Panhypopituitarism: an overview of information

Pangipopituitarism refers to the syndrome of endocrine deficiency, which causes a partial or complete loss of function of the anterior lobe of the pituitary gland. Patients have a very diverse clinical picture, the occurrence of which is due to a deficiency of specific tropic hormones (hypopituitarism). Diagnosis involves conducting specific laboratory tests with measurement of 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 appointment of substitution therapy.

[1], [2], [3],

Causes of decreased pituitary function

Causes directly related to the pituitary gland (primary hypopituitarism)

• Tumors:
  • Adenomas of the pituitary gland.
  • Craniopharyngiomas
• Infarction or ischemic necrosis of the pituitary gland:
• Hemorrhagic infarction (apoplexy or rupture of the pituitary gland) - postpartum (Shiena syndrome) or developing in diabetes mellitus or sickle cell anemia.
• Vascular thrombosis or aneurysm, especially the internal carotid artery
• Infectious and inflammatory processes: Meningitis (tuberculous etiology caused by other bacteria, fungal or malarial etiology). Abscesses of the pituitary gland. Sarcoidosis
• Infiltrative processes: Hemochromatosis.
• Granulomatosis of Langerhans cells (histiocytosis - Khand-Shuler-Christian disease)
• Idiopathic, isolated or multiple, deficiency of pituitary hormones
• Iatrogenic:
• Radiation therapy.
• Surgical removal
• Autoimmune dysfunction of the pituitary gland (lymphocytic hypophysitis)

The causes directly related to the pathology of the hypothalamus (secondary hypopituitarism)

• Tumors of the hypothalamus:
  • Epidendymoma.
  • Meningioma.
  • Tumor metastases.
  • Pinealoma (swelling of the pineal body)
• Inflammatory processes, such as sarcoidosis
• Isolated or multiple deficits in the neurohormones of the hypothalamus
• Surgery on the pituitary foot
• Trauma (sometimes associated with fractures of the base of the skull)

Other causes of panhypopituitarism

[4]

Symptoms of panhypopituitarism

All clinical signs and symptoms are in direct connection with the immediate cause that caused this pathology, and are associated with developing deficits or complete absence of appropriate pituitary hormones. Manifestations usually make themselves felt gradually and can not be noted by the patient; Occasionally, the disease is characterized by acute and vivid manifestations.

As a rule, first of all the quantity of gonadotropins, then GH and finally TTG and ACTH is reduced. Nevertheless, there are cases when the levels of TSH and ACTH decrease first. Deficiency of ADH is rarely a result of the primary pathology of the pituitary gland and is most characteristic for damage to the pituitary and hypothalamus legs. The function of all endocrine gland targets decreases in conditions of total deficiency of pituitary hormones (panhypopituitarism).

The lack of luteinizing (LH) and follicle-stimulating hormones of the pituitary (FSH) in children leads to a delay in sexual development. Women in the pre-menopausal period develop amenorrhea, libido decreases, there is a disappearance of secondary sexual characteristics and infertility. Men develop erectile dysfunction, testicular atrophy, decreased libido, secondary sexual characteristics disappear and spermatogenesis decreases with subsequent infertility.

Deficiency of GH may contribute to the development of increased fatigue, but usually occurs asymptomatically and is not clinically detected in adult patients. The assumption that the deficiency of GH accelerates the development of atherosclerosis is not proved. Deficiency of TTG leads to hypothyroidism with the presence of such symptoms as puffiness of the face, hoarseness of the voice, bradycardia and increased sensitivity to cold. Deficiency of ACTH leads to a decrease in the function of the adrenal cortex and the appearance of the corresponding symptoms (increased fatigue, impotence, reduced resistance to stress and resistance to infections). Hyperpigmentation, characteristic of primary adrenal insufficiency, is not detected with ACTH deficiency.

Damage to the hypothalamus, the result of which is hypopituitarism, can also lead to a violation of the appetite control center, manifested by a syndrome similar to anorexia nervosa.

Shiena's syndrome, which develops in women in the postpartum period, is a consequence of necrosis of the pituitary gland, which appeared as a result of hypovolemia and shock, which suddenly developed in the period of childbirth. After giving birth, women do not have lactation, and patients can complain of increased fatigue and hair loss in the pubic region and in the armpits.

Apoplexy of the pituitary gland is a whole symptom complex, developing either as a result of hemorrhagic infarction of the gland, or against the background of unchanged pituitary tissue, or more often the pituitary tumor is squeezed by the tumor. Acute symptoms include severe headache, stiff neck, fever, visual field defects and paralysis of the oculomotor muscles. Developing in this case, the edema may squeeze the hypothalamus, as a result of which a somnolent disorder of consciousness or coma may occur. Different degrees of impaired pituitary function can develop suddenly, and the patient may develop a collapoid state due to a deficiency of ACTH and cortisol. In the cerebrospinal fluid, blood is often present, and MRI shows signs of hemorrhage.

Diagnosis of panhypopituitarism

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

Pituitary dysfunction 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 in the patient. Especially can be a confusing clinical picture, when the function of more than one endocrine organ decreases simultaneously. It is necessary to prove the presence of structural pathology of the pituitary gland and neurohormonal deficiency.

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Samples required for visualization

All patients should have positive CT results (with a high degree of resolution) or MRI performed using contrast agents in special techniques (in order to exclude structural abnormalities such as pituitary adenomas). Positron emission tomography (PET), used as a method of research in several specialized centers, is nevertheless performed extremely rarely in wide clinical practice. In the case where there is no possibility to conduct a modern neuroradiologic examination, use a simple cone lateral craniography of the Turkish saddle, with which it is possible to detect a pituitary macroadenoma with a diameter of more than 10 mm. Cerebral angiography is prescribed only if the results of other diagnostic tests indicate the presence of paraselar vascular anomalies or aneurysms.

Differential diagnosis of generalized hypopituitarism with other diseases

Pathology	Differential diagnostic criteria
Neurogenic anorexia	The predominance of women, cachexia, the pathological mood for eating and inadequate evaluation of their body, the safety of secondary sexual characteristics, with the exception of amenorrhea, increased basal levels of GH and cortisol
Alcoholic liver damage or hemochromatosis	Verified liver disease, appropriate laboratory parameters
Dystrophic myotonia	Progressive weakness, premature baldness, cataracts, external signs of accelerated growth, appropriate laboratory indicators
Polyendocrine autoimmune syndrome	Appropriate levels of pituitary hormones

[8], [9]

Laboratory diagnostics

First of all, tests should be included in the diagnostic arsenal to determine the deficiency of TGG and ACTH, since both these neurohormonal deficits need long-term therapy throughout their life. Tests for the determination of other hormones are outlined below.

The levels of CT4 and TSH should be determined. In the case of generalized hypopituitarism, the levels of both hormones are usually low. There may be cases when the level of TGH is normal, and the T4 level is low. In contrast, a high TSH level with a low T4 count indicates a primary pathology of the thyroid gland.

Intravenous jet injection of synthetic thyrotropin-releasing hormone (TRH) at a dose of 200 to 500 mcg for 15-30 s can help to identify patients with hypothalamic pathology that causes pituitary dysfunction, although this test is not very often used in clinical practice. The plasma TSH level is usually determined at 0, 20 and 60 minutes after the injection. If the function of the pituitary gland does not suffer, the plasma TSH level should rise more than 5 IU / L with a peak concentration to the 30th minute after the injection. Delay in elevation of plasma TSH level can occur in patients with hypothalamic pathology. However, in some patients with primary pituitary disease, a delay in elevating the level of TGH is also detected.

Only one level of serum cortisol is not a reliable criterion for detecting impaired function of the pituitary-adrenal axis. Therefore, one of several provocative samples should be considered. One test used to assess the reserve of ACTH (equally reliable for it can be judged about the reserve of GR and prolactin) is a test of tolerance to insulin. Short-acting insulin at a dose of 0.1 U / kg body weight is administered intravenously for 15-30 seconds and then the venous blood is examined to determine the level of GH, cortisol and basal glucose (before insulin administration) and after 20,30,45, 60 and 90 minutes after the injection. If the level of glucose in venous blood drops below 40 mg / ml (less than 2.22 mmol / l) or if symptoms of hypoglycemia develop, then cortisol should increase to> 7 μg / ml or> 20 μg / ml.

(CAUTION: This test is risky in patients with proven panhypopituitarism or diabetes mellitus and in the elderly, and it is contraindicated if the patient has a severe form of ischemic heart disease or epilepsy.) The sample must be monitored by a doctor.)

Usually, during the test, only transient dyspnea, tachycardia and anxiety are observed. If patients complain of palpitations, lose consciousness or have an attack, the samples should be stopped immediately, quickly injecting 50 ml of 50% glucose solution intravenously to the patient. The results of only a test for tolerance to insulin do not give the possibility to differentiate the primary (Addison's disease) and secondary (hypopituitarism) adrenal insufficiency. Diagnostic tests that allow such differential diagnosis and evaluate the function of the hypothalamic-pituitary-adrenal axis are described below, after the description of Addison's disease. An alternative to the above provocative test is a trial with corticotropin-releasing hormone (CRF). CRF is injected intravenously in a dose of 1 μg / kg. ACTH and plasma cortisol levels are measured 15 minutes prior to injection and at 15, 30.60.90 and 120 minutes after injection. Side effects include the occurrence of temporary hyperemia of the facial skin, metallic taste in the mouth and short-term hypotension.

Usually, the prolactin level is always measured, which is often increased 5-fold relative to normal values if there is a large pituitary tumor, even when tumor cells do not produce prolactin. The tumor mechanically compresses the pituitary foot, preventing the release of dopamine, which inhibits the production and release of prolactin by the pituitary. Patients with such hyperprolactinemia often have secondary hypogonadism.

Measurement of basal levels of LH and FSH is the best way to assess the presence of hypopituitary disorders in postmenopausal women who do not use exogenous estrogens, in which concentrations of circulating gonadotropins are usually high (more than 30 mIU / ml). Although gonadotropin levels tend to decrease in other patients with panhypopituitarism, their levels overlap the range (ie, overlap) of normal values. The levels of both these hormones should increase in response to intravenous gonadotropin-releasing factor (gonadoliberin) at a dose of 100 μg, with an LH peak about 30 minutes later and a FSH peak at 40 minutes after gonadoliberin administration. And yet, in the case of hypothalamic-pituitary dysfunction, there may be a normal or reduced response or the absence of any response to the administration of gonadoliberin. The mean values of increased levels of LH and FSH in response to stimulation with gonadoliberin vary greatly. Therefore, the appointment of an exogenous stimulation test with gonadoliberin does not allow the exact differentiation of primary hypothalamic disorders from the primary pituitary pathology.

Screening for GH deficiency is not recommended in adults unless there is an intention to prescribe GH therapy (for example, in the case of an unexplained decrease in muscle strength and quality of life in patients with hypopituitarism who are prescribed complete substitution therapy). GH deficiency is suspected if the patient has a deficiency of two or more pituitary hormones. Due to the fact that the blood levels in the blood vary greatly depending on the time of day and the influence of other factors, there are certain difficulties in interpreting them; in laboratory practice, the definition of insulin-like growth factor (IGF-1), the level of which reflects the GH content in the blood . Low levels of IGF-1 suggest a deficiency of GH, but its normal levels do not exclude it. In this case, it may be necessary to conduct a provocative test for the release of GH.

Evaluation of the laboratory response to the introduction of several hormones at once is the most effective method for assessing the function of the pituitary gland. GR-releasing hormone (1 μg / kg), corticotropin-releasing hormone (1 μg / kg), thyrotropin-releasing hormone (TRH) (200 μg / kg) and gonadotropin-releasing hormone (gonadoliberin) (100 μg / kg) are injected together intravenously in 15-30 seconds. Then, at certain equal time intervals, blood glucose levels in venous blood, cortisol, GH, TGG, prolactin, LH, FSH and ACTH are measured for 180 minutes. The final role of these releasing factors (hormones) in assessing the function of the pituitary gland is still established. Interpretation of the values of the levels of all the hormones in this sample is the same as previously described for each of them.

Treatment of panhypopituitarism

Treatment consists in replacement therapy with hormones of the corresponding endocrine glands, whose function is reduced. In adults up to the age of 50 years, the incidence of GH sometimes treat GH at a dose of 0.002-0.012 mg / kg body weight, subcutaneously, once a day. A special role in the treatment is improving nutrition and increasing muscle mass and fighting obesity. The hypothesis that substitution therapy of GH prevents the acceleration of systemic atherosclerosis induced by GH deficiency was not confirmed.

In cases where hypopituitarism is caused by a pituitary tumor, along with substitution therapy, adequate special tumor treatment should be prescribed. Therapeutic tactics in the case of the development of such tumors is controversial. In case the tumor is small and is not prolactin-secreting, most recognized endocrinologists recommend carrying out its transsphenoidal removal. Most endocrinologists believe that dopamine agonists, such as bromocriptine, pergolide or long-acting cabergoline, are quite acceptable for initiating drug therapy with prolactin regardless of its size. Patients with pituitary macroadenomas (> 2 cm) and a significant increase in the level of prolactin circulating in the blood may require surgical treatment or radiation therapy in addition to therapy with dopamine agonists. High-voltage irradiation of the pituitary gland can be included in complex therapy or used alone. In the case of the development of large tumors, with suprasellar growth, complete surgical removal of the tumor both transsphenoidally and transfrontal may not be possible; in this case, the appointment of high-voltage radiation therapy is justified. In the case of development of apoplexy of the pituitary gland, urgent surgical treatment is justified in the event that the pathological areas are visualized or the paralysis of the oculomotor muscles develops suddenly or if the somnolence increases, right up to the development of the coma, due to the development of hypothalamic compression. Although the therapeutic tactics using high doses of glucocorticoids and generally restorative treatment in some cases may be sufficient, it is nevertheless recommended that transsephenoidal decompression of the tumor be performed immediately.

Surgical treatment and radiotherapy can be used in the case of a low content of pituitary hormones in the blood. In the case of radiotherapy in patients, the decrease in the endocrine function of the affected areas of the pituitary gland can occur for many years. Nevertheless, after such treatment it is often necessary to evaluate the hormonal status, preferably immediately after 3 months, then 6 months and then annually. Such monitoring should include, at least, a study of the function of the thyroid and adrenal glands. Patients may also develop visual defects associated with fibrosis of the optic nerve cross area. Pictures of the area of the Turkish saddle and visualization of the affected areas of the pituitary gland should be made at least every 2 years, over a 10-year period, especially if there is residual tumor tissue.