Hypopituitarism overview

# Overview
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.

# Historical Perspective
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.

# Classification
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.

# Pathophysiology
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
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.

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

# Epidemiology and Demographics
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.

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

# Natural History, Complications, and Prognosis
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.

# Diagnosis

## History and Symptoms
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.

## Physical Examination
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.

## Laboratory Findings
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.

## Electrocardiogram
There are no electrocardiogram findings associated with hypopituitarism.

## X ray
There are no X ray findings associated with hypopituitarism.

## CT scan
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
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.

## Ultrasound
There are no ultrasound findings associated with hypopituitarism.

## Other imaging findings
There are no other specific imaging findings for hypopituitarism.

## Other diagnostic studies
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.

# Treatment

## Medical Therapy
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.

## Surgery
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.

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

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