Hypopituitarism

Template:DiseaseDisorder infobox

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2], Ahmed Elsaiey, MBBCH [3]

Hypopituitarism is referred to the deficiency of one of the pituitary gland hormones or more while the deficiency of all pituitary hormones is known as panhypopituitarism. A study comprising two cross-sectional surveys showed the prevalence of hypopituitarism to be 29 per 100,000 individual in the first survey and 45.5 per 100,000 individual in the second survey. Hypopituitarism can be classified on the basis of the anatomical location of pathology into primary (pituitary) and secondary (hypothalamic) hypopituitarism. It can also be classified on the basis of the portion of gland involvement into partial or complete glandular involvement. The pathophysiology of hypopituitarism mainly involves ischemic injury of the pituitary gland. The ischemia may be due to hemorrhage, tumors, brain injury, and compression or occlusion of the hypophyseal blood vessels. Causes of hypopituitarism may be classified based upon the etiology such as congenital or acquired. Common congenital causes include idiopathic, anatomic lesion in the sella turcica and CNS malformations. Common acquired causes may include pituitary macroadenoma, craniopharyngioma, surgery, radiation, traumatic brain injury, Sheehan’s syndrome, apoplexy, SAH, meningitis, hypophysitis, meningioma, lymphoma, hemochromatosis and Wegner’s granulomatosis. Less common causes include peri-natal insults, genetic causes, and pituitary hypoplasia or aplasia. Hypopituitarism should be differentiated from other diseases causing panhypopituitarism, hypothyroidism, hypogonadism, ACTH deficiency, GH deficiency, ADH deficiency and high prolactin level. Common risk factors in the development of hypopituitarism may include pituitary tumor or space occupying lesion, pituitary apoplexy, severe blood loss such as Sheehan’s syndrome, pituitary surgery, cranial radiation, genetic defects, hypothalamic disease, immunosuppression, inflammatory processes, pituitary infarction and non-compliance with hormone replacement therapy. Less common risk factors include infiltrative disorders, traumatic brain injury causing skull fractures, ischemic stroke and subarachnoid hemorrhage. Screening of hypopituitarism has been recommended for the patients with traumatic brain injury and patients with a history of radiation exposure on the head. The natural history of hypopituitarism depends on the severity of damage leading to partial or complete hormonal deficiency. If left untreated can lead to critical consequences. Complications of hypopituitarism include adrenal crisis, osteoporosis, electrolyte abnormalities, and diabetes mellitus. Hypopituitarism is often associated with vascular conditions and has a high mortality rate. Hypopituitarism has a good prognosis as long as the hormonal replacement therapy is given adequately. A positive history of head trauma, adenoma, a lesion such as a sellar lesion, or any symptom related to pituitary hormonal deficiency is suggestive of hypopituitarism. Patients of hypopituitarism may be asymptomatic or show symptoms which can be nonspecific or specific for the deficient hormone. Patients with acute onset of hypopituitarism can present with a headache, nausea, vomiting, visual impairment, fatigue, cold intolerance, hypotension, and dizziness. Patients with chronic hypopituitarism can present with pallor, weight loss, and anorexia. Clinical presentation in hypopituitarism depends upon the onset, the severity of hormonal deficiency and the number of deficient hormones. A subnormal or reduced concentration of pituitary hormones is diagnostic of hypopituitarism. Patients with complete hormonal deficiencies are mostly symptomatic and have low serum concentrations of both, the pituitary hormones as well as the target-organ hormones. Patients having partial hormonal deficiencies are detected by dynamic tests/stimulatory tests such as corticotropin stimulation, insulin-induced hypoglycemia, and metyrapone test. MRI scan with intravenous gadolinium is the imaging procedure of choice in the diagnosis of hypopituitarism. It is preferred over the CT scan as optic chiasm, pituitary stalk, and cavernous sinuses can be seen in MRI. Treatment involves appropriate hormone replacement therapy, which must be taken for the rest of your life that results in significant improvement and reversal of not only the physical symptoms but also the psychological symptoms. Conditions that need a surgical consideration may include pituitary apoplexy , microadenomas with GH or ACTH hypersecretion and debulking macroadenomas with mass symptoms and resistant to medical therapy. Hypopituitarism can be prevented by good obstetric care, minimizing radiation exposure and high-resolution microscopic hypophyseal surgery done by experienced neurosurgeons.

Hypopituitarism was first described by Dr. Simmonds for the first time in 1914. Dr. Yalow and Berson discovered the radioimmunoassay in 1950. Causes of the hypopituitarism were being described through the 20th and 21st centuries.

Hypopituitarism can be classified on the basis of location of pathology into primary or secondary hypopituitarism. It can also be classified on the basis of the extent of gland involved into partial or complete glandular involvement. 

Hypopituitarism occurs secondary to ischemia of the pituitary gland. This ischemia can be due to hemorrhage, tumors, or brain injury. Compression of the blood vessels is one of the mechanisms that cause ischemia to the pituitary gland and leads to hypopituitarism. Pituitary adenomas cause compression of the hypophyseal vessels leading to interruption in the blood supply of the pituitary gland. Traumatic brain injury either primary or secondary also leads to pituitary gland dysfunction.

Causes of hypopituitarism can be classified based upon the etiology into congenital or acquired. Common congenital causes include idiopathic, anatomiclesion in the sella turcica and CNS malformations. Common acquired causes may include pituitary macroadenoma, craniopharyngioma, surgery, radiation,traumatic brain injury, Sheehan’s syndrome, apoplexy, SAH, meningitis, hypophysitis, meningioma, lymphoma, hemochromatosis and Wegner’s granulomatosis. Less common causes include Peri-natal insults, genetic causes, such as Kallman syndrome, Pallister-Hall syndrome, Rieger syndrome, and pituitary hypoplasia or aplasia.

Hypopituitarism should be differentiated from other diseases causing panhypopituitarism, hypothyroidism, hypogonadism, ACTH deficiency, GH deficiency,ADH deficiency and high prolactin level.

In a longitudinal survey (1992-1999), the incidence of hypopituitarism was estimated to be 4.2 cases per 100,000. A study comprising two cross-sectional surveys showed the prevalence of hypopituitarism to be 29 – 45.5 per 100.000 individual.

Common risk factors in the development of hypopituitarism may include pituitary tumor or space occupying lesion, pituitary apoplexy, severe blood loss such as Sheehan’s syndrome, pituitary surgery, cranial radiation, genetic defects, hypothalamic disease, immunosuppression, inflammatory processes,pituitary infarction and non-compliance with hormone replacement therapy. Less common risk factors include infiltrative disorders, traumatic brain injurycausing skull fractures, ischemic stroke and subarachnoid hemorrhage.

Screening of hypopituitarism has been recommended for the patients with traumatic brain injury and patients with a history of radiation exposure on the head. 

The natural history of hypopituitarism depends on the severity of damage leading to partial or complete hormonal deficiency. If left untreated, hypopituitarism can lead to critical consequences. Complications of hypopituitarism include adrenal crisis, osteoporosis, electrolyte abnormalities anddiabetes mellitus. Hypopituitarism is often associated with vascular conditions. Hypopituitarism has a good prognosis as long as the hormonal replacement therapy is given adequately.

A positive history of head trauma, adenoma, a lesion such as a sellar lesion, or any symptom related to pituitary hormonal deficiency is suggestive ofhypopituitarism. Patients of hypopituitarism may be asymptomatic or show symptoms which can be nonspecific or specific for the deficient hormone. Patients with acute onset of hypopituitarism can present with a headache, nausea, vomiting, visual impairment, fatigue, cold intolerance, hypotension, anddizziness. Patients with chronic hypopituitarism can present with pallor, weight loss, and anorexia.

Clinical presentation in hypopituitarism depends upon the onset, the severity of hormonal deficiency and the number of deficient hormones. Patients with hypopituitarism are ill-appearing and usually look tired. Physical examination of patients with hypopituitarism is usually remarkable for the respectivehormonal deficiency and present with features of that specific hormone such as hypothyroidism presents as delayed relaxation of tendon reflexes,bradycardia, coarse skin, puffy facies, and loss of eyebrows. ACTH deficiency can present with postural hypotension, tachycardia, and weight loss.Gonadotropin deficiency may present with breast atrophy, soft testes, and regression of sexual characteristics. Growth hormone deficiency can present with short stature, decreased sweating with impaired thermogenesis, and reduced muscle mass.

A subnormal or reduced concentration of pituitary hormones is diagnostic of hypopituitarism. Patients with complete hormonal deficiencies are mostlysymptomatic and have low serum concentrations of both, the pituitary hormones as well as the target-organ hormones. Patients having partial hormonaldeficiencies are detected by dynamic tests/stimulatory tests such as corticotropin stimulation, insulin-induced hypoglycemia and metyrapone test.Corticotropin deficiency is detected by assessing basal cortisol secretion. Patients with intermediate cortisol levels need to be tested foradrenocorticotrophic hormone (ACTH) reserve. There are several tests to check the ACTH reserve. Metyrapone test is preferred over others as it is applicable to all adults with no age restriction and has good correlation with stress related cortisol response. Patients with hypopituitarism are screened forhypothyroidism by measuring thyroxine, total thyroxine (T4) and triiodothyronine (T3) uptake, and free T4. Gonadotropin deficiency is confirmed with lowestradiol, low testosterone, and low/normal serum FSH/LH. Growth hormone deficiency is confirmed with provocative tests (insulin induced hypoglycemiaand arginine and GHRH combination) for GH secretion resulting in subnormal levels of serum GH levels, serum insulin-like growth factor-1 levels lower than the age-specific lower limit of normal and deficiency of more than one pituitary hormones e.g ACTH, TSH, and gonadotropins. ADH deficiency is assessed by water deprivation test and ADH suppression test. Prolactin deficiency can be confirmed by directly measuring prolactin levels on more than 1 occasion as its secretion is episodic but it is not done routinely as it is not clinically significant.

There are no electrocardiogram findings associated with hypopituitarism.

There are no X ray findings associated with hypopituitarism.

CT scan is preferred over MRI for visualization of calcification in a meningioma or a craniopharyngioma. Routine CT is insensitive to the diagnosis unless frank intracranial hemorrhage is present.The pituitary mass may be evident and be hyperdense.

MRI is the imaging procedure of choice in the diagnosis of hypopituitarism. It is preferred over the CT scan as optic chiasm, pituitary stalk, and cavernous sinuses can be seen in MRI. An MRI lesion needs to be related to clinical and lab findings. The absence of an MRI lesion mostly indicates a non-organic etiology. Cystic lesions, such as Rathke’s cleft cysts may have a low-intensity signal on T1-weighted images and a high-intensity signal on T2-weighted images. Meningiomas have a homogenous postcontrast enhancement than pituitary adenomas and have a suprasellar attachment. Hemorrhage into the pituitary gland results in a high-intensity signal on both T1- and T2-weighted images.

There are no ultrasound findings associated with hypopituitarism.

There are no other specific imaging findings for hypopituitarism.

Other diagnostic findings may include serum and CSF angiotensin converting enzyme activities, serum ferritin to rule out hemochromatosis, human chorionic gonadotrophin (HCG) and genetic testing.

The mainstay of treatment for hypopituitarism is hormone replacement therapy and treating the underlying cause. Adrenocorticotrophic hormone (ACTH) deficiency is treated with glucocorticoids. Gonadotropin deficiency is treated with testosterone in men and estrogen with or without progesterone in women.Hypothyroidism is treated with levothyroxine. Growth hormone (GH) is usually replaced in children and replaced in adults only if symptomatic and after replacement of all other pituitary hormones.

The feasibility of surgery depends on the clinical condition and underlying etiology. Conditions that need a surgical consideration may include pituitary apoplexy, microadenomas with growth hormone (GH) or adrenocorticotrophic hormone (ACTH) hypersecretion and debulking macroadenomas with masssymptoms and resistant to medical therapy.

Hypopituitarism can be prevented by good obstetric care, minimizing radiation exposure and high-resolution microscopic hypophyseal surgery done by experienced neurosurgeons.

Secondary prevention may be done by long-term monitoring of patients for complications of hormonal replacement therapy and by dose adjustments in stressful situations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Hypopituitarism was first described by Dr. Simmonds for the first time in 1914. Dr. Yalow and Berson discovered the radioimmunoassay, in 1950. Causes of the hypopituitarism were being described through the 20th and 21st centuries.

• In 1914, Dr. Simmonds was the first one to describe hypopituitarism. He described it as the inability of the pituitary gland to secrete hormones matching the organs need.^[1]
• In 1950, Dr. Yalow and Berson discovered the radioimmunoassay, which helped with the measurement of the pituitary hormones for the diagnosis of hypopituitarism. Previously, it was based on only the presenting signs and symptoms of the patients.^[2]
• In 1973, combined stimulation tests of insulin, gonadotrophin releasing hormone (GnRH), and thyroid releasing hormone (TRH) were performed for the first time, to assess the pituitary gland function.^[3]
• Through the 20th and 21st centuries, causes of the hypopituitarism were further explained.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Hypopituitarism can be classified on the basis of location of pathology into primary or secondary hypopituitarism. It can also be classified on the basis of the extent of gland involved into partial or complete glandular involvement.

Hypopituitarism can be classified on the basis of location of pathology and the extent of glandular involvement:^[1]

• Primary hypopituitarism: Represents intrinsic pathology in pituitary and decreased pituitary hormone levels

• Secondary hypopituitarism: Represents pathology in hypothalamus and decreased hypothalamic hormone levels

• Partial hypopituitarism: Means deficiency of one or more than one hormones (can be anterior or posterior pituitary gland lobe)

• Complete/Panhypopituitarism: Means deficiency of all of the pituitary hormones (both anterior and posterior lobes)

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Template:DiseaseDisorder infobox

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2], Iqra Qamar M.D.[3]

Hypopituitarism occurrs secondarly to ischemia of the pituitary gland. This ischemia can be due to hemorrhage, tumors, or brain injury. Compression of the blood vessels is one of the mechanisms that cause ischemia to the pituitary gland and leads to hypopituitarism. Pituitary adenomas cause compression of the hypophyseal vessels leading to interruption in the blood supply of the pituitary gland. Traumatic brain injury either primary or secondary also leads to pituitary gland dysfunction.

• In order to understand the pathophysiology of hypopituitarism, it is necessary to know the blood supply of the pituitary gland, because hypopituitarism occurs mainly by ischemia through different mechanisms like hemorrhage, tumors or brain injury.^[1][2]
• The pituitary gland is composed of two parts anterior (adenohypophysis) and posterior (neurohypophysis). Both parts are supplied by the carotid arteries.
• Adenohypophysis: It receives blood supply from the long and short hypophyseal arteries, which arise from the internal carotid artery and the anterior portion of the circle of Willis.
• Neurohypophysis: It receives the blood supply from the inferior and middle hypophyseal arteries.

• Anterior pituitary does not have a direct blood supply and is supplied by the hypophyseal portal system.
• The hypophyseal portal system is a fenestrated set of capillaries that allows rapid exchange of hormones between the hypothalamus and anterior pituitary.
• Occlusion of the blood supply and other vascular abnormalities of the hypophyseal portal system may also cause complications with the exchange of hormones between the hypothalamus and the pituitary gland leading to hypopituitarism.

• Posterior pituitary has its own blood supply via inferior hypophyseal artery and is less commonly affected as compared to anterior pituitary.
• If posterior pituitary is affected, it can result in neurohypophseal dysfunction and ischemic necrosis of thirst center leading to increased osmotic threshold for thirst onset.^[4]

	Hypothalamic hormone	Axis involved	Mode of action	Pituitary hormone or target organ	Action
Anterior pituitary hormones	Thyrotropin-releasing hormone	Hypothalmic-pituitary-thyroid (HPT) axis	Stimulatory	Thyrotropin	Stimulates triiodothyronine and thyroxine production
	Corticotropin-releasing hormone	Hypothalmic-pituitary-adrenal (HPA) axis	Stimulatory	Corticotropin	Stimulates production of cortisol and adrenal androgens
			Stimulatory	Prolactin	Stimulates milk production from breasts in females
	Gonadotropin-releasing hormone	Hypothalamus pituitary testicles (HPG) axis	Stimulatory	Follicle stimulating hormone Leutinizing hormone	Males: stimulates testosterone production and spermatogenesis Female: stimulates estradiol and progesterone production, ovulation and folliculogenesis
	Dopamine		Inhibitory	Prolactin	_
	Growth hormone-releasing hormone		Stimulatory	Growth hormone	Stimulates insulin-like growth factor 1 production
	Somatostatin		Inhibitory	Growth hormone	_
Posterior pituitary hormones	Vasopressin		Stimulatory		Stimulates free water reabsorption in the collecting ducts
	Oxytocin		Stimulatory	Breast, uterus	Stimulates milk ejection and uterine contraction

• Hypopituitarism occurrs mainly due to the destruction of the pituitary gland cells via ischemia, inflammation or infiltration. However, ischemia is believed to be the cornerstone of the pathogenesis of hypopituitarism.^[9][10]

(a) Pituitary adenoma

• Pituitary adenoma (secretory or non-secretory) is one of the common causes of compression of the hypophyseal vessels resulting in ischemia.^[11]
• Large adenomas (more than 1.5 cm) cause greater loss of function than microadenomas. They cause compression (due to a greater mass effect) of the pituitary stalk and the hypophyseal portal vessels, which supply the pituitary gland with blood.
• The tumor growth in the pituitary gland participates in increasing the intrasellar pressure, which causes a decrease in the hypophyseal blood flow leading to a decrease of hormonal delivery from the hypothalamus to the pituitary gland.

(b) Sheehan’s syndrome

• Pituitary gland enlargement due to hypertrophy and hyperplasia of lactotrophic cells in anterior pituitary result in superior hypophyseal artery compression, which may be complicated by decreased portal pressure and vasospasm during delivery, playing an important role in the pathogenesis of Sheehan’s syndrome leading to hypopituitarism.^[12]

(c) Carotid artery aneurysm

(d) Meningioma

(e) Craniopharyngioma

Hypopituitarism may occur via any of the following mechanisms:

(a) Primary brain injury

(b) Trauma

• The anatomical sitting of the pituitary gland increases its susceptibility to getting injured from trauma.
• It is believed that tissue necrosis results in the release of sequestered antigens, precipitating autoimmunity of the pituitary gland and hypopituitarism in Sheehan’s syndrome.^[13][14][15]

(c) Brain injury due to other events like hypotension or hypoxia

Hypopituitarism is caused by a mutation in any one of the following genes.^{[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]}

Isolated hormonal abnormalities	Gene	Inheritance [Autosomal Recessive (AR), Autosomal Dominant (AD), X-linked (XL)]	Phenotype
	GH1	AD, AR	Isolated GH deficiency
	GHRHR	AR	Isolated GH deficiency
	TSHB	AR	Isolated TSH deficiency
	TRHR	AR	Isolated TSH deficiency
	TPIT	AR	Isolated ACTH deficiency
	GnRHR	AR	HH
	PC1	AR	ACTH deficiency, hypoglycemia, HH, obesity
	POMC	AR	ACTH deficiency, obesity, red hair
	DAX1	XL	Adrenal hypoplasia congenital and HH
	CRH	AR	CRH deficiency
	KAL1	XL	Kallman syndrome, renal agenesis, synkinesia
	FGFR1	AD, AR	Kallman syndrome, cleft lip and palate, facial dysmorphism
	Leptin	AR	HH, obesity
	Leptin-R	AR	HH, obesity
	GPR54	AR	HH
	Kisspeptin	AR	HH
	FSHB	AR	Primary amenorrhea, defective spermatogenesis
	LHB	AR	Delayed puberty
	PROK2	AD	Kallman syndrome, severe sleep disorder, obesity
	PROKR2	AD, AR	Kallman syndrome
	AVP-NPII	AR, AD	Diabetes insipidus
Combined pituitary hormone deficiency	POU1F1	AR, AD	GH, TSH, and prolactin deficiencies
	PROP1	AR	GH, TSH, LH, FSH, prolactin, and evolving ACTH deficiencies
Specific syndromes	HESX1	AR, AD	Septo-optic dysplasia
	LHX3	AR	GH, TSH, LH, FSH, prolactin deficiencies, limited neck rotation
	LHX4	AD	GH, TSH, ACTH deficiencies with cerebellar abnormalities
	SOX3	XL	Hypopituitarism and mental retardation
	GLI2	AD	Holoprosencephaly and multiple midline defects
	SOX2	AD	Anophthalmia, hypopituitarism, oesophageal atresia
	GLI3	AD	Pallister-Hall syndrome
	PITX2	AD	Rieger syndrome

• The predominant finding is hemorrhage with or without necrosis.
• Pale, necrotic material is particularly found when there is a long interval between the acute clinical event and surgery.

On microscopy, the following findings may be observed:

• Ischemic necrosis leading to scarring of neurohypophysis
• Scarring of paraventricular and supraoptic nuclei
• Electron microscopic shows evidence of abnormal fenestration of tumor vessels (pituitary adenoma) with fragmented basal membranes that may predispose the patient to hemorrhage

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Causes of hypopituitarism can be classified based upon the etiology into congenital or acquired. Common congenital causes include idiopathic, anatomic lesion in the sella turcica and CNS malformations. Common acquired causes may include pituitary macroadenoma, craniopharyngioma, surgery, radiation, traumatic brain injury, Sheehan’s syndrome, apoplexy, SAH, meningitis, hypophysitis, meningioma, lymphoma, hemochromatosis and Wegner’s granulomatosis. Less common causes include Peri-natal insults, genetic causes, such as Kallman syndrome, Pallister-Hall syndrome, Rieger syndrome, and pituitary hypoplasia or aplasia.

Causes can be classified based upon the etiology into congenital or acquired. The most common cause is a pituitary tumor. Other possible causes may include cyst or a tumor in hypothalamus or infundibulum, vascular disorders, infiltrative diseases, genetic disorders, radiation, and surgery.

Etiology	Underlying cause/disease
Congeital	Idiopathic
	Anatomic lesion in sella turcica: Rathke’s cyst
	CNS malformations: septo-optic–dysplasia, Kallmann syndrome, and pituitary stalk interruption syndrome
Acquired	Pituitary tumor: mainly displacing macroadenoma (non-functioning or functioning adenomas)
	Posterior pituitary tumor: astrocytoma, ganglioneuroma
	Metastatic: breast, lungs, colon, prostate
	Peripituitary lesions: Craniopharyngioma, meningioma, chordoma, optic nerve glioma
	Surgery: Transsphenoidal or transcranial surgery in the hypothalamo-pituitary region
	Radiation
	Systemic cancer treatment
	Traumatic brain injury
	Sheehan’s syndrome
	Pituitary apoplexy
	Meningitis
	Hypophysitis
	Lymphoma

Less common causes of hypopituitarism include:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14]}

• Perinatal insults
• Genetic causes involving isolated/multiple pituitary hormone deficits (MPHD) such as Kallman syndrome, Pallister-Hall syndrome, and Rieger syndrome. To see a complete list of genetic causes, click here.
• Head trauma
• Pituitary hypoplasia or aplasia
• Empty sella syndrome
• Infiltrative diseases
• Ischemic stroke
• Subarachnoid hemorrhage
• Internal carotid artery aneurysm

Cardiovascular	Congestive heart failure, arteriosclerosis, arteritis temporalis, eclampsia, intracranial cartoid branch aneurysm
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Anticoagulant therapy
Ear Nose Throat	No underlying causes
Endocrine	Empty sella syndrome, diabetes mellitus, Sheehan’s Syndrome, pituitary apoplexy
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	Hemochromatosis, Genetic mutations: GHRHR, GH1, TSHB, TRHR, TPIT, GnRHR, PC1, POMC, DAX1, CRH, KAL1, FGFR1, leptin, leptin-R, GPR54, Kisspeptin, FSHB, LHB, PROK2, PROKR2, AVP-NPII, POU1F1, PROP1, HESX1, LHX3, LHX4, SOX3, GLI2, SOX2, GLI3, PITX2
Hematologic	Blood dyscrasias, sickle cell anemia
Iatrogenic	Radiation, surgery
Infectious Disease	Fungal, malaria, meningitis, syphillis, tuberculosis
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	Stroke
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	Peri-natal insults
Oncologic	Brain tumor, meningioma, craniopharyngioma, metastasis, optic nerve neuroma, lymphoma
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	Anorexia nervosa, bulimia nervosa
Pulmonary	Sarcoidosis
Renal/Electrolyte	Renal failure
Rheumatology/Immunology/Allergy	Wegener’s granulomatosis
Sexual	No underlying causes
Trauma	Head trauma
Urologic	No underlying causes
Miscellaneous	Infiltrative lesions (sarcoidosis, Langerhans cell histiocytosis, hypophysitis, hemochromatosis)

• Arteriosclerosis
• Arteritis temporalis
• Blood dyscrasias
• Congestive Heart Failure
• Diabetes Mellitus
• Empty Sella Syndrome
• Idiopathic
• Infections
• Infiltrative lesions
• Internal carotid artery aneurysm
• Pituitary apoplexy
• Radiation
• Renal Failure
• Sheehan’s Syndrome
• Surgery
• Trauma
• Tumors
• Wegener’s Granulomatosis

Hypopituitarism can be classified based upon the anatomical location of pathology such as hypothalamus or pituitary gland.^{[15][16][17][18][19][20][21][22][3][10][23][9][12][24][25][26][27][8][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]}

Anatomical location	Cause
Hypothalmic	Mass lesions:  Benign tumors (craniopharyngiomas) Malignant tumors (metastatic from lung and breast)
	Radiation : CNS and nasopharyngeal malignancies
	Infections: Tuberculous meningitis
	Infiltrative lesions: Sarcoidosis Langerhans cell histiocytosis
	Other : Traumatic brain injury Stroke
Pituitary	Mass lesions: Pituitary adenomas Other benign tumors Cysts
	Pituitary radiation
	Pituitary surgery
	Infection or abscess
	Infiltrative lesions: 1. Hypophysitis: Lymphocytic hypophysitis Granulomatous hypophysitis Plasmacytic (IgG4-associated) hypophysitis 2. Hemochromatosis
	Infarction: Sheehan’s syndrome
	Apoplexy
	Empty sella
	Genetic mutations

Hypopituitarism is caused by mutation in any one of the following genes.^{[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63]}

Isolated hormone abnormalities	Gene	Inheritance	Phenotype
	GH1	AR, AD	Isolated GH deficiency
	GHRHR	AR	Isolated GH deficiency
	TSHB	AR	Isolated TSH deficiency
	TRHR	AR	Isolated TSH deficiency
	TPIT	AR	Isolated ACTH deficiency
	GnRHR	AR	HH
	PC1	AR	ACTH deficiency, hypoglycemia, HH, obesity
	POMC	AR	ACTH deficiency, obesity, red hair
	DAX1	XL	Adrenal hypoplasia congenital and HH
	CRH	AR	CRH deficiency
	KAL1	XL	Kallman syndrome, renal agenesis, synkinesia
	FGFR1	AD, AR	Kallman syndrome, cleft lip and palate, facial dysmorphism
	Leptin	AR	HH, obesity
	Leptin-R	AR	HH, obesity
	GPR54	AR	HH
	Kisspeptin	AR	HH
	FSHB	AR	Primary amenorrhea, defective spermatogenesis
	LHB	AR	Delayed puberty
	PROK2	AD	Kallman syndrome, severe sleep disorder, obesity
	PROKR2	AD, AR	Kallman syndrome
	AVP-NPII	AR, AD	Diabetes insipidus
Combined pituitary hormone deficiency	POU1F1	AR, AD	GH, TSH, and prolactin deficiencies
	PROP1	AR	GH, TSH, LH, FSH, prolactin, and evolving ACTH deficiencies
Specific syndromes	HESX1	AR, AD	Septo-optic dysplasia
	LHX3	AR	GH, TSH, LH, FSH, prolactin deficiencies, limited neck rotation
	LHX4	AD	GH, TSH, ACTH deficiencies with cerebellar abnormalities
	SOX3	XL	Hypopituitarism and mental retardation
	GLI2	AD	Holoprosencephaly and multiple midline defects
	SOX2	AD	Anophthalmia, hypopituitarism, oesophageal atresia
	GLI3	AD	Pallister-Hall syndrome
	PITX2	AD	Rieger syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2], Ahmed Elsaiey, MBBCH [3]

Hypopituitarism should be differentiated from other diseases causing panhypopituitarism, hypothyroidism, hypogonadism, ACTH deficiency, GH deficiency, ADH deficiency and high prolactin level.

• For the differential of hypopituitarism on the basis of thyroid hormone deficiency, click here.
• For the differential of hypopituitarism on the basis of panhypopituitarism, click here.
• For the differential of hypopituitarism on the basis of gonadotropins (FSH/LH) deficiency, click here.
• For the differential of hypopituitarism on the basis of high prolactin level, click here.
• For the differential of hypopituitarism on the basis of growth hormone deficiency, click here.
• For the differential of hypopituitarism on the basis of ADH deficiency, click here.

Hypopituitarism should be differentiated from other diseases causing panhypopituitarism, hypothyroidism, hypogonadism, ACTH deficiency, GH deficiency, ADH deficiency and high prolactin level.^{[1][2][3][4][5][6][7]}

Diseases	Onset	Manifestations					Diagnosis
		History and Symptoms				Physical examination	Laboratory findings	Gold standard	Imaging	Other investigation findings
		Trumatic delivery	Lactation failure	Menstrual irregularities	Other features
Panhypopituitarism	Chronic	–	+	Oligo/amenorrhea	Polyuria Polydipsia Features of hypothyroidism and hypoadrenalism	Growth failure B/L hemianopsia Papilledema	All pituitary hormones decreased	MRI		Left hand and wrist radiograph for bone age
Sheehan’s syndrome	Acute	++	++	Oligo/amenorrhea	Adrenal insufficiency symptoms Hypothyroidism features	Breast tissue atrophy Decreased axillary and pubic hair growth	Pancytopenia Eosinophilia Hyponatremia Low fasting plasma glucose Decreased levels of anterior pituitary hormones in blood	Dx is clinical Most sensitive test: low baseline prolactin levels w/o response to TRH	CT/MRI: Sequential changes of pituitary enlargement followed by Shrinkage and necrosis leading to decreased sellar volume or empty sella	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Lymphocytic hypophysitis	Acute	+/-	+	Oligo/amenorrhea	Associated with autoimmune conditions Generalized headache Retro-orbital or Bitemporal pain Mass lesion effect such as visual field defects	DI Autoimmune thyroiditis	Decreased pituitary hormones(Gonadotropins most common) Hyperprolactinemia(40%) GH excess	Pituitary biopsy: lymphocytic infiltration	CT & MRI: Features of a pituitary mass Diffuse and homogeneous contrast enhancement	Assays for: Anti-TPO Anti-Tg Ab
Pituitary apoplexy	Acute	+/-	++	Oligo/amenorrhea	Severe headache Nausea and vomiting Paralysis of eye muscles (diplopia) Changes in vision	Visual acuity defects CN palsies (nerves III, IV, V , and VI)	Decreased levels of anterior pituitary hormones in blood.	MRI	CT scan without contrast: Hemorrhage on CT presents as a hyperdense lesion MRI: If inconclusive CT	Blood tests may be done to check: PT/INR and aPTT Pituitary hormonal assay
Empty sella syndrome	Chronic	–	+	Oligo/amenorrhea	Erectile dysfunction Headache Low libido	Signs of raised intracranial pressure may be present Nipple discharge	Decreased levels of pituitary hormones in blood.	MRI	Empty sella containing CSF	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Simmond’s disease/Pituitary cachexia	Chronic	+/-	+	Oligo/amenorrhea	Cachexia Premature aging	Progressive emaciation Loss of body hair	Decreased levels of anterior pituitary hormones in blood.	MRI		Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)

^{[8] [9][10][11]}

Disease		History and symptoms			Laboratory findings							Additional findings
		Fever	Goiter	Pain	TSH	Free T4	T3	T3RU	Thyroglobin	TRH	TPOAb
Primary hypothyroidism	Autoimmune	+	+/- Diffuse	–	↑	↓	N/↓	Normal	N/↑	Normal	↑	May be accompanied by other autoimmune diseases
	Thyroiditis	+	+/-	+	↑	↓	Normal	Normal	N/↑	Normal	Normal	Infectious thyroiditis associated with neck pain
	Others	–	+/-	–	↑	↓	Normal	Normal	N/↑	Normal	Normal	History of hyperthyroidism Drug history
Transient hypothyroidism		+/-	–	+/-	↑	↑	Normal	Normal	↑	Normal	Normal	May present primarily with hyperthyroidism
Subclinical hypothyroidism		–	–	–	↑	Normal	Normal	Normal	↑	Normal	N/↑	Asymptomatic
Central Hypothyroidism	Pituitary	+	–	–	N/↓	N/↓	N/↓	↓	Normal	Normal	Normal	Other pituitary hormone deficiencies signs
	Hypothalamus	+	–	–				↓	Normal	↓	Normal	Other pituitary hormone deficiencies signs
Resistance to TSH/TRH		–	–	–	↑	N/↓	N/↓	Normal	Normal	↑/↓	Normal	Rare

Legend:’TSH: Thyroid stimulating hormone, T4: Teraiodothyronine, T3: Triiodothyronine, T3RU: Triiodothyronine reuptake, TRH: Thyrotrophin releasing hormone, TPOAb: Thyroid peroxidase antibody, N: Normal, +: Present, -: Absent

^{[12][13][14][15][16][17][18][19][20][21]}

Diseases		Clinical findings	Diagnosis	Manangement
Congenital diseases	Klinefelter syndrome	Clinical features of Klinefelter syndrome are as the following:[12] Language learning impairment. Neuropsychological testing often reveals deficits in executive functions. Delays in motor development.	Karyotyping Semen count Serum estradiol levels (a type of estrogen) Serum follicle stimulating hormone Serum luteinizing hormone Serum testosterone	Testosterone therapy may be indicated to treat the symptoms of the disease
	Kallmann syndrome	Clinical features of Kallmann syndrome include: Hypogonadism Anosmia	Serum follicle stimulating hormone Serum luteinizing hormone Serum testosterone Gonadotropin hormones	Testosterone replacement therapy Estrogen replacement therapy (in females)

^{[22][23][24][25][26][27][28][29][30]}

Disease	Clinical Findings	Laboratory findings	Management
Somatotroph adenoma: Acromegaly	Clinical features of acromegaly are due to high level of human growth hormone (hGH): Soft tissue swelling of the hands and feet Brow and lower jaw protrusion Enlarged hands Enlarged feet Arthritis and carpal tunnel syndrome Increase in teeth spacing Macroglossia (enlarged tongue) Heart failure Kidney failure Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia) Headache Diabetes mellitus Hypertension Cardiomegaly	Elevated insulin-like growth factor-1 (IGF-1) levels Elevated growth hormone levels	Medical management: Octreotide Bromocriptine Surgical management: Endonasal transsphenoidal surgery Radiation therapy
Corticotroph adenoma: Cushing’s syndrome	Clinical features of Cushing’s syndrome are due to increased levels of cortisol: Rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity) Proximal muscle weakness A round face often referred to as a “moon face“ Excess sweating Headache The excess cortisol may also affect other endocrine systems and cause, for example: Insomnia Reduced libido Impotence Amenorrhea Infertility Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common.	Dexamethasone suppression test 24 hour urinary measurement of cortisol	Medical management: Pasireotide Cabergoline Ketoconazole Metyrapone Mitotane Mifepristone Surgical management: Transsphenoidal pituitary resection
Hypothyroidism	Clinical features of hypothyroidism are due to deficiency of thyroxine: Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain Hoarseness Goiter Fullness in the throat and neck Depression Emotional lability Attention deficit	Elevated TSH Low T4 Low T3 Elevated anti-thyroid antibodies(anti-TPO)	Levothyroxine
Chronic renal failure	There are no pathognomonic symptoms associated with chronic renal failure. Common non-specific symptoms of chronic renal failure include: Malaise Nausea Unintentional weight loss Pruritus Lower extremity edema Sleep disorders	Urinalysis: Albuminuria Hematuria Pyuria Red cell or white cell casts and crystals Fluid and electrolyte disturbances: Hyponatremia Hyperkalemia Hyperphosphatemia Hyperchloremia Metabolic acidosis Hypocalcemia Endocrine and metabolic disturbances: Hyperuricemia Hypertriglyceridemia Decreased HDL levels Vitamin D deficiency Increased Parathyroid hormone levels Hematologic abnormalities: Normocytic normochromic anemia Lymphocytopenia Leukopenia Thrombocytopenia	Medical management: Blood pressure management Control of blood glucose Protein restriction Management of anemia Management of electrolyte disturbance Dialysis Surgical management Kidney transplant
Liver disease: Cirrhosis	The clinical features of liver cirrhosis are very nonspecific. These include: Right upper quadrant abdominal pain Fever Fatigue and weakness Loss of appetite Diarrhea Nausea and vomiting Weight loss Abdominal pain and bloating when fluid accumulates in the abdomen Itching Menstrual irregularities	Elevated aminotransferases (AST & ALT) Elevated alkaline phosphatase (ALP) Elevated gamma-glutamyl transpeptidase Elevated bilirubin Low albumin Elevated prothrombin time Elevated globulin Hyponatremia Anemia Leukopenia and neutropenia Thrombocytopenia	Medical management: Treatment is usually directed towards the treatment of complications like ascites, esophageal varices, hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis. Some chronic constitutional symptoms that should be treated include: Pruritis: Cholestyramine is the drug of choice Hypogonadism: Topical testosterone preparations Osteoporosis: Calcium and vitamin D Pain management: NSAIDS, celecoxib, opioids Nutrition: Adequate caloric and protein intake, and multivitamin supplementation Surgical management: Liver transplantation
Seizure disorder	The clinical features of seizure disorder may include: Change in alertness, orientation and time perception Mood changes, such as unexplainable fear, panic, joy, or laughter Changes in sensation of the skin, usually spreading over the arm, leg, or trunk Vision changes, including seeing flashing lights Rarely, hallucinations (seeing things that aren’t there) Falling, loss of muscle control, occurs very suddenly Muscle twitching that may spread up or down an arm or leg Muscle tension or tightening that causes twisting of the body, head, arms, or legs Shaking of the entire body Tasting a bitter or metallic flavor	Electroencephalogram	Medical management: Antiepileptic medications
Medication-induced	Clinical features of hyperprolactinemia after a specific period of regular medication ingestion	Discontinuation of the medication for 3 days and remeasurement of prolactin levels[31]	Change to alternate medication

Diseases	History and symptoms	Physical Examination				Laboratory findings
		Puberty development	Height velocity	Parents height	Characteristic facies	Bone age	Genetic analysis	GH level
Growth hormone deficiency[32]	Children: delayed developmental milestones and muscle weakness Adults: increased lean body mass, osteopenia, and dyslipidemia	Delayed	Decreased	Normal	Doll-like fat distribution pattern Immature face with under developed nasal bridge Infantile voice	Dlayed	POU1F1 gene mutations  GH1 gene mutations	Low
Achondroplasia[33]	Normal Intelligence quotient A trunk of average size Arms and legs of diminished length Spinal stenosis Kyphosis and lordosis	Normal	Decreased	Decreased	Large heads Prominent forehead Midface hypoplasia	Delayed	FGFR3 gene mutations	Normal
Familial short stature[34]	A normal variant with normal signs, investigations Positive family history	Normal	Decreased	Decreased	Normal	Normal	Heterozygous IGF1 Splicing mutation	Normal
Constitutional growth delay[35]	Family history of delayed growth and puberty Childhood short stature but relatively normal adult height Normal size at birth A delayed growth rate begins at three to six months of age A family history of delayed growth and puberty in one or both parents	Delayed	Normal	Normal	Normal	Normal	Mutations in Variation in FGFR1, GNRHR, TAC3, and TACR3 genes	Normal
Growth Hormone Resistance[36]	Growth hormone insensitivity is an absence of the biological effects of growth hormone despite a normal production of GH. Its severity correlates to IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels.	Delayed	Decreased	Normal	Small face in relation to head circumference Delayed dentition	Delayed	Growth hormone receptor mutations IGF-I gene mutations	Normal
Pediatric Hypothyroidism[37]	Low muscle tone Cold intolerance Persistent constipation Fatigue and weaknessExcessive sleeping Exaggerated jaundice	Delayed	Decreased	Normal	Puffy facies Macroglossia Large fontanels Micrognathia	Delayed	Mutations in: Paired box 8 (PAX8) Thyroid Transcription factor-2 (TTF2 Transcription factors NK2	Normal
Turner Syndrome[38]	Females only Infertility Webbed neck Widely spaced nipples Broad chest Genu valgum Short neck Ovarian failure	Absent	Decreased	Decreased	Low hairline Low-set ears Characteristic facial features	Normal	45 X0	Normal
Silver-Russell Syndrome[39]	Hemihypertrophy Hypoglycemia Wide fontanelle Clinodactyly Precocious puberty	Delayed	Decreased	Decreased	Prominent forehead Triangular face Downturned corners of the mouth Small jaw Pointed chin	Normal	Methylation involving the H19 and IGF2 genes	Normal
Noonan Syndrome[40]	Bleeding tendency Webbed neck Cryptorchidism Intellectual disability	Delayed	Decreased	Decreased	Minor facial dysmorphism	Normal	PTPN11 and SOS1 genes abnormality	Normal
Psychosocial Short Stature[41]	A disorder of short stature or growth that is observed in association with emotional deprivation A disturbed relationship between child and caregiver is usually noted. A history of abuse or neglect and emotional deprivation The relationship between the caregiver and the child appears to be abnormal.	Delayed	Decreased	Normal	Failure to thrive Poor dental hygiene Sad Affect	Normal	Normal	May be low
Short stature accompanying systemic disease[42]	Growth failure is seen in children with systemic diseases such as chronic kidney disease, malignancy, Chron’s disease, and Cushing disease. The primary causes of growth failure in children include metabolic acidosis, poor nutrition secondary to dietary restrictions, disturbances of growth hormone metabolism and its main mediator, insulin-like growth factor-I (IGF-I).	Delayed	Decreased	Normal	Failure to thrive	Delayed	Normal	Normal
Idiopathic short stature[43]	A height below 2 standard deviations (SD) of the mean for age, in the absence of any endocrine, metabolic, or other diagnosis	Normal	Decreased	Normal	Normal	Delayed	SHOX gene mutations[44]	Normal

Type of DI	Subclass	Disease	Defining signs and symptoms	Lab/Imaging findings
Central	Acquired	Histiocytosis	Bone lysis and fracture Purulent otitis media Diabetes insipidus and delayed puberty Maxillary, mandibular, and gingival disease Rash and maculoerythematous skin lesions Scaly, erythematous scalp patches Lung involvement GI bleeding Lymph node enlargement[45]	CD1a and CD45 + Interleukin-17 (ILITA)
		Craniopharyngioma	Headache Endocrine dysfunction Diabetes insipidus Hypothyroidism Adrenal failure Diabetes insipidus (eg, excessive fluid intake and urination) Growth failure and delayed puberty	Suprasellar calcified cyst on MRI
		Sarcoidosis	Systemic complaints Fever Anorexia Arthralgias Pulmonary complaints Dyspnea on exertion Cough Chest pain, Hemoptysis (rare) Diabetes mellitus	Hypercalcemia Hypercalciuria (noncaseating granulomas) Elevated alkaline phosphatase Serum amyloid A (SAA) ACE levels may be elevated
	Congenital	Hydrocephalus	Cognitive deterioration Headaches Neck pain Blurred vision Unsteady gait Incontinence such as polyuria	Dilated ventricles on CT and MRI
		Wolfram Syndrome (DIDMOAD)	Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness	Negative islet cell antibodies Optic atrophy on electroretinogram Deafness on audiogram Atrophy of brain stem on MRI
Nephrogenic	Acquired	Drug-induced (demeclocycline, lithium)	Polyuria Polydipsia Nocturia	Urine osmolality <100 mmol/ Arginine vasopressin level >4.6 pmol/ little or no response to administration of exogenous arginine vasopressin
		Hypercalcemia	Polyuria Polydipsia Gastrointestinal disturbances Pathological fractures Confusion Palpitations and cardiac arrhythmias	Ca levels greater than 11 meq/L
		Hypokalemia	Polyuria Hyporeflexia Palpitations and cardiac arrhythmias	K levels less than 3meq/L on CBC
		Multiple myeloma	Pathologic bone fractures Bleeding Hypercalcemia leading to polyuria Infection Hyperviscosity Anemia	IgG or IgA spike on serum protein electrophoresis Monoclonal M spike Disordered plasma cell proliferation on bone marrow biopsy
		Sickle cell disease	Chronic pain Anemia Aplastic crisis Splenic sequestration Infection Isosthenuria presenting with polyuria	Hemoglobin level is 5-9 g/dL Hematocrit is decreased to 17-29% Peripheral blood smears demonstrate target cells, elongated cells, and characteristic sickle erythrocytes MRI can demonstrate avascular necrosis of the femoral and humeral heads
Primary polydipsia		Psychogenic	Polyuria Polydipsia Nocturia	Dry mucus membrane History of psychiatric disorders
Gestational diabetes insipidus			Polyuria Polydipsia Nocturia Pregnancy	Dry mucus membranes Pregnancy
Diabetes mellitus			Polyuria Polydipsia Nocturia Weight gain	Elevated blood sugar levels >126 Elevated HbA1c > 6.5

Hypopituitarism must be differentiated from other causes of headache, polyuria and polydypsia.

Disease	Causes	Symptoms	Diagnosis and treatment
SIADH	SIADH is a syndrome characterized by excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary gland or another source. The result is hyponatremia, and sometimes fluid overload	Nausea / vomiting Cramps Depressed mood Irritability Confusion Hallucinations Seizures, stupor or coma	Hyponatremia <135 mmol/l Effective serum osmolality<275mosm Urine sodium concentration>40mmol/litre Plasma uric acid <200;FeUrate>12% Absence of edematous disease likecardiac failure, liver cirrhosis,nephrotic syndrome. Normal adrenal and thyroid function
Cerebral salt wasting syndrome	Cerebral salt wasting syndrome is defined as therenal loss of sodium during intracranial disease leading to hyponatremia and a decrease in extracellular fluid volume Trauma Tumor Hematoma	The patient is Hypovolemic Hyponatremic	Treatment is Hydration and Sodium replacement
Adrenal insufficiency	Adrenal insufficiency Mineralocorticoid deficiency is present. Secondary or tertiary adrenal insufficiency will have preservedmineralocorticoid function owing to separate feedback mechanisms Adrenal insufficiency can be Primary Secondary Tertiary Common causes of primary adrenal insufficiency: Autoimmune Iatrogenic Drugs Adrenal hemorrhage Cancer Infection Congenital Secondary adrenal insufficiency: ( Aldosterone) levels normal Most common causes are: Traumatic brain injury (TBI) Panhypopituitarism Tertiary adrenal insufficiency Exogenoussteroid administration is the most common cause of tertiary adrenal insufficiency	Fatigue Muscle weakness Loss of appetite Weight loss Abdominal pain Diarrhea Vomiting Chronic disease is characterized by Weight loss Sparse axillary hair Hyperpigmentation Orthostatic hypotension. Acute addisonian crisis is characterized by: Fever Hypotension	The diagnosis of Addisons disease is made through rapid ACTH administration and measurement of cortisol. Lab findings include: White blood cell count with moderate neutropenia Lymphocytosis Eosinophilia Hyperkalemia Hypoglycemia Hyponatremia Morning low plasma cortisol. The definitive diagnosis is the cosyntropin or ACTH stimulation test. Acortisol level is obtained before and after administering ACTH. A normal person should show a brisk rise in cortisol level after ACTH administration. Management: The management of Addison disease involves: Gluocorticoid Mineralocorticoid Sodium chloride replacement. Adrenal crisis: In adrenal crisis,measure cortisol level,then rapidly administer Fluids Hydrocortisone
Hypopituitarism	Abnormality in anterior pituitary function Etiology is as follows: Pituitary tumors Sellar tumors Head trauma Infection Empty sella Infiltration Idiopathic Congenital	Signs and symptoms ofhypopituitarism vary, depending on the deficient hormone and severity of the disorder,some of the symptoms may be as follows: Fatigue Weight loss Decreased libido Decreased appetite Facial puffiness Anemia Infertility Cold insensitivity. Amenorrha Inability to lactate in breast feeding women Decreased facial orbody hair in men Short stature in children	History andphysical examination, including visual field testing, are important. The treatment of permanent hypopituitarism consists of replacement of the peripheral hormones Hydrocortisone DHEA Thyroxine Testosterone or oestradiol Growth hormone Surgery and/or Radiotherapy to restore normal endocrine function and quality of life Life long monitoring of serum hormone levels and symptoms of hormone deficiency or excess is needed in these patients
Hypothyroidism	Hypofunctioning of the thyroid gland due to multifactorial etiology ranging from congenital to autoimmune causes described below: Congenital Autoimmune Drugs Post surgery Post radiation Infiltrative e.g., amyloid	Fatigue Constipation Dry skin Weight gain Cold intolerance Puffy face Hoarseness Muscle weakness Elevated blood cholesterol level Bradycardia Myopathy Depression Impaired memory	Diagnosis of hypothyroidism is based on blood tests: T3(triiodothyronine) T4(Thyroxine) and TSH (thyroid stimulating hormone). Signs and symptoms are neither sensitive nor specific for the diagnosis. TSH is the most sensitive tool for screening,diagnosis and treatment follow up, whenpituitary is normal. The drug of choice for treatment is Levothyroxine
Psychogenic polydipsia	Also called as primary polydipsia is characterized bypolyuria and polydipsia. Causes are: Adverse effect of a medication Traumaticbrain injury Psychiatric disorders such as schizophrenia Defect in the hypothalamus	Polyuria Polydipsia Confusion Lethargy Psychosis Seizures and Sometimes, even death	Evaluation ofpsychiatric patients with polydipsia requires an evaluation for other medical causes of polydipsia, polyuria,hyponatremia, and the syndrome of inappropriate secretion of antidiuretic hormone. The management strategy inpsychiatric patients should include: Fluid restriction andbehavioral and pharmacologic modalities. The water deprivation test is the gold standard test

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2], Iqra Qamar M.D.[3]

In a longitudinal survey (1992-1999), the incidence of hypopituitarism was estimated to be 4.2 cases per 100,000. A study comprising two cross-sectional surveys showed the prevalence of hypopituitarism to be 29 – 45.5 per 100.000 individual.

• There is one study performed in northern Spain, regarding hypopituitarism epidemiology combining two cross-sectional surveys (from 1992 and 1999).^[1]

• In a longitudinal survey (1992-1999), the incidence of hypopituitarism was estimated to be 4.2 cases per 100,000.^[1]
• A study was done to find out etiological distribution among 773 adults with hypopituitarism that showed:^[2]
  • Non-tumoral etiology (50%)
  • Pituitary tumors (43.6 %)
  • Extra-pituitary tumors (7.2%)

• There is a limited information regarding the prevalence of hypopituitarism.
• The prevalence of hypopituitarism was found to be 29 – 45.5 per 100,000 individual in the two cross-sectional studies.^[1]

• Men and women are affected equally by hypopituitarism.

• Hypopituitarism occurs at any age.

• There is no racial predilection for hypopituitarism.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2] Iqra Qamar M.D.[3]

Common risk factors in the development of hypopituitarism may include pituitary tumor or space occupying lesion, pituitary apoplexy, severe blood loss such as Sheehan’s syndrome, pituitary surgery, cranial radiation, genetic defects, hypothalamic disease, immunosuppression, inflammatory processes, pituitary infarction, and non-compliance with hormone replacement therapy. Less common risk factors, include infiltrative disorders, traumatic brain injury causing skull fractures, ischemic stroke and subarachnoid hemorrhage.

Common risk factors of hypopituitarism include the following: ^{[1][2][3][4][3][5][6][7][8]}

• Pituitary tumor or space occupying lesion
• Pituitary apoplexy
• Severe loss of blood, such as Sheehan syndrome or postpartum hypopituitarism
• Pituitary surgery, such as hypophysectomy
• Cranial radiation
• Genetic defects
• Hypothalamic disease
• Immunosuppression, such as HIV and high dose glucocorticoid intake
• Inflammatory processes such as hypophysitis
• Pituitary infarction
• Non-compliance with hormone replacement therapy

Less common risk factors include:

• Infiltrative disorders such as sarcoidosis and histiocytosis^[9]
• Traumatic brain injury causing skull fractures^{[10][11][12][13][14]}
• Ischemic stroke^[15]
• Subarachnoid hemorrhage^{[11][16][17][18]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Screening of hypopituitarism has been recommended for the patients with traumatic brain injury and patients with a history of radiation exposure to the head.

• Hypopituitarism screening has been recommended for patients with traumatic brain injury.^[1]
• Screening also is recommended in patients with a history of radiation exposure.

​​ Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

The natural history of hypopituitarism depends on the severity of damage leading to partial or complete hormonal deficiency. If left untreated, hypopituitarism can lead to critical consequences. Complications of hypopituitarism include adrenal crisis, osteoporosis, electrolyte abnormalities, and diabetes mellitus. Hypopituitarism is often associated with vascular conditions. Hypopituitarism has a good prognosis as long as the hormonal replacement therapy is given adequately.

If left untreated, hypopituitarism may lead to the development of different symptoms according to the area/lobe of the pituitary gland affected and the deficient hormone. The natural history is variable and depends upon the severity of damage leading to partial or complete hormonal deficiency, age, rapidity of onset, and the underlying cause:^[1]

Hypogonadism

• In both genders, if left untreated, it will lead to a decrease in bone density and osteoporosis.^[2][3][4]
• In women, there may be an increased risk of coronary artery disease due to a reduction estrogen levels.^[5][6]
• In men, decreased muscle mass due to a reduction in testosterone hormone levels.

Vasopressin deficiency

• It may lead to dehydration and electrolyte abnormalities such as hypernatremia.

Growth hormone deficiency

• It may lead to serious vascular conditions most likely due to increased serum cholesterol and triglyceride concentrations causing increased mortality.^[7][8][9]

Complications that can develop as a result of hypopituitarism are include:

• Adrenal crisis, the most serious complication of hypopituitarism. It occurs in case of improper glucocorticoids replacement therapy.

• Osteoporosis
• Electrolyte abnormalities such as hypernatremia
• Diabetes insipidus
• Metabolic syndrome

• Complications of growth hormone replacement therapy:^[10]
  • Pseudotumor cerebri
  • Benign intracranial hypertension.
  • Slipped capital femoral epiphyses.
  • Diabetes mellitus due to insulin resistance.

• Hypopituitarism has a good prognosis as long as the patient is given optimum hormonal replacement therapy.^[1]
• Hypopituitarism is often associated with vascular conditions and has a high mortality rate.^[11]
• There are 6 major retrospective studies done that have shown increased mortality in patients with hypopituitarism.^{[7][12][13][14][15]}

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