Panhypopituitarism - Information Review

Panhypopituitarism refers to an endocrine deficiency syndrome that causes partial or complete loss of function of the anterior pituitary gland. Patients have a very diverse clinical picture, the occurrence of which is due to a deficiency of specific tropic hormones (hypopituitarism). Diagnosis includes specific laboratory tests measuring basal levels of pituitary hormones and their levels after various provocative tests. Treatment depends on the cause of the pathology, but usually consists of surgical removal of the tumor and the administration of replacement therapy.

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Causes of decreased pituitary function

Causes directly related to the pituitary gland (primary hypopituitarism)

• Tumors:
  • Pituitary adenomas.
  • Craniopharyngiomas
• Infarction or ischemic necrosis of pituitary tissue:
• Hemorrhagic infarction (apoplexy or rupture of the pituitary gland) - postpartum (Sheehan syndrome) or developing with diabetes mellitus or sickle cell anemia.
• Vascular thrombosis or aneurysm, especially of the internal carotid artery
• Infectious and inflammatory processes: Meningitis (of tuberculosis etiology, caused by other bacteria, fungal or malarial etiology). Pituitary abscesses. Sarcoidosis
• Infiltrative processes: Hemochromatosis.
• Langerhans cell granulomatosis (histiocytosis - Hand-Schuler-Christian disease)
• Idiopathic, isolated or multiple, pituitary hormone deficiency
• Iatrogenic:
• Radiation therapy.
• Surgical removal
• Autoimmune dysfunction of the pituitary gland (lymphocytic hypophysitis)

Causes directly related to pathology of the hypothalamus (secondary hypopituitarism)

• Hypothalamic tumors:
  • Epidendymomas.
  • Meningiomas.
  • Tumor metastases.
  • Pinealoma (tumor of the pineal gland)
• Inflammatory processes such as sarcoidosis
• Isolated or multiple hypothalamic neurohormone deficiency
• Surgery on the pituitary stalk
• Trauma (sometimes associated with basal skull fractures)

Other causes of panhypopituitarism

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Symptoms of panhypopituitarism

All clinical signs and symptoms are directly related to the immediate cause of this pathology and are associated with the developing deficiency or complete absence of the corresponding pituitary hormones. Manifestations usually make themselves known gradually and cannot be noted by the patient; occasionally the disease is characterized by acute and vivid manifestations.

As a rule, the amount of gonadotropins decreases first, then GH, and finally TSH and ACTH. However, there are cases when TSH and ACTH levels decrease first. ADH deficiency is quite rarely the result of primary pituitary pathology and is most typical for damage to the pituitary stalk and hypothalamus. The function of all endocrine target glands decreases in conditions of total deficiency of pituitary hormones (panhypopituitarism).

Deficiency of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) of the pituitary gland in children leads to delayed sexual development. In premenopausal women, amenorrhea develops, libido decreases, secondary sexual characteristics disappear, and infertility is observed. In men, erectile dysfunction, testicular atrophy, decreased libido, secondary sexual characteristics disappear, and spermatogenesis decreases with subsequent infertility.

GH deficiency may contribute to fatigue, but is usually asymptomatic and clinically undetectable in adults. The hypothesis that GH deficiency accelerates atherosclerosis has not been proven. TSH deficiency results in hypothyroidism with symptoms such as facial puffiness, hoarseness, bradycardia, and increased sensitivity to cold. ACTH deficiency results in decreased adrenal cortex function and the corresponding symptoms (fatigue, impotence, decreased stress tolerance, and resistance to infections). Hyperpigmentation, characteristic of primary adrenal insufficiency, is not detected in ACTH deficiency.

Damage to the hypothalamus that results in hypopituitarism may also result in a disruption of the appetite control center, resulting in a syndrome similar to anorexia nervosa.

Sheehan's syndrome, which develops in women in the postpartum period, is a consequence of pituitary necrosis resulting from hypovolemia and shock that suddenly developed during labor. After childbirth, women do not lactate, and patients may complain of increased fatigue and hair loss in the pubic area and armpits.

Pituitary apoplexy is a whole symptom complex that develops either as a result of a hemorrhagic infarction of the gland, or against the background of unchanged pituitary tissue, or more often, compression of the pituitary tissue by a tumor. Acute symptoms include severe headache, stiff neck, fever, visual field defects, and paralysis of the oculomotor muscles. The swelling that develops can compress the hypothalamus, which can result in a somnolent impairment of consciousness or coma. Different degrees of pituitary dysfunction can develop suddenly, and the patient may develop a collapse state due to a deficiency of ACTH and cortisol. Blood is often present in the cerebrospinal fluid, and MRI reveals signs of hemorrhage.

Diagnosis of panhypopituitarism

Clinical signs are often nonspecific and the diagnosis must be confirmed before lifelong replacement therapy is recommended for the patient.

Dysfunction of the pituitary gland can be recognized by the presence of clinical signs of neurogenic anorexia, chronic liver disease, muscular dystrophy, autoimmune polyendocrine syndrome and pathology of other endocrine organs. The clinical picture can be especially confusing when the function of more than one endocrine organ is reduced simultaneously. The presence of structural pathology of the pituitary gland and neurohormonal deficiency should be demonstrated.

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Samples required for visualization

All patients should have positive results on high-resolution CT or MRI with special contrast agents (to exclude structural abnormalities such as pituitary adenomas). Positron emission tomography (PET), which has been used in a few specialized centers, is rarely performed in routine clinical practice. When modern neuroradiological examination is not possible, simple lateral cone beam craniography of the sella turcica can detect a pituitary macroadenoma larger than 10 mm in diameter. Cerebral angiography is indicated only when other diagnostic tests indicate parasellar vascular abnormalities or aneurysms.

Differential diagnosis of generalized hypopituitarism with other diseases

Pathology	Differential diagnostic criteria
Neurogenic anorexia	Predominance in women, cachexia, abnormal appetite for food intake and inadequate assessment of one's own body, preservation of secondary sexual characteristics, with the exception of amenorrhea, elevated basal levels of GH and cortisol
Alcoholic liver disease or hemochromatosis	Verified liver disease, corresponding laboratory parameters
Dystrophic myotonia	Progressive weakness, premature baldness, cataracts, external signs of accelerated growth, corresponding laboratory parameters
Polyendocrine autoimmune syndrome	Appropriate levels of pituitary hormones

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Laboratory diagnostics

The diagnostic arsenal should primarily include tests for THG and ACTH deficiency, as both of these neurohormonal deficiencies require long-term, lifelong therapy. Tests for other hormones are outlined below.

The levels of free T4 and TSH should be determined. In cases of generalized hypopituitarism, the levels of both hormones are usually low. There may be cases where the TG level is normal and the T4 level is low. In contrast, a high TG level with low free T4 indicates primary thyroid pathology.

Intravenous bolus administration of synthetic thyrotropin-releasing hormone (TRH) at a dose of 200 to 500 mcg over 15 to 30 seconds may help identify patients with hypothalamic pathology causing pituitary dysfunction, although this test is not very often used in clinical practice. Plasma TSH levels are usually determined at 0, 20, and 60 minutes after injection. If pituitary function is normal, the plasma TSH level should rise to more than 5 IU/L with a peak concentration at 30 minutes after injection. A delayed rise in plasma TSH may occur in patients with hypothalamic pathology. However, some patients with primary pituitary disease also have a delayed rise in TSH levels.

Serum cortisol levels alone are not a reliable indicator of pituitary-adrenal axis dysfunction. Therefore, one of several provocative tests should be considered. One test used to assess ACTH reserve (and is also a good indicator of GH and prolactin reserve) is the insulin tolerance test. Short-acting insulin at 0.1 U/kg body weight is injected intravenously over 15-30 sec, and venous blood is then tested for GH, cortisol, and basal glucose levels (before insulin administration) and at 20, 30, 45, 60, and 90 min after injection. If the venous blood glucose level falls below 40 mg/ml (less than 2.22 mmol/l) or symptoms of hypoglycemia develop, cortisol should increase to a level of approximately > 7 μg/ml or to > 20 μg/ml.

(CAUTION: This test is risky in patients with proven panhypopituitarism or diabetes mellitus and in the elderly, and is contraindicated in patients with severe coronary heart disease or epilepsy. The test must be performed under the supervision of a physician.)

Typically, the test will only produce transient dyspnea, tachycardia, and anxiety. If patients complain of palpitations, faint, or have an attack, the test should be stopped immediately by rapidly administering 50 ml of 50% glucose solution intravenously. The results of the insulin tolerance test alone do not differentiate between primary (Addison's disease) and secondary (hypopituitarism) adrenal insufficiency. Diagnostic tests that allow such differential diagnosis and assessment of the hypothalamic-pituitary-adrenal axis function are described below, after the description of Addison's disease. An alternative to the provocative test described above is the corticotropin-releasing hormone (CRF) test. CRF is administered intravenously by jet stream at a dose of 1 mcg/kg. Plasma ACTH and cortisol levels are measured 15 minutes before injection and 15, 30, 60, 90 and 120 minutes after. Side effects include temporary flushing of the face, metallic taste in the mouth and transient hypotension.

Prolactin levels are usually measured and are often elevated 5 times above normal in the presence of a large pituitary tumor, even in cases where the tumor cells do not produce prolactin. The tumor mechanically compresses the pituitary stalk, preventing the release of dopamine, which inhibits the production and release of prolactin by the pituitary gland. Patients with such hyperprolactinemia often have secondary hypogonadism.

Measurement of basal LH and FSH levels is the optimal way to assess for hypopituitarism in postmenopausal women not using exogenous estrogens, in whom circulating gonadotropin concentrations are typically high (>30 mIU/mL). Although gonadotropin levels tend to be low in other patients with panhypopituitarism, their levels still span the normal range. Levels of both hormones should increase in response to 100 mcg of intravenous gonadotropin-releasing hormone (GnRH), with LH peaking at approximately 30 minutes and FSH peaking at 40 minutes after GnRH administration. However, in the case of hypothalamic-pituitary dysfunction, there may be a normal or decreased response or no response to GnRH administration. The mean values of increased LH and FSH levels in response to GnRH stimulation vary greatly. Therefore, the administration of an exogenous stimulation test with GnRH does not allow for accurate differentiation of primary hypothalamic disorders from primary pituitary pathology.

Screening for GH deficiency is not recommended in adults unless GH therapy is intended (e.g., in patients with hypopituitarism who are being treated with total replacement therapy for unexplained loss of muscle strength and quality of life). GH deficiency is suspected when two or more pituitary hormones are deficient. Because circulating GH levels vary widely with time of day and other factors, making them difficult to interpret, laboratory practice uses insulin-like growth factor (IGF-1), which reflects circulating GH. Low IGF-1 levels are suggestive of GH deficiency, but normal levels do not rule it out. In this case, a provocative GH release test may be necessary.

The most effective method for assessing pituitary function is the evaluation of the laboratory response to the introduction of several hormones at once. GH-releasing hormone (1 μg/kg), corticotropin-releasing hormone (1 μg/kg), thyrotropin-releasing hormone (TRH) (200 μg/kg), and gonadotropin-releasing hormone (GnRH) (100 μg/kg) are administered together intravenously by jet stream over 15-30 s. Then, at certain equal time intervals, the levels of venous blood glucose, cortisol, GH, THG, prolactin, LH, FSH, and ACTH are measured for 180 minutes. The final role of these releasing factors (hormones) in assessing pituitary function is still being established. Interpretation of the values of the levels of all hormones in this test is the same as described earlier for each of them.

Treatment of panhypopituitarism

Treatment consists of hormone replacement therapy of the corresponding endocrine glands whose function is reduced. In adults up to and including 50 years of age, GH deficiency is sometimes treated with GH at a dose of 0.002-0.012 mg/kg body weight, subcutaneously, once a day. Of particular importance in treatment is improved nutrition, increased muscle mass, and the fight against obesity. The hypothesis that GH replacement therapy prevents the acceleration of systemic atherosclerosis induced by GH deficiency has not been confirmed.

In cases where hypopituitarism is caused by a pituitary tumor, adequate specific treatment of the tumor should be prescribed along with replacement therapy. Therapeutic tactics in case of development of such tumors are controversial. In case of small tumors that are not prolactin-secreting, most recognized endocrinologists recommend its transsphenoidal resection. Most endocrinologists consider dopamine agonists such as bromocriptine, pergolide or long-acting cabergoline to be quite acceptable for initiating drug therapy of prolactinomas regardless of their size. In patients with pituitary macroadenomas (> 2 cm) and significantly increased levels of circulating prolactin in the blood, surgery or radiation therapy may be required in addition to dopamine agonist therapy. High-voltage irradiation of the pituitary gland can be included in complex therapy or used independently. In the case of large tumors with suprasellar growth, complete surgical removal of the tumor, either transsphenoidally or transfrontally, may not be possible; in this case, high-voltage radiation therapy is justified. In the case of pituitary apoplexy, emergency surgical treatment is justified if pathological areas are visualized or paralysis of the oculomotor muscles suddenly develops, or if somnolence increases, up to the development of a comatose state, due to the development of hypothalamic compression. And although therapeutic tactics using high doses of glucocorticoids and general strengthening treatment may be sufficient in some cases, it is still recommended to immediately perform transsphenoidal decompression of the tumor.

Surgery and radiation therapy may also be used in cases of low pituitary hormone levels in the blood. In patients undergoing radiation therapy, the endocrine function of the affected pituitary areas may decline over many years. However, hormonal status should be assessed frequently after such treatment, preferably immediately after 3 months, then 6 months, and then annually. Such monitoring should include at least thyroid and adrenal function testing. Patients may also develop visual defects associated with fibrosis of the optic chiasm. Sella turcica imaging and imaging of the affected pituitary areas should be performed at least every 2 years for a 10-year period, especially if residual tumor tissue is present.