, full hormonal replacement therapy must be undertaken, generally for life.
	• Adrenocorticotrophic hormone deficiency is best treated with glucocorticoid replacement therapy using steroids with moderate biological half-lives such as prednisone; to mimic the diurnal variation, these steroids are given twice a day, with two thirds of the dose after rising and one third of the dose in the late afternoon.
	• Surgical resection is recommended as the preferred primary intervention for symptomatic nonfunctioning pituitary macroadenomas.
	• Long-term radiologic, endocrinologic, and ophthalmologic surveillance monitoring after surgical or radiation therapy treatment of nonfunctioning pituitary macroadenomas is recommended to evaluate for tumor recurrence or regrowth, and to monitor pituitary and visual status.

The goals of hormone replacement therapy in hypopituitarism are to achieve normal levels of the circulating hormones with minimal side effects (82). The treatment of hypopituitarism may require a multidisciplinary team of endocrinologists, neurosurgeons, neurologists, ophthalmologists, and otorhinolaryngologists. It must include therapies directed at the underlying disease process and endocrine replacement therapy. Tumors may be treated with medical therapy, surgery, radiotherapy, or a combination. A macroprolactinoma, for instance, may be amenable to treatment with dopamine agonists, but a recurrent ACTH producing pituitary neoplasm is likely to require a combination of surgical and nonsurgical treatments.

For isolated hormone deficiencies, treatment consists of replacing individual hormones and periodically checking for the effectiveness of treatment as well as development of additional hormone deficiencies. For panhypopituitarism, full hormonal replacement therapy must be undertaken, generally for life. For the initiation of chronic maintenance therapy, it is imperative that coexistent thyroid and glucocorticoid deficiency be identified; an increase in metabolic rate associated with thyroid replacement therapy without appropriate glucocorticoid replacement can precipitate an adrenal crisis, which can be fatal. Prolactin and oxytocin deficiencies are typically not replaced. Growth hormone replacement therapy should also be considered for symptomatic adult patients.

Adrenocorticotrophic hormone deficiency is best treated with glucocorticoid replacement therapy using steroids with moderate biological half-lives such as prednisone. To mimic the diurnal variation, these steroids are given twice a day, with two thirds of the dose after rising and one third of the dose in the late afternoon. For prednisone, this is 5 and 2.5 mg, respectively. Use of short-acting glucocorticoids such as cortisone acetate (25 mg/12.5 mg) or hydrocortisone (20 mg/10 mg) works in many individuals, but the rapid peaks and troughs produce severe cyclical symptoms of fatigue, weakness, and mild nausea in some patients. These symptoms can sometimes be minimized by changing the dosage to three times daily. Occasionally, individuals will require even longer-acting steroids such as dexamethasone to feel well. Mineralocorticoid treatment is not required in hypopituitarism because aldosterone biosynthesis by the adrenal cortex remains functional via the renin-angiotensin system.

Thyroid hormone is administered daily as levothyroxine (generally in the 0.075 to 0.2 mg range). In many instances, hypopituitarism arises from macroadenomas in the older patient population, and thyroid hormone replacement therapy should be undertaken conservatively because occult cardiovascular disease may be coincidentally present. Initial therapy using 0.0125 to 0.025 mg per day will generally be sufficient to prevent myxedematous symptoms and avoid hyperkinetic cardiovascular status, which can result in dysrhythmias (atrial fibrillation, tachycardia, etc.), which in the long-term result in cardiac remodeling and systolic heart failure (20). The thyroid replacement dosage can then be gradually increased over months to a full replacement level while following serum thyroxine levels. (Thyroid stimulating hormone levels, in contrast to the more common primary hypothyroidism, should not be followed.)

Thyroxine is the treatment of choice taken once a day, starting with 100 mg in young patients and in the absence of cardiac disease, and 25 mg in elderly patients and those with coronary artery disease. ACTH deficiency should be identified and treated if present before starting thyroxine replacement. In patients with pituitary disease, thyroid stimulating hormone monitoring is unhelpful and, therefore, its measurement is pointless; the goals of thyroxine replacement should be clinical improvement along with the placing of the serum free thyroxine level within the normal range (82).

Sex steroid replacement therapy should be considered to preserve remaining bone mass, possibly restore libido, and provide a feeling of well-being. In men, testosterone therapy also helps preserve muscle mass. However, this should not be undertaken in individuals with macroadenomas until it is clear that they do not harbor macroprolactinomas, which may become enlarged when stimulated by sex steroids (83; 43). Estrogen is given for postmenopausal hormone replacement and is administered with progesterone for women with intact uteri to avoid endometrial hyperplasia. Young women often will not cycle well on the low postmenopausal estrogen dosages (eg, 0.625 mg of conjugated estrogens daily) and may require two to three times higher dosages of estrogen to experience withdrawal bleeding. Oral contraceptive therapy is another reasonable alternative. Although treatment with estrogen with or without progestogen is accepted as conventional therapy in women with hypopituitarism, testosterone supplementation in physiological doses for androgen-deficient women with hypopituitarism may improve psychological well-being and sexual function and increase bone mineral density and lean body mass (111). Population-based studies reveal that low testosterone levels predict development of type 2 diabetes mellitus, metabolic syndrome, and survival. Also, testosterone replacement therapy has been shown to have positive effects on sexual function, mood, body composition, muscle mass, and bone density in men with hypogonadism (17). Testosterone is currently available for administration by depot injection (200 to 300 mg every 2 to 3 weeks) and by scrotal or dermal patches.

Diabetes insipidus is not life-threatening unless thirst is also deficient or the patient cannot access fluids. The polyuria and polydipsia are treated only to relieve symptoms. Therapy is with desmopressin, a long-acting analog of vasopressin. Both a nasal solution and oral tablets are currently available. Patients should be instructed to use the minimum amount to provide symptomatic relief (typically 0.05 to 0.2 mL [5 to 20 mcg] intranasally once or twice a day).

Patients and their families need to be made aware of the potential seriousness of stressful situations that increase the requirements for glucocorticoids. Patients should carry medical-alert identification at all times in case of traumatic injury or sudden illness, requiring assistance from emergency medical personnel. Glucocorticoids should be doubled or tripled in mild to moderate organic illnesses, especially those associated with fever. No increases are required for mental stressors or mild upper respiratory syndromes not accompanied by fever. For vomiting, the patient should assume medication taken within the past hour is not absorbed and repeat the dose. If vomiting or diarrhea preclude adequate administration, parenteral glucocorticoids are necessary. Reliable patients should be given a syringe prefilled with dexamethasone (4 mg) for intramuscular self-injection to use in emergencies prior to presentation to a medical facility. This is especially important for those who reside in remote areas or who travel to underdeveloped countries.

Both fractionated radiotherapy and stereotactic radiosurgery are efficient treatment modalities for the control of tumor growth in patients with pituitary adenomas. One study indicated that single-dose radiosurgery more promptly produces an effect on the hypersecretion of pituitary hormones and may be recommended over fractionated radiotherapy for suitable patients (59). Szerlip and colleagues report the use of iMRI for pituitary adenoma resection (99). They find its use helpful in clinical decision making, guiding safe resection, identification and preservation of pituitary stalk and normal pituitary gland and potential avoidance of hypopituitarism. iMRI also helps to detect postoperative complications sooner helping with improved outcomes. Hypopituitarism in patients presenting with a pituitary adenoma is generally considered to be permanent. However, it has been suggested that in a significant number of patients, pituitary function recovers after transsphenoidal adenomectomy. This may be due to normalization of intrasellar pressure and blood flow (105).

Symptomatic macroadenomas. Both fractionated radiotherapy and stereotactic radiosurgery can be effective treatment modalities for the control of tumor growth in patients with pituitary macroadenomas. In one study, single-dose radiosurgery promptly produced an effect on the hypersecretion of pituitary hormones and was recommended over fractionated radiotherapy for suitable patients (59).

Transsphenoidal surgery is the treatment of choice for Сushing disease, with an effectiveness ranging from 70 to 90% and recurrence after successful treatment of about 25% (109). If surgical treatment is unsuccessful or recurrence occurs, radiation treatment is the next therapeutic option, with about 90% effectiveness, but the hypopituitarism rate as a side effect of treatment is higher (109).

Surgical resection is recommended as the preferred primary intervention for symptomatic nonfunctioning pituitary macroadenomas. Hypopituitarism is present in 80% of patients with nonfunctioning pituitary macroadenomas, and about half achieve sustained improvement after surgical resection (02). Hyperprolactinemia at diagnosis and lower tumor dimensions are associated with favorable endocrine prognosis. These results support the option of early surgery in patients with nonfunctioning pituitary macroadenomas who have pituitary deficits, independent of the presence of visual disturbances.

In a 2016 systematic review and evidence-based guideline, the Congress of Neurological Surgeons found that multiple retrospective studies and some prospective studies had demonstrated consistent effectiveness of primary surgical resection of symptomatic nonfunctioning pituitary macroadenomas with acceptable morbidity rates (66). Surgery produces an immediate tumor volume reduction in nearly all patients and a residual tumor rate of 10% to 36% (66). One prospective, observational cohort study and multiple retrospective studies showed improved visual function (75% to 91% of surgically treated patients) and improved hypopituitarism (35% to 50% of surgically treated patients). Limited class II evidence showed inconsistent benefits for observation alone, primary radiation-based treatment, or primary medical treatment (ie, using somatostatin analogs, dopamine agonists, or combination therapy) for improving vision, headaches, hypopituitarism, or tumor volume. One retrospective study of observation alone showed tumor progression in half of the patients and a requirement for surgery in 21%. Studies reporting primary radiosurgery treatment of nonfunctioning pituitary macroadenomas showed decreased tumor size in 38% to 60% of patients. Although reports for alternative treatment strategies to primary surgical resection are limited and inconsistent, such modalities may play a valid role in patients who are not surgical candidates.

Posttreatment follow-up. In a 2016 systematic review and evidence-based guideline, the Congress of Neurological Surgeons made recommendations for the posttreatment follow-up evaluation of patients with nonfunctioning pituitary macroadenomas (112). The authors recommended long-term radiologic, endocrinologic, and ophthalmologic surveillance monitoring after surgical or radiation therapy treatment of nonfunctioning pituitary macroadenomas to evaluate for tumor recurrence or regrowth, and to monitor pituitary and visual status. The first radiologic study to evaluate the extent of resection of a nonfunctioning pituitary macroadenomas should be performed at least 3 months after surgical intervention (112).

Outcomes

Postoperative visual outcome following microscopic transsphenoidal surgery for pituitary adenomas is proportional to preoperative visual acuity (34). Although the visual outcomes are good in the long run, regardless of the duration of symptoms, the speed of recovery is proportional to the presurgical duration of visual deficits (34).

Hypopituitarism in patients presenting with a pituitary adenoma is generally considered to be permanent. However, pituitary function recovers after transsphenoidal adenomectomy in some patients, possibly due to normalization of intrasellar pressure and blood flow (105). In addition, approximately 50% of patients with pituitary adenomas and preoperative hypopituitarism recover pituitary function after endoscopic endonasal transsphenoidal resection, whereas 10% of patients with normal function develop new deficits (04). Patients with nonfunctioning pituitary adenomas with visual involvement and operated on in the first 4 years of the neurosurgeon's learning curve, and patients with functioning pituitary adenomas with presurgical visual impairment and tumor size larger than 3 cm, have a higher risk of postoperative hypopituitarism (04).

With appropriate hormonal replacement therapy, patients with hypopituitarism can lead reasonably normal lives. Some (89), but not all (15) studies have demonstrated increased mortality among compared patients with hypopituitarism to age-matched control groups with most of the increased risk attributable to death from cardiovascular diseases. The principal complications are those of inappropriately replaced hormones (either too high or too low). Acute adrenal insufficiency may develop in the setting of severe stressors such as major surgery, illness, or accidents, if glucocorticoid administration is not appropriately increased. Central hypogonadism produces infertility, which can be overcome only by intensive hormonal therapy. Adequate replacement of pituitary hormones can greatly enhance quality of life, morbidity, and mortality associated with hypopituitarism (91). Osmotic demyelination syndrome and generalized dystonia have been reported with rapid correction of hyponatremia in two patients with preoperative sellar region tumors associated with hypopituitarism and secondary adrenal insufficiency (97). Persistent hyponatremia has been reported with Sheehan syndrome (11).

Special considerations

Pregnancy

The first documentation of enlargement of the pituitary gland during pregnancy was recorded in a doctoral dissertation by the French physician Louis Comte (1870-?) in 1898 (26). Uterine atony results in significant bleeding immediately after delivery, or the puerperium period, and is usually accompanied by significant hypotension or severe anemia, leading to hypoperfusion of the enlarged pituitary gland. Sheehan syndrome is hypopituitarism caused by necrosis of the anterior pituitary gland after severe blood loss, classically after childbirth. Essential criteria for the diagnosis of Sheehan syndrome include severe postpartum uterine bleeding, deficiency of at least one pituitary hormone deficiency, or a partial or complete empty sella on MRI or CT imaging. Severe hypotension during delivery, postpartum amenorrhea, or postpartum agalactia are also strongly suggestive of Sheehan syndrome (33). Delayed recognition of Sheehan syndrome of more than 30 years has been reported (106).

Face of a woman with hypopituitarism due to Sheehan syndrome

A 66-year-old woman with hypopituitarism due to Sheehan syndrome more than 30 years earlier after her last delivery was complicated by postpartum hemorrhage. She has pale skin but reddish eye mucosa. A marked wrinkling around t...
Legs of a woman with hypopituitarism due to Sheehan syndrome

A 66-year-old woman with hypopituitarism due to Sheehan syndrome more than 30 years earlier after her last delivery was complicated by postpartum hemorrhage. The patient's legs show a complete absence of hair, suggesting that a...
Empty sella turcica with pituitary tissue compressed against the sellar floor and lateral stalk deviation (MRI)

Cranial MRI of a 66-year-old woman with hypopituitarism due to Sheehan syndrome more than 30 years earlier after her last delivery was complicated by postpartum hemorrhage. The images show an empty sella turcica (arrows) with p...

The hypogonadal state resulting from hypopituitarism makes it unlikely that future spontaneous pregnancy can occur without assisted reproductive techniques (08). If pregnancy occurs in a woman with hypopituitarism, some have suggested that only the thyroid hormone needs to be adjusted (increased by about 50% on average) (67). Others have advocated a more inclusive replacement of deficient hormones (ie, increased dosage of replacement treatment for thyroid stimulating hormone, ACTH, and antidiuretic hormone deficits and discontinuation of growth hormone) (08). At the onset of labor, "stress doses" of glucocorticoids (eg, 100 mg of hydrocortisone every 8 hours) should be given until the first day postpartum and then quickly tapered back to maintenance dosages. Patients with diabetes insipidus often require exogenous infusion of oxytocin to initiate and maintain labor. Pregnancy outcomes in women with panhypopituitarism are comparable to those of the general population (36), though with a high rate of excessive gestational weight gain and cesarean section (08).

In a large group of pregnancies associated with growth hormone deficiency and hypopituitarism identified from 85 outpatient clinics at medical centers in 15 countries, pregnancy outcomes and pregnancy complications were not related to growth hormone replacement therapy treatment patterns, method of conception, or number of additional pituitary deficiencies (107).

Anesthesia

The physiological stress response to surgery includes an increase in circulating cortisol. In a patient with hypopituitarism, this cortisol response must be pharmacologically created; using the minimal amount of steroid replacement will optimize postoperative recovery and avoid deleterious side-effects.

The necessary amount of perioperative hydrocortisone varies depending on the length and type of surgery.

Generally, 150 to 300 mg of hydrocortisone is given on the day of surgery with around 60 to 200 mg given on postoperative day 1 with a following taper over several days (41).

Media

References

01: Acerini CL, Tasker RC. Traumatic brain injury induced hypothalamic-pituitary dysfunction: a paediatric perspective. Pituitary 2007;10(4):373-80. PMID 17570066
02: Alexopoulou O, Everard V, Etoa M, et al. Outcome of pituitary hormone deficits after surgical treatment of nonfunctioning pituitary macroadenomas. Endocrine 2021;73(1):166-76. PMID 33852154
03: Arafah BM. Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 1986;62:1173-9. PMID 3009521
04: Araujo-Castro M, Mariño-Sánchez F, García Fernández A, Acitores Cancela A, Rodríguez Berrocal V. Endoscopic endonasal approach to pituitary adenomas: impact on adenohypophyseal function. Study of 231 cases. Neurocirugia (Astur : Engl Ed) 2022;33(6):300-9. PMID 36333087
05: Asa SL, Bilbao JM, Kovacs K, Josse RG, Kreines K. Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: a distinct clinicopathologic entity. Ann Intern Med 1981;95:166-71. PMID 7196190
06: Atmaca H, Tanriverdi F, Gokce C, Unluhizarci K, Kelestimur F. Posterior pituitary function in Sheehan’s syndrome. Eur J Endocrinol 2007;156(5):563-7. PMID 17468192
07: Auer MK, Stieg MR, Crispin A, Sievers C, Stalla GK, Kopczak A. Primary empty sella syndrome and the prevalence of hormonal dysregulation. Deutsches Ärzteblatt International 2018;115(7):99-105. PMID 29510819
08: Aulinas A, Stantonyonge N, García-Patterson A, et al. Hypopituitarism and pregnancy: clinical characteristics, management and pregnancy outcome. Pituitary 2022;25(2):275-84. PMID 34846622
09: Baby N, Varghese P, Kunnathuparambil SG, Kuriakose AM. Hypophysitis: a rare cause of impaired consciousness in a middle-aged woman. Neurol India 2020;68(5):1214-6. PMID 33109880
10: Bacigaluppi S, Robba C, Bragazzi NL. Pituitary dysfunction after aneurysmal subarachnoidal hemorrhage. Handb Clin Neurol 2021;181:41-49. PMID 34238475
11: Bamoulid J, Courivaud C, Kazory A, Bonneville JF, Ducloux D. The case: a female with hyponatremia. Diagnosis: Postpartum panhypopituitarism (Sheehan syndrome). Kidney Int 2009;76(3):351-2. PMID 19904259
12: Bandeira L, de Oliveira LB, de Lima MVS, Rêgo D, Griz L, Bandeira F. Hypopituitarism due to a large osteoclastoma arising from the sphenoid bone invading the pituitary fossa in a patient with parathyroid carcinoma. Case Rep Endocrinol 2023;2023:8274108. PMID 38156081
13: Bando H, Iguchi G, Yamamoto M, Hidaka-Takeno R, Takahashi Y. Anti-PIT-1 antibody syndrome; a novel clinical entity leading to hypopituitarism. Pediatr Endocrinol Rev 2015;12(3):290-6. PMID 25962206
14: Bando H, Kanie K, Takahashi Y. Paraneoplastic autoimmune hypophysitis: an emerging concept. Best Pract Res Clin Endocrinol Metab 2022;36(3):101601. PMID 34876362
15: Bates AS, Van't Hoff W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996;81(3):1169-72. PMID 8772595
16: Bautista G. Overview of congenital hypopituitarism for the neonatologist. Neoreviews 2022;23(5):e300-10. PMID 35490188
17: Beg S, Al-Khoury L, Cunningham GR. Testosterone replacement in men. Curr Opin Internal Med 2008;7(5):470-6. PMID 18594278
18: Benvenga S, Campenni A, Ruggeri RM, Trimarchi F. Clinical review 113: hypopituitarism secondary to head trauma. J Clin Endocrinol Metab 2000;85:1353-61. PMID 10770165
19: Busch W. Die Morphologie der Sella turcica und ihre Beziehungen zur Hypophyse [Morphology of sella turcica and its relation to the pituitary gland]. Virchows Archiv für pathologische Anatomie und Physiologie und für klinische Medizin 1951;320:437-58.
20: Calsolaro V, Niccolai F, Pascualetti G, et al. Hypothyroidism in the elderly: who should be treated and how? J Endocr Soc 2019;3(1):146-58. PMID 30607373
21: Castets S, Thomas-Teinturier C, Villanueva C, et al. Diagnosis and management of congenital hypopituitarism in children. Arch Pediatr 2024;31(3):165-71. PMID 38538470
22: Cheer K, Trainer P. Evaluation of pituitary function. Handb Clin Neurol 2014;124:141-9. PMID 25248585
23: Chen CC, Carter BS, Wang R, et al. Congress of Neurological Surgeons systematic review and evidence-based guideline on preoperative imaging assessment of patients with suspected nonfunctioning pituitary adenomas. Neurosurgery 2016;79(4):E524-6.** PMID 27635958
24: Chen H, Li Y, Zhang P, Wang Y. A case report of empty Sella syndrome secondary to Hantaan virus infection and review of the literature. Medicine (Baltimore) 2020;99(14):e19734. PMID 32243412
25: Claessen LO, Kristjánsdóttir H, Jónsdóttir MK, Lund SH, Kristensen ISU, Sigurjónsdóttir HÁ. Screening for possible hypopituitarism following mild traumatic brain injury: the first all-female study. Who do we need to evaluate further? NeuroRehabilitation 2023;52(2):259-71. PMID 36641687
26: Comte L. Contribution a l’etude de l’hypophyse humaine. Thesis. Lausanne, Switzerland, 1898.
27: Cooksley T, Knight T, Lindsay D, et al. Immune checkpoint inhibitor-mediated hypophysitis: no place like home. Clin Med (Lond) 2023;23(1):81-4. PMID 36697002
28: Crespo I, Santos A, Webb SM. Quality of life in patients with hypopituitarism. Curr Opin 2015;22(4): 306-312. PMID 26103454
29: Cuesta M, Hannon MJ, Crowley RK, et al. Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury. Clin Endocrinol (Oxf) 2016;84(1):92-8. PMID 26252757
30: Cushing H. The pituitary body and its disorders. Philadelphia: J B Lippincott, 1912.**
31: Danesh-Meyer H, Wong A, Papchenko T, et al. 2015. Optical coherence tomography predicts visual outcome for pituitary tumors. J Clin Neurosci 2015;22(7):1098-104. PMID 25891894
32: de Herder WW. Acromegaly and gigantism in the medical literature. Case descriptions in the era before and the early years after the initial publication of Pierre Marie (1886). Pituitary 2009;12(3):236-44.** PMID 18683056
33: Diri H, Karaca Z, Tanriverdi F, Unluhizarci K, Kelestimur F. Sheehan’s syndrome: new insights into an old disease. Endocrine 2016;51(1):22-31. PMID 26323346
34: Dutta P, Gyurmey T, Bansal R, et al. Visual outcome in 2000 eyes following microscopic transsphenoidal surgery for pituitary adenomas: protracted blindness should not be a deterrent. Neurol India 2016;64(6):1247-53.** PMID 27841194
35: Edwards OM, Clark JD. Post-traumatic hypopituitarism. Six cases and a review of the literature. Medicine 1986;65:281-90. PMID 3018425
36: Feferkorn I, Badeghiesh A, Baghlaf H, Dahan MH. Pregnancy outcomes in women with panhypopituitarism: a population-based study. Reprod Biomed Online 2022;44(3):532-7. PMID 35031238
37: Fernandez Rodriguez E, Villar Taibo R, Bernabeu I. Hypopituitarism after traumatic brain injury in adults: clinical guidelines of the neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition (SEEN). Endocrinol Diabetes Nutr (Engl Ed) 2023;70(9):584-91. PMID 37977921
38: Ferreira NGBP, Madeira JLO, Gergics P, et al. Homozygous CDH2 variant may be associated with hypopituitarism without neurological disorders. Endocr Connect 2023;12(8):e220473. PMID 37166408
39: Fleseriu M, Bodach ME, Tumialan LM, et al. Congress of Neurological Surgeons systematic review and evidence-based guideline for pretreatment endocrine evaluation of patients with nonfunctioning pituitary adenomas. Neurosurgery 2016;79(4):E527-9.** PMID 27635959
40: Freda PU, Bruce JN, Khandji AG, et al. Presenting features in 269 patients with clinically nonfunctioning pituitary adenomas enrolled in a prospective study. J Endocr Soc 2020;4(4):bvaa021. PMID 32258955
41: Fridman-Bengtsson O, Hoybye C, Porthen L, Stjarne P, Hultin A, Sunnergren O. Evaluation of different hydrocortisone treatment strategies in transphenoidal pituitary surgery. Acta Neurochir (Wien) 2019;161(8):1715-21. PMID 31065892
42: Furuichi N, Naganuma A, Kaburagi T, et al. Three cases of immune-related hypopituitarism after atezolizumab-bevacizumab treatment for hepatocellular carcinoma. Clin J Gastroenterol 2023;16(3):422-31. PMID 36821067
43: Gooren LJ, Assies J, Asscheman H, de Slegte R, van Kessel H. Estrogen-induced prolactinoma in a man. J Clin Endocrinol Metab 1988;66:444-6. PMID 3339116
44: Gregory LC, Cionna C, Cerbone M, Dattani MT. Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders. Genet Med 2023;25(9):100881. PMID 37165954
45: Haimi M, Gershoni-Baruch R. Autosomal recessive Oliver-McFarlane syndrome: retinitis pigmentosa, short stature (GH deficiency), trichomegaly, and hair anomalies or CPD syndrome (chorioretinopathy-pituitary dysfunction). Am J Med Genet A 2005;138A(3):268-71. PMID 16152639
46: Han X, Meng M, Zhang T, et al. Hypophysitis: a rare but noteworthy immune-related adverse event secondary to camrelizumab therapy. J Cancer Res Ther 2022;18(5):1440-3. PMID 36204895
47: Hanawa K, Sawada N, Aikawa J, et al. Hypopituitarism induced by pembrolizumab plus axitinib in the treatment of metastatic renal cell carcinoma: a case report. Oncol Lett 2023;27(2):66. PMID 38192652
48: Hannon M, Crowley R, Behan L, et al. Acute glucocorticoid deficiency and diabetes insipidus are common following acute traumatic brain injury and predict mortality. J Clin Endocrinol Metab 2013;98(8):3229-37. PMID 23690314
49: Heshmati HM, Fatourechi V, Dagam SA, Piepgras DG. Hypopituitarism caused by intrasellar aneurysms. Mayo Clin Proc 2001;76(8):789-93. PMID 11499817
50: Iguchi G, Bando H, Takahashi Y. A novel clinical entity of autoimmune endocrinopathy: anti-PIT-1 antibody syndrome. Front Horm Res 2017;48:76-83. PMID 28245453
51: Inzucchi SE. Growth hormone in adults: indications and implications. Hosp Pract (1995)1997;32(1):79-96. PMID 9006584
52: Jacques JP, Valadares LP, Moura AC, Oliveira MRF, Naves LA. Frequency and clinical characteristics of hypophysitis and hypopituitarism in patients undergoing immunotherapy - a systematic review. Front Endocrinol (Lausanne) 2023;14:1091185. PMID 36875457
53: Joshi MN, Whitelaw BC, Carroll PV. Mechanisms in endocrinology: hypophysitis: diagnosis and treatment. Eur J Endocrinol 2018;179(3):R151-63. PMID 29880706
54: Kanie K, Iguchi G, Inuzuka M, et al. Two cases of anti-PIT-1 hypophysitis exhibited as a form of paraneoplastic syndrome not associated With thymoma. J Endocr Soc 2020;5(3):bvaa194. PMID 33506159
55: Kırkgoz T, Gürsoy S, Acar S, et al. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4 and POU1F1 genes. Arch Endocrinol Metab 2023;68:e220254. PMID 37948564
56: Kızılgul M, Bayır Ö, Uçan B, et al. Metastatic diffuse follicular variant papillary thyroid cancer without cervical lymph node metastasis presenting with symptoms related to hypopituitarism. Einstein (Sao Paulo) 2023;21:eRC0229. PMID 37493833
57: Klose M, Feldt-Rasmussen U. Hypopituitarism in traumatic brain injury-a critical note. J Clin Med 2015;4(7):1480-97. PMID 26239687
58: Kokshoorn NE, Wassenaar MJ, Biermasz NR, et al. Hypopituitarism following traumatic brain injury: prevalence is affected by the use of different dynamic tests and different normal values. Eur J Endocrinol 2010;162(1):11-8. PMID 19783619
59: Kong DS, Lee JI, Lim do H, et al. The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: long-term results of 125 consecutive patients treated in a single institution. Cancer 2007;110(4):854-60. PMID 17599761
60: Kurtoglu S, Ozdemir A, Hatipoglu N. Neonatal hypopituitarism: approaches to diagnosis and treatment. J Clin Res Pediatr Endocrinol 2019;11(1):4-12. PMID 29739730
61: Lawson EA, Buchbinder BR, Daniels GH. Hypopituitarism associated with a giant aneurysm of the internal carotid artery. J Clin Endocrinol Metab 2008;93(12):461. PMID 19056841
62: Lee I, Hackman K, Liubinas S, Maartens N, Colman P. A giant aneurysm of internal carotid artery causing hypopituitarism. Intern Med J 2010;40(6):464-5. PMID 20636831
63: Littley MD, Shalet SM, Beardwell CG, et al. Hypopituitarism following external radiotherapy for pituitary tumors in adults. Q J Med 1989;70:145-60. PMID 2594955
64: Liu F, Li G, Yao Y, et al. Diagnosis and management of pituitary abscess: experiences from 33 cases. Clin Endocrinol (Oxf) 2011;74(1):79-88. PMID 21039726
65: Lo Iudice G, D'Alessandro B, Esposito V, et al. Hypopituitarism following a direct bullet injury to the pituitary. A case report. Minerva Endocrinol 1989;14:251-4. PMID 2700015
66: Lucas JW, Bodach ME, Tumialan LM, Oyesiku NM, et al. Congress of Neurological Surgeons systematic review and evidence-based guideline on primary management of patients with nonfunctioning pituitary adenomas. Neurosurgery 2016;79(4):E533-5.** PMID 27635961
67: Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990;323:91-6. PMID 2359428
68: Marie P. Sur deux cas d'acromeglaie; hypertrophie singuliere non congenitale des extremites superieures et inferieures cephalique. Rev de med 1886;6:297-333.
69: McLachlan MSF, Williams ED, Doyle FH. Applied anatomy of the pituitary gland and fossa. A radiological and histopathological study based on 50 necropsies. Br J Radiol 1968;41:782-8.
70: McLoughlin RJ, Swanson RL 2nd. Hypopituitarism after mild traumatic brain injury: a case report. Cureus 2023;15(7):e41282. PMID 37405126
71: Mehta A, Hindmarsh PC, Mehta H, et al. Congenital hypopituitarism: clinical, molecular and neuroradiological correlates. Clin Endocrinol (Oxf) 2009;71(3):376-82. PMID 19320653
72: Menon RK, Ball WS, Sperling MA. Choroideremia and hypopituitarism: an association. Am J Med Genet 1989;34(4):511-3. PMID 2624260
73: Miura M, Ushio Y, Kuratsu J, et al. Lymphocytic adenohypophysitis: report of two cases. Surg Neurol 1989;32:463-70. PMID 2700055
74: Molitch M, Elton RL, Blackwell RE, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter trial. J Clin Endocrinol Metab 1986;60:698-705. PMID 3882737
75: Mnif-Feki M, Safi W, Bougacha-Elleuch N, et al. Occurrence of hypopituitarism in Tunisian Turner syndrome patients: familial versus sporadic cases. Gynecol Endocrinol 2021;37(9):848-52. PMID 34124982
76: Nakaguma M, Ferreira NGBP, Benedetti AFF, et al. Allelic variants in established hypopituitarism genes expand our knowledge of the phenotypic spectrum. Genes (Basel) 2021;12(8):1128. PMID 34440302
77: Nakata Y, Sato N, Masumoto T, et al. Parasellar T2 dark sign on MR imaging in patients with lymphocytic hypophysitis. AJNR Am J Neuroradiol 2010;31(10):1944-50. PMID 20651017
78: Newman SA, Turbin RE, Bodach ME, et al. Congress of Neurological Surgeons systematic review and evidence-based guideline on pretreatment ophthalmology evaluation in patients with suspected nonfunctioning pituitary adenomas. Neurosurgery 2016;79(4):E530-2.** PMID 27635960
79: Ntali G, Wass JA. Epidemiology, clinical presentation and diagnosis of non-functioning pituitary adenomas. Pituitary 2018;21(2):111-8.** PMID 29368293
80: Olmes GL, Solomayer EF, Radosa JC, et al. Acute Sheehan's syndrome manifesting initially with diabetes insipidus postpartum: a case report and systematic literature review. Arch Gynecol Obstet 2022;306(3):699-706. PMID 34779875
81: Ooi TC, Russell NA. Hypopituitarism resulting from an intrasellar carotid aneurysm. Can J Neurol Sci 1986;13:70-1. PMID 3955456
82: Prabhakar VK, Shalet SM. Aetiology, diagnosis, and management of hypopituitarism in adult life. Postgrad Med J 2006;82(966):259-66. PMID 16597813
83: Prior JC, Cox TA, Fairholm D, Kostashuk E, Nugent R. Testosterone-related exacerbation of a prolactin-producing macroadenoma: possible role for estrogen. J Clin Endocrinol Metab 1987;64:391-4. PMID 3793856
84: Prodam F, Gasco V, Caputo M, et al. Metabolic alterations in patients who develop traumatic brain injury (TBI)-induced hypopituitarism. Growth Horm IGF Res 2013;23(4):109-13. PMID 23660372
85: Reye E. Das klinische Bild der Simmons schen Krankheit (hypophysare Kachexie) in ihrem Anfangsstadium und ihrem Anfangsstadium und ihre Behandlung. Munch Med Wochenschr 1926;73:902-6.
86: Reye E. Die ersten klinischen Symptome bei Schwund des Hypophysenvorderlappens (Simmondssche Krankheit) und ihre erfolgreiche Behandlung. Deutsche Medizinische Wochenschrift 1928;54:696.
87: Reynaud R, Jayakody SA, Monnier C, et al. PROKR2 Variants in Multiple Hypopituitarism with Pituitary Stalk Interruption. J Clin Endocrinol Metab 2012;97(6):E1068-73. PMID 22466334
88: Robba C, Aspide R, Pegoli M, et al. Pituitary dysfunction after aneurysmal subarachnoid hemorrhage: a prospective cohort study. J Neurosurg Anesthesiol 2022;34(1):44-50. PMID 32604221
89: Rosen T, Bengtsson B. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285. PMID 1973979
90: Sampson JR, Tolmie JL, Cant JS. Oliver McFarlane syndrome: a 25-year follow-up. Am J Med Genet 1989;34(2):199-201. PMID 2816997
91: Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, Stalla GK, Ghigo E. Hypopituitarism. Lancet 2007a;369(9571):1461-70. PMID 17467517
92: Schneider HJ, Kreitschman-Andermahr I, Ghigo E, Stalla GK, Agha A. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage. JAMA 2007b;298(12):1429-38. PMID 17895459
93: Sheehan HL. Post-partum necrosis of the anterior pituitary. J Pathol Bacteriol 1937;45:189-214.**
94: Sheehan HL. Simmond's disease due to post-partum necrosis of the anterior pituitary. Q J Med 1939;8:277-309.**
95: Simmonds M. Uber embolische Prozesse in der Hypophysis. Virchows Arch 1914;217:226-39.
96: Slagboom TNA, Deijen JB, Van Bunderen CC, Knoop HA, Drent ML. Psychological well-being and illness perceptions in patients with hypopituitarism. Pituitary 2021;24(4):542-54. PMID 33606176
97: Srimanee D, Bhidayasiri R, Phanthumchinda K. Extrapontine myelinolysis in preoperative sellar region tumor: report of two cases. J Med Assoc Thai 2009;92(11):1548-53. PMID 19938750
98: Stojanovic M, Pekic S, Cvijovic G, et al. High risk of hypopituitarism in patients who recovered from hemorrhagic fever with renal syndrome. J Clin Endocrinol Metab 2008;93(7):2722-8. PMID 18430769
99: Szerlip NJ, Zhang YC, Placantonakis DG, et al. Transsphenoidal resection of sellar tumors using high-field intraoperative magnetic resonance imaging. Skull Base 2011;21(4):223-32. PMID 22470265
100: Tahara S, Otsuka F, Endo T. Recognition and practice of hypopituitarism after traumatic brain injury and subarachnoid hemorrhage in Japan: a survey. Neurol Ther 2024;13(1):39-51. PMID 37874463
101: Tanriverdi F, Kelestimur F. Pituitary dysfunction following traumatic brain injury: clinical perspectives. Neuropsychiatr Dis Treat 2015;11:1835-43. PMID 26251600
102: Tollin SR, Seely EW. Case report: postpartum hypopituitarism in a patient with sickle cell trait. Am J Med 1994;308:35-7. PMID 8010335
103: Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. Lancet 2001;357(9254):425-31. PMID 11273062
104: Toogood A, Stewart P. Hypopituitarism: clinical features, diagnosis, and management. Endocrinol Metab Clin N Am 2008;37(1):235-61.** PMID 18226739
105: Van Aken MO, Lamberts SW. Diagnosis and treatment of hypopituitarism: an update. Pituitary 2005;8(3-4):183-91.** PMID 16508719
106: Vasconcelos AL, Pinto Ribeiro R, Claúdio Ferreira P, Maciel J, Araújo R. A case report of Sheehan syndrome: a rare cause of hypopituitarism. Cureus 2024;16(2):e53544. PMID 38445135
107: Vila G, Akerblad AC, Mattsson AF, et al. Pregnancy outcomes in women with growth hormone deficiency. Fertil Steril 2015;104(5):1210-17.e1. PMID 26256649
108: Weiss RE. Hypopituitarism: emergencies. In: De Groot LJ, Chrousos G, Dungan K, et al, editors. Endotext [Internet]. South Dartmouth (MA):MDText.com, Inc, 2015.** PMID 25905291
109: Yanar EA, Makazan NV, Kareva MA, et al. Course of Cushing’s disease and treatment outcomes in correlation with pituitary MRI in children. Probl Endokrinol (Mosk) 2022;68(3):93-104. PMID 35841173
110: Yavas Abali Z, Gokpinar Ili E, Bas F, et al. A novel RNPC3 gene variant expands the phenotype in patients with congenital hypopituitarism and neuropathy. Horm Res Paediatr 2024;97(2):157-64. PMID 37463572
111: Zang H, Davis SR. Androgen replacement therapy in androgen-deficient women with hypopituitarism. Drugs 2008;68(15):2085-93. PMID 18840000
112: Ziu M, Dunn IF, Hess C, et al. Congress of Neurological Surgeons systematic review and evidence-based guideline on posttreatment follow-up evaluation of patients with nonfunctioning pituitary adenomas. Neurosurgery 2016;79(4):E541-3.** PMID 27635964

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile

Former Authors

Michael L Brines MD PhD
Silvio E Inzucchi MD
Sarika Shirsat MD
Tarakad S Ramachandran MD
Arun Ramachandran MD
Jonathan Nakhla MD
Yevgeniya Nepomnyashchaya MSN AGACNP-BC
Mousa K Hamad MD
Ryan M Holland MD
Aisha S Obeidallah BA
Reza Yassari MD MS

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Panhypopituitarism: E23.0

Hypothalamic dysfunction, not elsewhere classified: E23.3

Postprocedural hypopituitarism: E89.3
ICD-11: Hypopituitarism: 5A61.0

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Hypopituitarism

Associated Disorders

Craniopharyngioma
Diabetes insipidus
Diabetes mellitus
Direct trauma
Disconnected pituitary syndrome
- Dysgerminoma
- Empty sella syndrome
- Hemochromatosis
- Infiltrative diseases
- Langerhans cell histiocytosis
- Lymphocytic hypophysitis
- Pituitary macroadenoma
- Macroadenoma
- Meningioma
- Metastatic carcinoma
- Neurosarcoidosis
- Neurosyphilis
- Neurotuberculosis
- Pituitary apoplexy
- Pituitary ischemic necrosis
- Pituitary tumors
- Polyglandular failure syndrome
- Sheehan syndrome
- Wegener granulomatosis

Differential Diagnosis

primary endocrine gland failure
polyendocrine failure syndrome
anorexia nervosa
pituitary macroadenoma
pituitary microadenoma
- traumatic brain injury
- Wegener's granulomatosis
- sarcoidosis
- tuberculoma
- syphilitic gumma
- Langerhans cell histiocytosis (histiocytosis x)
- lymphocytic hypophysitis
- hemochromatosis
- tumor metastases to pituitary gland

Hypopituitarism

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Brain death/death by neurologic criteria

Hormonal contraception and stroke

Hepatic encephalopathy

Cervical spondylotic myelopathy

Bowel dysfunction in neurologic disorders

This is an article preview.
Start a Free Account
to access the full version.